{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Autoimmunity: Tolerance vs Infection-triggered", "entry_form": "phenomenon", "gradeable_restatement": "Autoimmunity is initiated by infection-triggered molecular mimicry and bystander activation that overcome baseline genetic deficiencies in immune tolerance.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Measured infection history, bacterial LOS genotype, HLA or tolerance-pathway genotype, baseline disease, age, strain, housing and intervention timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Autoimmunity: Tolerance vs Infection-triggered", "central_claim": "Autoimmunity is initiated by infection-triggered molecular mimicry and bystander activation that overcome baseline genetic deficiencies in immune tolerance.", "proposed_mechanism": "Autoimmunity is initiated by infection-triggered molecular mimicry and bystander activation that overcome baseline genetic deficiencies in immune tolerance.", "claimed_scope": "Human GBS, MS, T1D, RA and systemic autoimmunity, with baseline genotype, exposure, antigen, disease stage and host setting specified separately", "claimed_level": [ "initiation" ], "is_conjunctive": true, "conjunctive_note": "Use the index causal initiation claim and separate GBS from MS. Intrinsic tolerance evidence supports a rival and does not prove infection initiation. All registered components of the broad initiation proposition are required." }, "rubric_routing": { "primary_rubric": "05-immunology-inflammation.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the index causal initiation claim and separate GBS from MS. Intrinsic tolerance evidence supports a rival and does not prove infection initiation. All registered components of the broad initiation proposition are required." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Specific infections precede specific autoimmune diseases.", "subclaim_type": "existence", "scope": "prospective EBV/MS and C. jejuni/GBS exposures", "claimed_scope": "prospective EBV/MS and C. jejuni/GBS exposures", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Prediagnostic serology and incident disease", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Prediagnostic EBV seroconversion and C. jejuni antecedence are reproducible with temporal and exposure controls. This registered descriptive existence claim has no selective causal manipulation of its own and is graded Β. Its formal minimum must not re-cap the independent mechanistic evidence assessed separately." }, { "id": "SC2a", "statement": "Molecular mimicry initiates Guillain–Barré syndrome.", "subclaim_type": "mechanism", "scope": "defined ganglioside and bacterial genotypes", "claimed_scope": "defined ganglioside and bacterial genotypes", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Mimic subtraction and matched neuropathy rescue", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Within defined bacterial/ganglioside genotypes, chemical identity, bacterial mimic subtraction, matched antibody specificity, rabbit neuropathy and clinical isolate/phenotype contrasts converge across errors. Ζ credits the causal set, not the mutant antibody biomarker alone. Host resistance, non-mimicking isolates and absent human selective prevention limit Η and broader GBS sufficiency." }, { "id": "SC2b", "statement": "Molecular mimicry initiates multiple sclerosis.", "subclaim_type": "mechanism", "scope": "EBV and HLA-defined MS risk settings", "claimed_scope": "EBV and HLA-defined MS risk settings", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Antigen-specific perturbation with onset outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "EBNA1/GlialCAM, ANO2 and CRYAB cross-reactivity has human and functional support, but original Lanz Results show enhancement of induced EAE. ANO2 transfer and 2026 B-cell presentation/viral-signaling studies add model support without selective endogenous human mimic necessity at onset. The registered initiation link remains Γ." }, { "id": "SC3", "statement": "Intrinsic tolerance pathways are required to prevent autoimmunity.", "subclaim_type": "necessity", "scope": "AIRE, FOXP3 and checkpoint-defined settings", "claimed_scope": "AIRE, FOXP3 and checkpoint-defined settings", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Human inborn errors and conditional loss/rescue", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human FOXP3/CTLA4 inborn errors, lineage-specific CTLA4 loss, acute adult Treg removal and time-dependent reconstitution establish ongoing tolerance causality. Genotype-aligned abatacept changes clinical trajectories. Different failure structures support Η; incomplete penetrance, developmental effects and multiple tolerance routes prevent Θ/Ω for all pathways." }, { "id": "SC4", "statement": "Infection initiates endogenous human tolerance breakdown.", "subclaim_type": "primacy", "scope": "human autoimmune onset with baseline tolerance and exposure measured", "claimed_scope": "human autoimmune onset with baseline tolerance and exposure measured", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Prevention or selective eradication and onset mediation", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "A coherent infection-to-autoimmune injury route is established in defined C. jejuni/ganglioside settings, with rare human Aa eradication evidence and model perturbations in other diseases. EBV antecedence strongly supports an upstream MS risk role without identifying the initiating mimic. Prediagnostic baseline tolerance breakdown and onset mediation across human diseases are unresolved, so context-specific Ε is retained." }, { "id": "SC5", "statement": "Infection-triggered initiation generalizes across autoimmune diseases.", "subclaim_type": "generalization", "scope": "GBS, MS, type 1 diabetes, RA and systemic autoimmunity", "claimed_scope": "GBS, MS, type 1 diabetes, RA and systemic autoimmunity", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Disease-separated causal tests and negative contexts", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Causal microbial routes have positive and protective signs across genotypes and diseases. SFB promotes K/BxN arthritis but associates with female NOD protection; germ-free MyD88-null NOD develop diabetes. Thus bounded causality exists but the class-wide initiation generalization fails: Ε, not a denial that particular infections are causes." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "Use the index causal initiation claim and separate GBS from MS. Intrinsic tolerance evidence supports a rival and does not prove infection initiation. All registered components of the broad initiation proposition are required.", "primary_subclaim_id": "SC4", "aggregation_derivation": "The preregistered weakest-link rule returns Β because the descriptive antecedence subclaim SC1 is associational. This is an aggregation limitation, not a finding that all infection causality is merely correlational: defined Campylobacter/ganglioside GBS convergence reaches Ζ, intrinsic tolerance necessity Η, and broader context-dependent initiation Ε. Primary-subclaim and scope-matched sensitivities return Ε. Human MS mimic-specific initiation remains Γ. Do not publish the overall letter without this subclaim explanation or interpret it as refuting EBV risk causality.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Ε", "scope_matched_would_return": "Ε", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M5", "is_nominal": false, "name": "Gene-environment threshold", "core_claim": "Host regulatory state, tissue injury and defined microbial exposure jointly set disease-specific thresholds.", "explains_what_nominal_does_not": "Host regulatory state, tissue injury and defined microbial exposure jointly set disease-specific thresholds.", "strongest_supporting_evidence": [ "Conditional infection effects, HLA presentation, innate sensing and opposite microbial signs support context dependence." ], "strongest_contradictory_evidence": [ "A flexible integrated model must predict genotype/exposure outcomes prospectively and cannot define susceptible hosts after disease." ], "hsef_level_for_this_model": "Ε", "rationale": "Conditional infection effects, HLA presentation, innate sensing and opposite microbial signs support context dependence. A flexible integrated model must predict genotype/exposure outcomes prospectively and cannot define susceptible hosts after disease." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Intrinsic tolerance failure", "core_claim": "Central and peripheral regulatory pathways prevent pathogenic self-reactivity.", "explains_what_nominal_does_not": "Central and peripheral regulatory pathways prevent pathogenic self-reactivity.", "strongest_supporting_evidence": [ "Human FOXP3/CTLA4 natural experiments, conditional/acute depletion, reconstitution and genotype-aligned clinical therapy converge." ], "strongest_contradictory_evidence": [ "Rare syndromic causality does not establish that all ordinary autoimmunity starts with a measurable intrinsic deficit; CTLA4 penetrance is incomplete." ], "hsef_level_for_this_model": "Η", "rationale": "Human FOXP3/CTLA4 natural experiments, conditional/acute depletion, reconstitution and genotype-aligned clinical therapy converge. Rare syndromic causality does not establish that all ordinary autoimmunity starts with a measurable intrinsic deficit; CTLA4 penetrance is incomplete." }, { "rank_in_tournament": 3, "model_id": "M1", "is_nominal": true, "name": "Infection-triggered tolerance breakdown", "core_claim": "Specific pathogens initiate selected autoimmune injury through mimicry or licensing.", "explains_what_nominal_does_not": "Specific pathogens initiate selected autoimmune injury through mimicry or licensing.", "strongest_supporting_evidence": [ "C. jejuni carbohydrate specificity and LOS perturbations provide the clearest route; EBV prospective data strongly constrain temporal alternatives." ], "strongest_contradictory_evidence": [ "Defined GBS success does not establish one MS mimic or a common initiating infection across the class." ], "hsef_level_for_this_model": "Ε", "rationale": "C. jejuni carbohydrate specificity and LOS perturbations provide the clearest route; EBV prospective data strongly constrain temporal alternatives. Defined GBS success does not establish one MS mimic or a common initiating infection across the class." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Bystander inflammatory licensing", "core_claim": "Infection or tissue injury supplies antigen presentation and inflammatory help to pre-existing autoreactivity.", "explains_what_nominal_does_not": "Infection or tissue injury supplies antigen presentation and inflammatory help to pre-existing autoreactivity.", "strongest_supporting_evidence": [ "Viral-sensor perturbations, EBV LMP1 and oligodendrocyte injury support separate licensing routes." ], "strongest_contradictory_evidence": [ "Induced host systems and broad inflammatory changes do not identify a universal endogenous human initiating step." ], "hsef_level_for_this_model": "Ε", "rationale": "Viral-sensor perturbations, EBV LMP1 and oligodendrocyte injury support separate licensing routes. Induced host systems and broad inflammatory changes do not identify a universal endogenous human initiating step." }, { "rank_in_tournament": 5, "model_id": "M3", "is_nominal": false, "name": "Microbial-deprivation tolerance calibration", "core_claim": "Some microbial exposures reduce rather than cause autoimmune injury.", "explains_what_nominal_does_not": "Some microbial exposures reduce rather than cause autoimmune injury.", "strongest_supporting_evidence": [ "Germ-free/colonized MyD88-null NOD and early helminth-lupus experiments map protective effects." ], "strongest_contradictory_evidence": [ "Protection is strain, genotype, age and housing dependent; infection deprivation is not a universal explanation." ], "hsef_level_for_this_model": "Ε", "rationale": "Germ-free/colonized MyD88-null NOD and early helminth-lupus experiments map protective effects. Protection is strain, genotype, age and housing dependent; infection deprivation is not a universal explanation." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The strongest discriminator between a conditional threshold model and tolerance-only primacy is Wen: germ-free MyD88-null NOD retain autoimmunity while commensal colonization protects. It establishes an interaction, not a universal microbial requirement. Human tolerance variants and GBS mimic manipulations address distinct questions.", "study_separating_rank1_from_rank2": "The strongest discriminator between a conditional threshold model and tolerance-only primacy is Wen: germ-free MyD88-null NOD retain autoimmunity while commensal colonization protects. It establishes an interaction, not a universal microbial requirement. Human tolerance variants and GBS mimic manipulations address distinct questions.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "35025605", "title": "Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.", "citation": "Bjornevik K, Cortese M, Healy BC et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science (New York, N.Y.). 2022.", "doi": "10.1126/science.abj8222", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35025605/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35025605/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "DOD-serorepository-EBV-MS", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [ "M1", "M5" ], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EBV seroconversion precedes incident MS and neurofilament rise; CMV provides an exposure negative control.", "what_it_does_not_show": "Prospective natural exposure strongly constrains reverse causation but does not isolate mimicry or baseline tolerance mediation.", "confounders_present": [ "Prospective natural exposure strongly constrains reverse causation but does not isolate mimicry or baseline tolerance mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "35073561", "title": "Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.", "citation": "Lanz TV, Brewer RC, Ho PP et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022.", "doi": "10.1038/s41586-022-04432-7", "pmcid": "PMC9382663", "url": "https://pubmed.ncbi.nlm.nih.gov/35073561/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35073561/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35073561", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:Molecular mimicry between EBNA1AA386–405 and GlialCAM, 5:Phosphorylation of GlialCAMAA370–389 at pSer376 enables MS CSF-derived MS39p2w174 binding, 7:Immunization with EBNA1AA386–405 aggravates EAE. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Patient-derived antibody cross-binds EBNA1 and GlialCAM; peptide immunization aggravates PLP-induced EAE.", "what_it_does_not_show": "Selected Results show induced EAE amplification rather than spontaneous MS initiation or selective human mimic necessity.", "confounders_present": [ "Selected Results show induced EAE amplification rather than spontaneous MS initiation or selective human mimic necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "38497939", "title": "Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis.", "citation": "Cortese M, Leng Y, Bjornevik K et al. Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis. JAMA neurology. 2024.", "doi": "10.1001/jamaneurol.2024.0272", "pmcid": "PMC10949154", "url": "https://pubmed.ncbi.nlm.nih.gov/38497939/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38497939/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "DOD-serorepository-EBV-MS-peptidome", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2b" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Prediagnostic EBV peptidome responses are increased without one selectively targeted peptide.", "what_it_does_not_show": "Small military nested cohort shares a repository with other reports; adjusted estimates and wide intervals limit unique epitope inference.", "confounders_present": [ "Small military nested cohort shares a repository with other reports; adjusted estimates and wide intervals limit unique epitope inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Shares DOD repository with the antecedence study; not a second independent exposure intervention." ] }, { "n": 4, "pmid": "33091337", "title": "HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.", "citation": "Wang J, Jelcic I, Mühlenbruch L et al. HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis. Cell. 2020.", "doi": "10.1016/j.cell.2020.09.054", "pmcid": "PMC7707104", "url": "https://pubmed.ncbi.nlm.nih.gov/33091337/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33091337/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID33091337", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "HLA-DR15 presents self and foreign peptides to cross-reactive patient T-cell clones.", "what_it_does_not_show": "Immunopeptidomics and ex vivo recognition do not establish which antigen first caused human onset.", "confounders_present": [ "Immunopeptidomics and ex vivo recognition do not establish which antigen first caused human onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "40063790", "title": "Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls.", "citation": "Sattarnezhad N, Kockum I, Thomas OG et al. Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls. Proceedings of the National Academy of Sciences of the United States of America. 2025.", "doi": "10.1073/pnas.2424986122", "pmcid": "PMC11929495", "url": "https://pubmed.ncbi.nlm.nih.gov/40063790/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40063790/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Swedish-EBNA1-mimic-cohorts", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "GlialCAM/EBNA1 reciprocal blocking confirms cross-reactivity and HLA-associated risk patterns.", "what_it_does_not_show": "Established-case serology and overlapping mimic cohorts cannot establish onset mediation.", "confounders_present": [ "Established-case serology and overlapping mimic cohorts cannot establish onset mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Swedish mimicry cohorts/platforms recur; participant identity was not fully audited." ] }, { "n": 6, "pmid": "37196088", "title": "Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis.", "citation": "Thomas OG, Bronge M, Tengvall K et al. Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Science advances. 2023.", "doi": "10.1126/sciadv.adg3032", "pmcid": "PMC10191428", "url": "https://pubmed.ncbi.nlm.nih.gov/37196088/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37196088/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Swedish-EBNA1-mimic-cohorts", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "EBNA1/CRYAB reciprocal blocking and mouse responses support cross-reactive immunity.", "what_it_does_not_show": "Risk serology and immunization do not isolate CRYAB as a necessary initiator of MS.", "confounders_present": [ "Risk serology and immunization do not isolate CRYAB as a necessary initiator of MS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "41534529", "title": "Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis.", "citation": "Thomas OG, Rykaczewska U, Galešić M et al. Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis. Cell. 2026.", "doi": "10.1016/j.cell.2025.12.032", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41534529/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41534529/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41534529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ANO2 pre-immunization and transferred CD4 cells exacerbate EAE; human clones cross-recognize EBNA1.", "what_it_does_not_show": "Induced EAE enhancement is a phenotype but does not establish spontaneous human onset necessity.", "confounders_present": [ "Induced EAE enhancement is a phenotype but does not establish spontaneous human onset necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "38843296", "title": "Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis.", "citation": "Thomas OG, Haigh TA, Croom-Carter D et al. Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis. PLoS pathogens. 2024.", "doi": "10.1371/journal.ppat.1012177", "pmcid": "PMC11156336", "url": "https://pubmed.ncbi.nlm.nih.gov/38843296/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38843296/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38843296", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EBV-expanded T-cell lines recognize CNS antigens in both MS and healthy controls.", "what_it_does_not_show": "Cross-reactivity also in controls limits disease-specific sufficiency; peripheral viral load is unchanged.", "confounders_present": [ "Cross-reactivity also in controls limits disease-specific sufficiency; peripheral viral load is unchanged." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "26453645", "title": "No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT.", "citation": "Munger KL, Fitzgerald KC, Freedman MS et al. No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT. Neurology. 2015.", "doi": "10.1212/WNL.0000000000002099", "pmcid": "PMC4653109", "url": "https://pubmed.ncbi.nlm.nih.gov/26453645/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26453645/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID26453645", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "BENEFIT antibody titres do not predict CIS conversion or subsequent clinical/MRI activity.", "what_it_does_not_show": "A post-CIS titre null does not test preventing EBV infection before initiation.", "confounders_present": [ "A post-CIS titre null does not test preventing EBV infection before initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "31375628", "title": "Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk.", "citation": "Tengvall K, Huang J, Hellström C et al. Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1902623116", "pmcid": "PMC6708327", "url": "https://pubmed.ncbi.nlm.nih.gov/31375628/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31375628/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Swedish-MS-ANO2-EIMS-GEMS", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ANO2/EBNA1 blocking and genotype combinations link cross-reactivity to MS risk.", "what_it_does_not_show": "Case-control antibody positivity occurs in a minority and does not demonstrate individual causal initiation.", "confounders_present": [ "Case-control antibody positivity occurs in a minority and does not demonstrate individual causal initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "39742283", "title": "In-depth analysis of serum antibodies against Epstein-Barr virus lifecycle proteins, and EBNA1, ANO2, GlialCAM and CRYAB peptides in patients with multiple sclerosis.", "citation": "Vasilenko N, Tieck MP, Michel T et al. In-depth analysis of serum antibodies against Epstein-Barr virus lifecycle proteins, and EBNA1, ANO2, GlialCAM and CRYAB peptides in patients with multiple sclerosis. Frontiers in immunology. 2024.", "doi": "10.3389/fimmu.2024.1487523", "pmcid": "PMC11685087", "url": "https://pubmed.ncbi.nlm.nih.gov/39742283/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39742283/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39742283", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "ANO2 differs in MS but GlialCAM/CRYAB responses and disease-phase signatures do not distinguish consistently.", "what_it_does_not_show": "Cross-sectional assay/cohort heterogeneity qualifies universal mimic or reactivation narratives.", "confounders_present": [ "Cross-sectional assay/cohort heterogeneity qualifies universal mimic or reactivation narratives." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "15016009", "title": "A role of late Epstein-Barr virus infection in multiple sclerosis.", "citation": "Haahr S, Plesner AM, Vestergaard BF et al. A role of late Epstein-Barr virus infection in multiple sclerosis. Acta neurologica Scandinavica. 2004.", "doi": "10.1046/j.1600-0404.2003.00221.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15016009/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15016009/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID15016009", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Late EBV exposure and recalled mononucleosis associate with MS in a high-prevalence region.", "what_it_does_not_show": "Recall and geographic contrasts do not isolate infection timing from correlated exposures.", "confounders_present": [ "Recall and geographic contrasts do not isolate infection timing from correlated exposures." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "31226219", "title": "Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort.", "citation": "Munger KL, Hongell K, Cortese M et al. Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort. Annals of neurology. 2019.", "doi": "10.1002/ana.25532", "pmcid": "PMC6839107", "url": "https://pubmed.ncbi.nlm.nih.gov/31226219/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31226219/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31226219", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Prediagnostic maternal/offspring EBV antibody associations recur with CMV comparison.", "what_it_does_not_show": "Maternal antibodies are not the child's measured infection; observational confounding remains.", "confounders_present": [ "Maternal antibodies are not the child's measured infection; observational confounding remains." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "41534530", "title": "EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation.", "citation": "Wang J, Qiu Y, Marti Z et al. EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation. Cell. 2026.", "doi": "10.1016/j.cell.2025.12.046", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41534530/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41534530/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41534530", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "EBV reprograms HLA-DR15 B-cell presentation of MBP peptides recognized by MS T cells.", "what_it_does_not_show": "Human tissue alignment and infected-cell experiments support a route distinct from proving onset through molecular mimicry.", "confounders_present": [ "Human tissue alignment and infected-cell experiments support a route distinct from proving onset through molecular mimicry." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "42455903", "title": "CD4+ T cells reactive to Epstein-Barr virus late lytic antigens are enriched in individuals with multiple sclerosis.", "citation": "Bjornevik K, Mahler JV, Bilodeau PA et al. CD4+ T cells reactive to Epstein-Barr virus late lytic antigens are enriched in individuals with multiple sclerosis. Science translational medicine. 2026.", "doi": "10.1126/scitranslmed.adz6566", "pmcid": "PMC13374717", "url": "https://pubmed.ncbi.nlm.nih.gov/42455903/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42455903/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID42455903", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MS CD4 responses preferentially target late-lytic EBV antigens and fall after anti-CD20 treatment.", "what_it_does_not_show": "B-cell depletion changes multiple immune functions; reduced responses or shedding do not isolate viral initiation.", "confounders_present": [ "B-cell depletion changes multiple immune functions; reduced responses or shedding do not isolate viral initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "41644766", "title": "Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis.", "citation": "Hayashi F, Mittl K, Dandekar R et al. Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis. Nature immunology. 2026.", "doi": "10.1038/s41590-025-02412-3", "pmcid": "PMC12956596", "url": "https://pubmed.ncbi.nlm.nih.gov/41644766/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41644766/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39282370" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41644766", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Expanded CSF CD8 clonotypes include functionally EBV-reactive receptors; many mimotopes fail functional response.", "what_it_does_not_show": "Established-disease antigen specificity and the updated preprint are one report lineage, not prospective onset proof.", "confounders_present": [ "Established-disease antigen specificity and the updated preprint are one report lineage, not prospective onset proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "UpdateOf preprint PMID39282370; one article lineage." ] }, { "n": 17, "pmid": "41534531", "title": "Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation.", "citation": "Kim H, Schneider M, Raach Y et al. Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation. Cell. 2026.", "doi": "10.1016/j.cell.2025.12.031", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41534531/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41534531/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41534531", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4" ], "favors_models": [ "M4" ], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LMP1 or CD40L overrides death of antigen-capturing myelin-reactive B cells and enables lesions.", "what_it_does_not_show": "Engineered viral-protein signaling tests a bounded route; ectopic expression cannot establish endogenous human primacy alone.", "confounders_present": [ "Engineered viral-protein signaling tests a bounded route; ectopic expression cannot establish endogenous human primacy alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "30429369", "title": "Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis.", "citation": "Pender MP, Csurhes PA, Smith C et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI insight. 2018.", "doi": "10.1172/jci.insight.124714", "pmcid": "PMC6302936", "url": "https://pubmed.ncbi.nlm.nih.gov/30429369/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30429369/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33055421" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "EBV-T-cell-MS-phase1", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Open-label EBV-specific T-cell treatment is feasible and clinical improvement tracks product reactivity.", "what_it_does_not_show": "Small uncontrolled progressive-MS phase I trial does not prove efficacy or prevention; linked erratum details unexamined.", "confounders_present": [ "Small uncontrolled progressive-MS phase I trial does not prove efficacy or prevention; linked erratum details unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "7477117", "title": "Campylobacter jejuni infection and Guillain-Barré syndrome.", "citation": "Rees JH, Soudain SE, Gregson NA et al. Campylobacter jejuni infection and Guillain-Barré syndrome. The New England journal of medicine. 1995.", "doi": "10.1056/NEJM199511233332102", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7477117/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7477117/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID7477117", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2a", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Recent Campylobacter infection is enriched in incident GBS and links to motor/axonal severity.", "what_it_does_not_show": "Case-control antecedence does not alone prove mimicry or explain non-Campylobacter GBS.", "confounders_present": [ "Case-control antecedence does not alone prove mimicry or explain non-Campylobacter GBS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "16425134", "title": "Comprehensive analysis of bacterial risk factors for the development of Guillain-Barre syndrome after Campylobacter jejuni enteritis.", "citation": "Koga M, Gilbert M, Takahashi M et al. Comprehensive analysis of bacterial risk factors for the development of Guillain-Barre syndrome after Campylobacter jejuni enteritis. The Journal of infectious diseases. 2006.", "doi": "10.1086/499969", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16425134/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16425134/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Japanese-GBS-Campylobacter-isolate-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Bacterial LOS class and sialyltransferase genotype distinguish neuropathy from uncomplicated enteritis isolates.", "what_it_does_not_show": "Isolate ascertainment and linked strain features limit attributing clinical risk to one gene alone.", "confounders_present": [ "Isolate ascertainment and linked strain features limit attributing clinical risk to one gene alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "12183587", "title": "Campylobacter jejuni from patients with Guillain-Barré syndrome preferentially expresses a GD(1a)-like epitope.", "citation": "Nachamkin I, Liu J, Li M et al. Campylobacter jejuni from patients with Guillain-Barré syndrome preferentially expresses a GD(1a)-like epitope. Infection and immunity. 2002.", "doi": "10.1128/IAI.70.9.5299-5303.2002", "pmcid": "PMC128258", "url": "https://pubmed.ncbi.nlm.nih.gov/12183587/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12183587/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Dutch-GBS-Campylobacter-isolate-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "GBS isolates preferentially express GD1a-like mimicry with relevant biosynthesis genes.", "what_it_does_not_show": "Strain association is not a selective onset intervention.", "confounders_present": [ "Strain association is not a selective onset intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "8773599", "title": "Campylobacter jejuni infections and anti-GM1 antibodies in Guillain-Barré syndrome.", "citation": "Jacobs BC, van Doorn PA, Schmitz PI et al. Campylobacter jejuni infections and anti-GM1 antibodies in Guillain-Barré syndrome. Annals of neurology. 1996.", "doi": "10.1002/ana.410400209", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8773599/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8773599/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID8773599", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Anti-GM1 positivity associates with recent Campylobacter and a severe motor phenotype.", "what_it_does_not_show": "Antibody-positive disease subgroups are not all GBS and observational treatment differences are not randomized mediation.", "confounders_present": [ "Antibody-positive disease subgroups are not all GBS and observational treatment differences are not randomized mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "15304587", "title": "Does Campylobacter jejuni infection elicit \"demyelinating\" Guillain-Barre syndrome?", "citation": "Kuwabara S, Ogawara K, Misawa S et al. Does Campylobacter jejuni infection elicit \"demyelinating\" Guillain-Barre syndrome? Neurology. 2004.", "doi": "10.1212/01.wnl.0000133205.05169.04", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15304587/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15304587/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID15304587", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "what_it_does_not_show": "Clinical classification depends on timing; this limits broad demyelination transfer but does not refute axonal mimicry.", "confounders_present": [ "Clinical classification depends on timing; this limits broad demyelination transfer but does not refute axonal mimicry." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "10713352", "title": "Campylobacter jejuni lipopolysaccharides from Guillain-Barré syndrome patients induce IgG anti-GM1 antibodies in rabbits.", "citation": "Ang CW, Endtz HP, Jacobs BC et al. Campylobacter jejuni lipopolysaccharides from Guillain-Barré syndrome patients induce IgG anti-GM1 antibodies in rabbits. Journal of neuroimmunology. 2000.", "doi": "10.1016/s0165-5728(99)00279-9", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10713352/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10713352/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID10713352", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "GBS-strain LPS immunization induces GM1-cross-reactive rabbit antibodies.", "what_it_does_not_show": "Antibody induction alone is not demonstrated neuropathic functional injury.", "confounders_present": [ "Antibody induction alone is not demonstrated neuropathic functional injury." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "10660542", "title": "Biosynthesis of ganglioside mimics in Campylobacter jejuni OH4384. Identification of the glycosyltransferase genes, enzymatic synthesis of model compounds, and characterization of nanomole amounts by 600-mhz (1)h and (13)c NMR analysis.", "citation": "Gilbert M, Brisson JR, Karwaski MF et al. Biosynthesis of ganglioside mimics in Campylobacter jejuni OH4384. Identification of the glycosyltransferase genes, enzymatic synthesis of model compounds, and characterization of nanomole amounts by 600-mhz (1)h and (13)c NMR analysis. The Journal of biological chemistry. 2000.", "doi": "10.1074/jbc.275.6.3896", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10660542/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10660542/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID10660542", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cloned glycosyltransferases synthesize defined ganglioside-like structures with linkage confirmation.", "what_it_does_not_show": "Biochemical biosynthesis establishes the molecular mimic rather than human disease necessity.", "confounders_present": [ "Biochemical biosynthesis establishes the molecular mimic rather than human disease necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "11254608", "title": "Guillain-Barré syndrome- and Miller Fisher syndrome-associated Campylobacter jejuni lipopolysaccharides induce anti-GM1 and anti-GQ1b Antibodies in rabbits.", "citation": "Ang CW, De Klerk MA, Endtz HP et al. Guillain-Barré syndrome- and Miller Fisher syndrome-associated Campylobacter jejuni lipopolysaccharides induce anti-GM1 and anti-GQ1b Antibodies in rabbits. Infection and immunity. 2001.", "doi": "10.1128/IAI.69.4.2462-2469.2001", "pmcid": "PMC98180", "url": "https://pubmed.ncbi.nlm.nih.gov/11254608/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11254608/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11254608", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "GBS/MFS LPS induces matched antibody specificity; control-strain LPS lacks ganglioside reactivity.", "what_it_does_not_show": "Immunization establishes antigen specificity without showing spontaneous infection produces neuropathy in every host.", "confounders_present": [ "Immunization establishes antigen specificity without showing spontaneous infection produces neuropathy in every host." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "16162859", "title": "Campylobacter gene polymorphism as a determinant of clinical features of Guillain-Barré syndrome.", "citation": "Koga M, Takahashi M, Masuda M et al. Campylobacter gene polymorphism as a determinant of clinical features of Guillain-Barré syndrome. Neurology. 2005.", "doi": "10.1212/01.wnl.0000176914.70893.14", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16162859/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16162859/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Japanese-GBS-Campylobacter-isolate-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "cst-II polymorphism aligns bacterial mimic, patient autoantibody and neurological phenotype.", "what_it_does_not_show": "Same clinical isolate platform can share failure modes with other genotype association reports.", "confounders_present": [ "Same clinical isolate platform can share failure modes with other genotype association reports." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "8228822", "title": "A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like structure.", "citation": "Yuki N, Taki T, Inagaki F et al. A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like structure. The Journal of experimental medicine. 1993.", "doi": "10.1084/jem.178.5.1771", "pmcid": "PMC2191246", "url": "https://pubmed.ncbi.nlm.nih.gov/8228822/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8228822/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID8228822", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NMR and chemical analysis identify a GM1-identical terminal bacterial oligosaccharide.", "what_it_does_not_show": "Structural identity is not alone a causal neurological experiment.", "confounders_present": [ "Structural identity is not alone a causal neurological experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "15716397", "title": "Overexpression of GD1a ganglioside sensitizes motor nerve terminals to anti-GD1a antibody-mediated injury in a model of acute motor axonal neuropathy.", "citation": "Goodfellow JA, Bowes T, Sheikh K et al. Overexpression of GD1a ganglioside sensitizes motor nerve terminals to anti-GD1a antibody-mediated injury in a model of acute motor axonal neuropathy. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005.", "doi": "10.1523/JNEUROSCI.4279-04.2005", "pmcid": "PMC6725939", "url": "https://pubmed.ncbi.nlm.nih.gov/15716397/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15716397/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID15716397", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Anti-GD1a antibody plus complement injures high-antigen motor terminals and blocks function.", "what_it_does_not_show": "Tolerance bypass and ganglioside-overexpressing recipients are engineered; normal mice resist the same exposure.", "confounders_present": [ "Tolerance bypass and ganglioside-overexpressing recipients are engineered; normal mice resist the same exposure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "15277677", "title": "Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barre syndrome.", "citation": "Yuki N, Susuki K, Koga M et al. Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barre syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2004.", "doi": "10.1073/pnas.0402391101", "pmcid": "PMC509213", "url": "https://pubmed.ncbi.nlm.nih.gov/15277677/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15277677/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID15277677", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "what_it_does_not_show": "Patient/mouse antibody blocks coculture potentials but does not itself induce paralysis; selected full body unavailable.", "confounders_present": [ "Patient/mouse antibody blocks coculture potentials but does not itself induce paralysis; selected full body unavailable." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "15578098", "title": "The crucial role of Campylobacter jejuni genes in anti-ganglioside antibody induction in Guillain-Barre syndrome.", "citation": "Godschalk PC, Heikema AP, Gilbert M et al. The crucial role of Campylobacter jejuni genes in anti-ganglioside antibody induction in Guillain-Barre syndrome. The Journal of clinical investigation. 2004.", "doi": "10.1172/JCI15707", "pmcid": "PMC529276", "url": "https://pubmed.ncbi.nlm.nih.gov/15578098/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15578098/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Dutch-GBS-Campylobacter-isolate-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph62, 0:Publisher HTML paragraphs:paragraph65, 0:Publisher HTML paragraphs:paragraph70, 0:Publisher HTML paragraphs:paragraph82, 0:Publisher HTML paragraphs:paragraph92. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "cst-II/orf10 loss removes sialylated mimics and anti-GD1a induction while orf11 is a negative control.", "what_it_does_not_show": "Original publisher Methods use ganglioside-deficient mice and repeated adjuvant immunization; asialo-GM1 responses remain and neuropathy was not measured.", "confounders_present": [ "Original publisher Methods use ganglioside-deficient mice and repeated adjuvant immunization; asialo-GM1 responses remain and neuropathy was not measured." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "17261613", "title": "Structural characterization of Campylobacter jejuni lipooligosaccharide outer cores associated with Guillain-Barre and Miller Fisher syndromes.", "citation": "Godschalk PC, Kuijf ML, Li J et al. Structural characterization of Campylobacter jejuni lipooligosaccharide outer cores associated with Guillain-Barre and Miller Fisher syndromes. Infection and immunity. 2007.", "doi": "10.1128/IAI.00872-06", "pmcid": "PMC1828588", "url": "https://pubmed.ncbi.nlm.nih.gov/17261613/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17261613/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Dutch-GBS-Campylobacter-isolate-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2a", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes.", "what_it_does_not_show": "Post-isolation phase variation may differ from infection-time expression; these are boundaries rather than definitive mimic absence at onset.", "confounders_present": [ "Post-isolation phase variation may differ from infection-time expression; these are boundaries rather than definitive mimic absence at onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "33711260", "title": "Follicular regulatory T cells produce neuritin to regulate B cells.", "citation": "Gonzalez-Figueroa P, Roco JA, Papa I et al. Follicular regulatory T cells produce neuritin to regulate B cells. Cell. 2021.", "doi": "10.1016/j.cell.2021.02.027", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33711260/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33711260/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID33711260", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects.", "what_it_does_not_show": "Rescue primarily changes cellular/antibody endpoints and does not establish infection initiation.", "confounders_present": [ "Rescue primarily changes cellular/antibody endpoints and does not establish infection initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "18845758", "title": "CTLA-4 control over Foxp3+ regulatory T cell function.", "citation": "Wing K, Onishi Y, Prieto-Martin P et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science (New York, N.Y.). 2008.", "doi": "10.1126/science.1160062", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18845758/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18845758/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID18845758", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease.", "what_it_does_not_show": "Conditional lineage specificity supports tolerance function; developmental/immune interactions do not establish a universal trigger.", "confounders_present": [ "Conditional lineage specificity supports tolerance function; developmental/immune interactions do not establish a universal trigger." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "25329329", "title": "Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.", "citation": "Schubert D, Bode C, Kenefeck R et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature medicine. 2014.", "doi": "10.1038/nm.3746", "pmcid": "PMC4668597", "url": "https://pubmed.ncbi.nlm.nih.gov/25329329/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25329329/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25329329", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [ "M2", "M5" ], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "what_it_does_not_show": "Unaffected carriers invalidate complete-penetrance claims; no measured infectious mimic is required by the proposed genotype mechanism.", "confounders_present": [ "Unaffected carriers invalidate complete-penetrance claims; no measured infectious mimic is required by the proposed genotype mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "37595759", "title": "Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency.", "citation": "Taghizade N, Babayeva R, Kara A et al. Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency. The Journal of allergy and clinical immunology. 2023.", "doi": "10.1016/j.jaci.2023.08.004", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37595759/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37595759/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID37595759", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [ "M2" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort.", "what_it_does_not_show": "Nonrandomized treatment allocation and disease-duration differences limit comparative superiority estimates.", "confounders_present": [ "Nonrandomized treatment allocation and disease-duration differences limit comparative superiority estimates." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "34477806", "title": "Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation.", "citation": "Goldfarb Y, Givony T, Kadouri N et al. Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation. The Journal of experimental medicine. 2021.", "doi": "10.1084/jem.20201076", "pmcid": "PMC8421262", "url": "https://pubmed.ncbi.nlm.nih.gov/34477806/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34477806/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34477806", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription.", "what_it_does_not_show": "Mutant-line developmental biology and expression changes do not prove ordinary sporadic autoimmunity is AIRE-deficient.", "confounders_present": [ "Mutant-line developmental biology and expression changes do not prove ordinary sporadic autoimmunity is AIRE-deficient." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "12376594", "title": "Projection of an immunological self shadow within the thymus by the aire protein.", "citation": "Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the aire protein. Science (New York, N.Y.). 2002.", "doi": "10.1126/science.1075958", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12376594/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12376594/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID12376594", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity.", "what_it_does_not_show": "Constitutive loss has developmental confounds; thymic localization narrows but does not remove them.", "confounders_present": [ "Constitutive loss has developmental confounds; thymic localization narrows but does not remove them." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "11137993", "title": "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.", "citation": "Bennett CL, Christie J, Ramsdell F et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature genetics. 2001.", "doi": "10.1038/83713", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11137993/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11137993/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11137993", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Human FOXP3 mutations segregate with IPEX immune dysregulation.", "what_it_does_not_show": "Rare syndromic causality is not a class-wide requirement for pathogenic FOXP3 variants.", "confounders_present": [ "Rare syndromic causality is not a class-wide requirement for pathogenic FOXP3 variants." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "11137992", "title": "X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.", "citation": "Wildin RS, Ramsdell F, Peake J et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature genetics. 2001.", "doi": "10.1038/83707", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11137992/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11137992/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11137992", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology.", "what_it_does_not_show": "Genetic identification alone does not measure a specific infection or explain all polygenic disease.", "confounders_present": [ "Genetic identification alone does not measure a specific infection or explain all polygenic disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "7636184", "title": "Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.", "citation": "Sakaguchi S, Sakaguchi N, Asano M et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of immunology (Baltimore, Md. : 1950). 1995.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7636184/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7636184/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID7636184", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CD25-cell removal permits autoimmune disease and timely reconstitution prevents it.", "what_it_does_not_show": "Athymic transfer and imperfect CD25 lineage specificity constrain physiology; adult conditional depletion is an orthogonal follow-up.", "confounders_present": [ "Athymic transfer and imperfect CD25 lineage specificity constrain physiology; adult conditional depletion is an orthogonal follow-up." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "17136045", "title": "Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice.", "citation": "Kim JM, Rasmussen JP, Rudensky AY et al. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature immunology. 2007.", "doi": "10.1038/ni1428", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17136045/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17136045/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID17136045", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [ "M2" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence.", "what_it_does_not_show": "Mouse induced depletion establishes ongoing regulatory necessity, not that human infection always removes Tregs.", "confounders_present": [ "Mouse induced depletion establishes ongoing regulatory necessity, not that human infection always removes Tregs." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "25213377", "title": "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.", "citation": "Kuehn HS, Ouyang W, Lo B et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science (New York, N.Y.). 2014.", "doi": "10.1126/science.1255904", "pmcid": "PMC4371526", "url": "https://pubmed.ncbi.nlm.nih.gov/25213377/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25213377/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25213377", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph3, 1:Main text:paragraph5, 1:Main text:paragraph6, 1:Main text:paragraph10. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "what_it_does_not_show": "Original text preserves healthy carriers and culture rescue; common disease initiation is a separate scope.", "confounders_present": [ "Original text preserves healthy carriers and culture rescue; common disease initiation is a separate scope." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "10485649", "title": "Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.", "citation": "Nishimura H, Nose M, Hiai H et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999.", "doi": "10.1016/s1074-7613(00)80089-8", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10485649/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10485649/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID10485649", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "what_it_does_not_show": "Constitutive immune development and genetic background limit generalization.", "confounders_present": [ "Constitutive immune development and genetic background limit generalization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "11209085", "title": "Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice.", "citation": "Nishimura H, Okazaki T, Tanaka Y et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (New York, N.Y.). 2001.", "doi": "10.1126/science.291.5502.319", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11209085/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11209085/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11209085", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "what_it_does_not_show": "B/T-cell dependency and strain context do not identify an infectious initiator.", "confounders_present": [ "B/T-cell dependency and strain context do not identify an infectious initiator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "34183838", "title": "Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.", "citation": "Ogishi M, Yang R, Aytekin C et al. Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child. Nature medicine. 2021.", "doi": "10.1038/s41591-021-01388-5", "pmcid": "PMC8446316", "url": "https://pubmed.ncbi.nlm.nih.gov/34183838/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34183838/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34183838", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation.", "what_it_does_not_show": "Single affected child with TB cannot independently determine whether infection or tolerance loss initiated each lesion.", "confounders_present": [ "Single affected child with TB cannot independently determine whether infection or tolerance loss initiated each lesion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "39569589", "title": "Immune checkpoint inhibitor-related type 1 diabetes incidence, risk, and survival association.", "citation": "Kamitani F, Nishioka Y, Koizumi M et al. Immune checkpoint inhibitor-related type 1 diabetes incidence, risk, and survival association. Journal of diabetes investigation. 2025.", "doi": "10.1111/jdi.14362", "pmcid": "PMC11786175", "url": "https://pubmed.ncbi.nlm.nih.gov/39569589/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39569589/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39569589", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Incident T1D follows checkpoint therapy with regimen and baseline-disease risk contrasts.", "what_it_does_not_show": "Administrative coding and nonrandomized therapy comparisons constrain incidence attribution; survival analysis is vulnerable to time-dependent selection.", "confounders_present": [ "Administrative coding and nonrandomized therapy comparisons constrain incidence attribution; survival analysis is vulnerable to time-dependent selection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "41223250", "title": "Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus.", "citation": "Younis S, Moutusy SI, Rasouli S et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Science translational medicine. 2025.", "doi": "10.1126/scitranslmed.ady0210", "pmcid": "PMC12740198", "url": "https://pubmed.ncbi.nlm.nih.gov/41223250/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41223250/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41223250", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph1, 0:Results:paragraph10, 0:Results:paragraph11, 0:Results:paragraph17, 0:Results:paragraph18, 0:Results:paragraph19, 0:Results:paragraph20. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "what_it_does_not_show": "Original Results use diagnosed patients and cell-line genomic datasets; no prediagnostic onset sequence or selective in vivo viral depletion is established.", "confounders_present": [ "Original Results use diagnosed patients and cell-line genomic datasets; no prediagnostic onset sequence or selective in vivo viral depletion is established." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Integrates previously generated EBV cell-line genomic datasets with current patient profiling." ] }, { "n": 49, "pmid": "26656646", "title": "Oligodendrocyte death results in immune-mediated CNS demyelination.", "citation": "Traka M, Podojil JR, McCarthy DP et al. Oligodendrocyte death results in immune-mediated CNS demyelination. Nature neuroscience. 2016.", "doi": "10.1038/nn.4193", "pmcid": "PMC4837900", "url": "https://pubmed.ncbi.nlm.nih.gov/26656646/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26656646/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID26656646", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M4" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "what_it_does_not_show": "Engineered tissue injury establishes an alternative route in a model, not proof that human MS routinely begins without EBV.", "confounders_present": [ "Engineered tissue injury establishes an alternative route in a model, not proof that human MS routinely begins without EBV." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "34804036", "title": "Changes in MDA5 and TLR3 Sensing of the Same Diabetogenic Virus Result in Different Autoimmune Disease Outcomes.", "citation": "Lincez PJ, Shanina I, Horwitz MS et al. Changes in MDA5 and TLR3 Sensing of the Same Diabetogenic Virus Result in Different Autoimmune Disease Outcomes. Frontiers in immunology. 2021.", "doi": "10.3389/fimmu.2021.751341", "pmcid": "PMC8602094", "url": "https://pubmed.ncbi.nlm.nih.gov/34804036/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34804036/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34804036", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M4", "M5" ], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "what_it_does_not_show": "Sensor, local interferon and host state determine sign; this is not a universal infection-to-disease rule.", "confounders_present": [ "Sensor, local interferon and host state determine sign; this is not a universal infection-to-disease rule." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "31792456", "title": "Prospective virome analyses in young children at increased genetic risk for type 1 diabetes.", "citation": "Vehik K, Lynch KF, Wong MC et al. Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. Nature medicine. 2019.", "doi": "10.1038/s41591-019-0667-0", "pmcid": "PMC6898786", "url": "https://pubmed.ncbi.nlm.nih.gov/31792456/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31792456/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "TEDDY-virome", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TEDDY prolonged enterovirus-B shedding associates with islet autoimmunity but not T1D incidence.", "what_it_does_not_show": "Repeated stools measure exposure patterns and surrogate seroconversion, not necessary clinical initiation.", "confounders_present": [ "Repeated stools measure exposure patterns and surrogate seroconversion, not necessary clinical initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "28696303", "title": "Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children.", "citation": "Zhao G, Vatanen T, Droit L et al. Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proceedings of the National Academy of Sciences of the United States of America. 2017.", "doi": "10.1073/pnas.1706359114", "pmcid": "PMC5544325", "url": "https://pubmed.ncbi.nlm.nih.gov/28696303/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28696303/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30455315" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID28696303", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Virome changes precede autoimmunity but common enterovirus sequences do not associate in this small cohort.", "what_it_does_not_show": "Small sample and linked correction details unexamined limit precise diversity inference.", "confounders_present": [ "Small sample and linked correction details unexamined limit precise diversity inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "25422874", "title": "Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice.", "citation": "McCall KD, Thuma JR, Courreges MC et al. Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice. Endocrinology. 2015.", "doi": "10.1210/en.2013-2006", "pmcid": "PMC4298321", "url": "https://pubmed.ncbi.nlm.nih.gov/25422874/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25422874/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25422874", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "what_it_does_not_show": "Constitutive receptor loss and forced viral challenge establish model-specific causal contribution.", "confounders_present": [ "Constitutive receptor loss and forced viral challenge establish model-specific causal contribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "23469060", "title": "In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells.", "citation": "Bason C, Lorini R, Lunardi C et al. In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells. PloS one. 2013.", "doi": "10.1371/journal.pone.0057729", "pmcid": "PMC3585221", "url": "https://pubmed.ncbi.nlm.nih.gov/23469060/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23469060/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID23469060", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2b", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "what_it_does_not_show": "Culture killing does not establish the infection-to-human-onset chain; SC2b comparison illustrates mimicry transfer limits, not MS evidence.", "confounders_present": [ "Culture killing does not establish the infection-to-human-onset chain; SC2b comparison illustrates mimicry transfer limits, not MS evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "12699416", "title": "Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial.", "citation": "Sadeharju K, Hämäläinen AM, Knip M et al. Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial. Clinical and experimental immunology. 2003.", "doi": "10.1046/j.1365-2249.2003.02147.x", "pmcid": "PMC1808709", "url": "https://pubmed.ncbi.nlm.nih.gov/12699416/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12699416/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID12699416", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enterovirus infections precede islet autoantibodies in genetically at-risk children.", "what_it_does_not_show": "Formula allocation was randomized; viral infection exposure was not randomized and clinical T1D causality is unproven.", "confounders_present": [ "Formula allocation was randomized; viral infection exposure was not randomized and clinical T1D causality is unproven." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "37789144", "title": "Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial.", "citation": "Krogvold L, Mynarek IM, Ponzi E et al. Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial. Nature medicine. 2023.", "doi": "10.1038/s41591-023-02576-1", "pmcid": "PMC10667091", "url": "https://pubmed.ncbi.nlm.nih.gov/37789144/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37789144/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "DiViD-intervention-phase2", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph14, 1:Results:paragraph15, 2:Discussion:paragraph2, 2:Discussion:paragraph3, 2:Discussion:paragraph5, 2:Discussion:paragraph8, 3:Methods:paragraph11, 3:Methods:paragraph12, 3:Methods:paragraph15, 3:Methods:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "what_it_does_not_show": "Post-diagnosis functional secretion is not prevention; peripheral PCR is negative, drug effects cannot be separated, and insulin-dose/12-month HbA1c contrasts are null.", "confounders_present": [ "Post-diagnosis functional secretion is not prevention; peripheral PCR is negative, drug effects cannot be separated, and insulin-dose/12-month HbA1c contrasts are null." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "38369573", "title": "Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial.", "citation": "Hyöty H, Kääriäinen S, Laiho JE et al. Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial. Diabetologia. 2024.", "doi": "10.1007/s00125-024-06092-w", "pmcid": "PMC10954874", "url": "https://pubmed.ncbi.nlm.nih.gov/38369573/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38369573/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38369573", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Phase-I CVB vaccine is tolerable and induces neutralizing responses.", "what_it_does_not_show": "Healthy-adult safety/immunogenicity without autoimmune incidence outcomes does not prove prevention.", "confounders_present": [ "Healthy-adult safety/immunogenicity without autoimmune incidence outcomes does not prove prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "37993433", "title": "Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection.", "citation": "Lin J, Moradi E, Salenius K et al. Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection. Nature communications. 2023.", "doi": "10.1038/s41467-023-42763-9", "pmcid": "PMC10665402", "url": "https://pubmed.ncbi.nlm.nih.gov/37993433/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37993433/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID37993433", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Prediagnostic islet-autoantibody subgroups differ in transcription and antiviral-response signatures.", "what_it_does_not_show": "Cell composition, genotype and response correlates do not isolate infectious initiation.", "confounders_present": [ "Cell composition, genotype and response correlates do not isolate infectious initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "31744911", "title": "Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study.", "citation": "Lindfors K, Lin J, Lee HS et al. Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study. Gut. 2020.", "doi": "10.1136/gutjnl-2019-319809", "pmcid": "PMC7234892", "url": "https://pubmed.ncbi.nlm.nih.gov/31744911/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31744911/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "TEDDY-virome-celiac", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TEDDY enterovirus exposure interacts with gluten intake in celiac autoimmunity risk.", "what_it_does_not_show": "Nested observational analysis with autoantibody endpoint shares TEDDY data and does not remove the causal dietary antigen.", "confounders_present": [ "Nested observational analysis with autoantibody endpoint shares TEDDY data and does not remove the causal dietary antigen." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Shares TEDDY infrastructure and exposure measurement with T1D virome analyses." ] }, { "n": 60, "pmid": "18806780", "title": "Innate immunity and intestinal microbiota in the development of Type 1 diabetes.", "citation": "Wen L, Ley RE, Volchkov PY et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008.", "doi": "10.1038/nature07336", "pmcid": "PMC2574766", "url": "https://pubmed.ncbi.nlm.nih.gov/18806780/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18806780/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID18806780", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph2, 2:Main text:paragraph4, 2:Main text:paragraph5, 2:Main text:paragraph12, 2:Main text:paragraph13. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M3", "M5" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "what_it_does_not_show": "Original Results show protective microbiota and retained diabetogenic cells, with genotype/housing limits and no human prevention demonstration.", "confounders_present": [ "Original Results show protective microbiota and retained diabetogenic cells, with genotype/housing limits and no human prevention demonstration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "29590047", "title": "Translocation of a gut pathobiont drives autoimmunity in mice and humans.", "citation": "Manfredo Vieira S, Hiltensperger M, Kumar V et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aar7201", "pmcid": "PMC5959731", "url": "https://pubmed.ncbi.nlm.nih.gov/29590047/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29590047/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID29724927" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID29590047", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "what_it_does_not_show": "Human liver DNA is associative; antibiotic pleiotropy and induced colonization do not establish spontaneous human initiation; correction attached.", "confounders_present": [ "Human liver DNA is associative; antibiotic pleiotropy and induced colonization do not establish spontaneous human initiation; correction attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "30581114", "title": "A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity.", "citation": "Zegarra-Ruiz DF, El Beidaq A, Iñiguez AJ et al. A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity. Cell host & microbe. 2019.", "doi": "10.1016/j.chom.2018.11.009", "pmcid": "PMC6377154", "url": "https://pubmed.ncbi.nlm.nih.gov/30581114/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30581114/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID30581114", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "what_it_does_not_show": "Strain, diet and transgenic host set context; human fecal enrichment is not onset mediation.", "confounders_present": [ "Strain, diet and transgenic host set context; human fecal enrichment is not onset mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "27974664", "title": "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis.", "citation": "Konig MF, Abusleme L, Reinholdt J et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Science translational medicine. 2016.", "doi": "10.1126/scitranslmed.aaj1921", "pmcid": "PMC5384717", "url": "https://pubmed.ncbi.nlm.nih.gov/27974664/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27974664/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27974664", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "what_it_does_not_show": "Human exposure/ACPA association and ex vivo toxin action do not establish necessary RA onset.", "confounders_present": [ "Human exposure/ACPA association and ex vivo toxin action do not establish necessary RA onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "30459755", "title": "Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy.", "citation": "Mukherjee A, Jantsch V, Khan R et al. Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy. Frontiers in immunology. 2018.", "doi": "10.3389/fimmu.2018.02352", "pmcid": "PMC6232707", "url": "https://pubmed.ncbi.nlm.nih.gov/30459755/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30459755/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID30459755", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "what_it_does_not_show": "One RA-like infection-associated case lacks randomized withdrawal/rechallenge and cannot establish ordinary RA primacy.", "confounders_present": [ "One RA-like infection-associated case lacks randomized withdrawal/rechallenge and cannot establish ordinary RA primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "36288282", "title": "Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum.", "citation": "Chriswell ME, Lefferts AR, Clay MR et al. Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum. Science translational medicine. 2022.", "doi": "10.1126/scitranslmed.abn5166", "pmcid": "PMC9804515", "url": "https://pubmed.ncbi.nlm.nih.gov/36288282/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36288282/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID36288282", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "what_it_does_not_show": "At-risk human antibody selection plus germ-free strain challenge proves a bounded route rather than all RA initiation.", "confounders_present": [ "At-risk human antibody selection plus germ-free strain challenge proves a bounded route rather than all RA initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "20620945", "title": "Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.", "citation": "Wu HJ, Ivanov II, Darce J et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010.", "doi": "10.1016/j.immuni.2010.06.001", "pmcid": "PMC2904693", "url": "https://pubmed.ncbi.nlm.nih.gov/20620945/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20620945/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID20620945", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M5" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "what_it_does_not_show": "Transgenic host and immune background set context; one commensal can have the opposite sign in NOD diabetes.", "confounders_present": [ "Transgenic host and immune background set context; one commensal can have the opposite sign in NOD diabetes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 67, "pmid": "21709219", "title": "Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice.", "citation": "Kriegel MA, Sefik E, Hill JA et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proceedings of the National Academy of Sciences of the United States of America. 2011.", "doi": "10.1073/pnas.1108924108", "pmcid": "PMC3136249", "url": "https://pubmed.ncbi.nlm.nih.gov/21709219/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21709219/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID21709219", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M3", "M5" ], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "what_it_does_not_show": "Colonization is naturally incomplete and observational within the facility; sex dependence limits mechanistic certainty.", "confounders_present": [ "Colonization is naturally incomplete and observational within the facility; sex dependence limits mechanistic certainty." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 68, "pmid": "31954872", "title": "Suppression of systemic lupus erythematosus in NZBWF1 mice infected with Hymenolepis microstoma.", "citation": "Olia A, Shimokawa C, Imai T et al. Suppression of systemic lupus erythematosus in NZBWF1 mice infected with Hymenolepis microstoma. Parasitology international. 2020.", "doi": "10.1016/j.parint.2020.102057", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31954872/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31954872/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31954872", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "what_it_does_not_show": "Parasitic immune pleiotropy and unsuccessful nematode settlement limit target specificity and human transfer.", "confounders_present": [ "Parasitic immune pleiotropy and unsuccessful nematode settlement limit target specificity and human transfer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 69, "pmid": "27125291", "title": "The potential protective role of hepatitis B virus infection in pristane-induced lupus in mice.", "citation": "Liu X, Jiao Y, Cui B et al. The potential protective role of hepatitis B virus infection in pristane-induced lupus in mice. Lupus. 2016.", "doi": "10.1177/0961203316631637", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27125291/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27125291/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27125291", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology.", "what_it_does_not_show": "The actual manipulation is a transgene, not acquired HBV infection; the abstract's human-protection conclusion is unsupported by this experiment.", "confounders_present": [ "The actual manipulation is a transgene, not acquired HBV infection; the abstract's human-protection conclusion is unsupported by this experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "HBV-transgenic exposure is not acquired viral infection." ] }, { "n": 70, "pmid": "26214836", "title": "The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment.", "citation": "Zhang X, Zhang D, Jia H et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nature medicine. 2015.", "doi": "10.1038/nm.3914", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26214836/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26214836/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID26214836", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "RA oral/gut microbiota vary with disease and partly normalize after treatment.", "what_it_does_not_show": "Treatment-associated normalization permits reverse causation and does not show dysbiosis first initiated RA.", "confounders_present": [ "Treatment-associated normalization permits reverse causation and does not show dysbiosis first initiated RA." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 77, "verified": 77, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "Prediagnostic EBV seroconversion and C. jejuni antecedence are reproducible with temporal and exposure controls. This registered descriptive existence claim has no selective causal manipulation of its own and is graded Β. Its formal minimum must not re-cap the independent mechanistic evidence assessed separately.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC2b", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility plus ex vivo or in vitro immune functional support caps at Γ.", "specific_trigger": "EBNA1/GlialCAM, ANO2 and CRYAB cross-reactivity has human and functional support, but original Lanz Results show enhancement of induced EAE. ANO2 transfer and 2026 B-cell presentation/viral-signaling studies add model support without selective endogenous human mimic necessity at onset. The registered initiation link remains Γ.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Autoimmunity is initiated by infection-triggered molecular mimicry and bystander activation that overcome baseline genetic deficiencies in immune tolerance.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The immunology threshold credits lineage-specific depletion, target-aligned rescue and hard disease outcomes in their tested settings. In vitro cross-reactivity and biomarker-only mutant antibody induction cannot alone cross the human onset boundary. GBS convergence combines clinical strain/phenotype specificity with molecular subtraction and organismal weakness, and is not re-capped because its human clinical leg is observational. The universal forced-transfer/overexpression limits apply to extending induced EAE, LMP1 and gnotobiotic models to endogenous human initiation. Familial tolerance causality remains separate from sporadic infection claims.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Ex vivo functional assays alone — applicable to human cross-reactive clones and SLE APC cultures.", "Cytokine profiles plus in vitro work — insufficient for endogenous onset.", "Broad immunosuppression — does not identify an infectious initiator.", "Correlational human data plus in vitro mechanism — caps the human onset link when selective disease-relevant dependency is missing; independent GBS and tolerance causal sets are assessed separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Prediagnostic EBV seroconversion and C. jejuni antecedence are reproducible with temporal and exposure controls. This registered descriptive existence claim has no selective causal manipulation of its own and is graded Β. Its formal minimum must not re-cap the independent mechanistic evidence assessed separately.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2a", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID15304587, PMID10713352, PMID10660542, PMID11254608, PMID8228822, PMID15716397, PMID15277677, PMID15578098, PMID17261613", "gamma_hard_rules_triggered": [ "Ex vivo functional assays alone — applicable to human cross-reactive clones and SLE APC cultures.", "Cytokine profiles plus in vitro work — insufficient for endogenous onset.", "Broad immunosuppression — does not identify an infectious initiator.", "Correlational human data plus in vitro mechanism — caps the human onset link when selective disease-relevant dependency is missing; independent GBS and tolerance causal sets are assessed separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Within defined bacterial/ganglioside genotypes, chemical identity, bacterial mimic subtraction, matched antibody specificity, rabbit neuropathy and clinical isolate/phenotype contrasts converge across errors. Ζ credits the causal set, not the mutant antibody biomarker alone. Host resistance, non-mimicking isolates and absent human selective prevention limit Η and broader GBS sufficiency.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2b", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID35073561, PMID40063790, PMID37196088, PMID41534529, PMID31375628, PMID41534530, PMID41534531, PMID23469060", "gamma_hard_rules_triggered": [ "Ex vivo functional assays alone — applicable to human cross-reactive clones and SLE APC cultures.", "Cytokine profiles plus in vitro work — insufficient for endogenous onset.", "Broad immunosuppression — does not identify an infectious initiator.", "Correlational human data plus in vitro mechanism — caps the human onset link when selective disease-relevant dependency is missing; independent GBS and tolerance causal sets are assessed separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "EBNA1/GlialCAM, ANO2 and CRYAB cross-reactivity has human and functional support, but original Lanz Results show enhancement of induced EAE. ANO2 transfer and 2026 B-cell presentation/viral-signaling studies add model support without selective endogenous human mimic necessity at onset. The registered initiation link remains Γ.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID33711260, PMID18845758, PMID25329329, PMID37595759, PMID34477806, PMID12376594, PMID11137993, PMID11137992, PMID7636184, PMID17136045, PMID25213377, PMID10485649, PMID11209085, PMID34183838", "gamma_hard_rules_triggered": [ "Ex vivo functional assays alone — applicable to human cross-reactive clones and SLE APC cultures.", "Cytokine profiles plus in vitro work — insufficient for endogenous onset.", "Broad immunosuppression — does not identify an infectious initiator.", "Correlational human data plus in vitro mechanism — caps the human onset link when selective disease-relevant dependency is missing; independent GBS and tolerance causal sets are assessed separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Human FOXP3/CTLA4 inborn errors, lineage-specific CTLA4 loss, acute adult Treg removal and time-dependent reconstitution establish ongoing tolerance causality. Genotype-aligned abatacept changes clinical trajectories. Different failure structures support Η; incomplete penetrance, developmental effects and multiple tolerance routes prevent Θ/Ω for all pathways.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID35073561, PMID41534530, PMID41534531, PMID30429369, PMID15277677, PMID41223250, PMID26656646, PMID34804036, PMID25422874, PMID23469060, PMID37789144, PMID18806780, PMID29590047, PMID30581114, PMID27974664, PMID30459755, PMID36288282, PMID20620945, PMID21709219, PMID31954872, PMID27125291", "gamma_hard_rules_triggered": [ "Ex vivo functional assays alone — applicable to human cross-reactive clones and SLE APC cultures.", "Cytokine profiles plus in vitro work — insufficient for endogenous onset.", "Broad immunosuppression — does not identify an infectious initiator.", "Correlational human data plus in vitro mechanism — caps the human onset link when selective disease-relevant dependency is missing; independent GBS and tolerance causal sets are assessed separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "A coherent infection-to-autoimmune injury route is established in defined C. jejuni/ganglioside settings, with rare human Aa eradication evidence and model perturbations in other diseases. EBV antecedence strongly supports an upstream MS risk role without identifying the initiating mimic. Prediagnostic baseline tolerance breakdown and onset mediation across human diseases are unresolved, so context-specific Ε is retained.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID15304587, PMID17261613, PMID25329329, PMID25213377, PMID10485649, PMID11209085, PMID41223250, PMID26656646, PMID34804036, PMID25422874, PMID23469060, PMID37789144, PMID18806780, PMID29590047, PMID30581114, PMID27974664, PMID30459755, PMID36288282, PMID20620945, PMID21709219, PMID31954872, PMID27125291", "gamma_hard_rules_triggered": [ "Ex vivo functional assays alone — applicable to human cross-reactive clones and SLE APC cultures.", "Cytokine profiles plus in vitro work — insufficient for endogenous onset.", "Broad immunosuppression — does not identify an infectious initiator.", "Correlational human data plus in vitro mechanism — caps the human onset link when selective disease-relevant dependency is missing; independent GBS and tolerance causal sets are assessed separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Causal microbial routes have positive and protective signs across genotypes and diseases. SFB promotes K/BxN arthritis but associates with female NOD protection; germ-free MyD88-null NOD develop diabetes. Thus bounded causality exists but the class-wide initiation generalization fails: Ε, not a denial that particular infections are causes.", "ceiling_from_boundary_check": "Δ or higher" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "For this descriptive antecedence row, a causal restatement and prospective selective infection intervention would be required before grading it as causal. Any future aggregation amendment must be prospectively declared; this review preserves the original rule." }, { "subclaim_id": "SC2a", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[24] GBS-strain LPS immunization induces GM1-cross-reactive rabbit antibodies.", "[25] Cloned glycosyltransferases synthesize defined ganglioside-like structures with linkage confirmation.", "[26] GBS/MFS LPS induces matched antibody specificity; control-strain LPS lacks ganglioside reactivity.", "[28] NMR and chemical analysis identify a GM1-identical terminal bacterial oligosaccharide.", "[29] Anti-GD1a antibody plus complement injures high-antigen motor terminals and blocks function.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[31] cst-II/orf10 loss removes sialylated mimics and anti-GD1a induction while orf11 is a negative control.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2a", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[24] GBS-strain LPS immunization induces GM1-cross-reactive rabbit antibodies.", "[25] Cloned glycosyltransferases synthesize defined ganglioside-like structures with linkage confirmation.", "[26] GBS/MFS LPS induces matched antibody specificity; control-strain LPS lacks ganglioside reactivity.", "[28] NMR and chemical analysis identify a GM1-identical terminal bacterial oligosaccharide.", "[29] Anti-GD1a antibody plus complement injures high-antigen motor terminals and blocks function.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[31] cst-II/orf10 loss removes sialylated mimics and anti-GD1a induction while orf11 is a negative control.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2a", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "yes", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[24] GBS-strain LPS immunization induces GM1-cross-reactive rabbit antibodies.", "[25] Cloned glycosyltransferases synthesize defined ganglioside-like structures with linkage confirmation.", "[26] GBS/MFS LPS induces matched antibody specificity; control-strain LPS lacks ganglioside reactivity.", "[28] NMR and chemical analysis identify a GM1-identical terminal bacterial oligosaccharide.", "[29] Anti-GD1a antibody plus complement injures high-antigen motor terminals and blocks function.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[31] cst-II/orf10 loss removes sialylated mimics and anti-GD1a induction while orf11 is a negative control.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2a", "threshold": "Η", "requirement_quoted": "Requires robust upstream causal evidence across systems and interventions.", "satisfied": "no", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[24] GBS-strain LPS immunization induces GM1-cross-reactive rabbit antibodies.", "[25] Cloned glycosyltransferases synthesize defined ganglioside-like structures with linkage confirmation.", "[26] GBS/MFS LPS induces matched antibody specificity; control-strain LPS lacks ganglioside reactivity.", "[28] NMR and chemical analysis identify a GM1-identical terminal bacterial oligosaccharide.", "[29] Anti-GD1a antibody plus complement injures high-antigen motor terminals and blocks function.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[31] cst-II/orf10 loss removes sialylated mimics and anti-GD1a induction while orf11 is a negative control.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes." ], "what_would_cross_it": "Physiological infection-time mimic subtraction/restoration with neuropathic outcomes and prospective human onset prediction, rather than adjuvant immunization or antibody induction alone." }, { "subclaim_id": "SC2b", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [ "[2] Patient-derived antibody cross-binds EBNA1 and GlialCAM; peptide immunization aggravates PLP-induced EAE.", "[5] GlialCAM/EBNA1 reciprocal blocking confirms cross-reactivity and HLA-associated risk patterns.", "[6] EBNA1/CRYAB reciprocal blocking and mouse responses support cross-reactive immunity.", "[7] ANO2 pre-immunization and transferred CD4 cells exacerbate EAE; human clones cross-recognize EBNA1.", "[10] ANO2/EBNA1 blocking and genotype combinations link cross-reactivity to MS risk.", "[14] EBV reprograms HLA-DR15 B-cell presentation of MBP peptides recognized by MS T cells.", "[17] LMP1 or CD40L overrides death of antigen-capturing myelin-reactive B cells and enables lesions.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis." ], "what_would_cross_it": "Suppress the defined cross-reactive epitope or clone before onset while preserving antiviral control; demonstrate less disease and matched rescue." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[33] Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects.", "[34] Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[36] Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort.", "[37] Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription.", "[38] Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity.", "[39] Human FOXP3 mutations segregate with IPEX immune dysregulation.", "[40] Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology.", "[41] CD25-cell removal permits autoimmune disease and timely reconstitution prevents it.", "[42] Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[46] Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[33] Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects.", "[34] Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[36] Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort.", "[37] Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription.", "[38] Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity.", "[39] Human FOXP3 mutations segregate with IPEX immune dysregulation.", "[40] Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology.", "[41] CD25-cell removal permits autoimmune disease and timely reconstitution prevents it.", "[42] Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[46] Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "yes", "supporting_evidence": [ "[33] Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects.", "[34] Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[36] Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort.", "[37] Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription.", "[38] Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity.", "[39] Human FOXP3 mutations segregate with IPEX immune dysregulation.", "[40] Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology.", "[41] CD25-cell removal permits autoimmune disease and timely reconstitution prevents it.", "[42] Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[46] Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Η", "requirement_quoted": "Requires robust upstream causal evidence across systems and interventions.", "satisfied": "yes", "supporting_evidence": [ "[33] Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects.", "[34] Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[36] Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort.", "[37] Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription.", "[38] Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity.", "[39] Human FOXP3 mutations segregate with IPEX immune dysregulation.", "[40] Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology.", "[41] CD25-cell removal permits autoimmune disease and timely reconstitution prevents it.", "[42] Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[46] Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Θ", "requirement_quoted": "Requires predictive consistency and minimal contradiction in the claimed disease scope.", "satisfied": "no", "supporting_evidence": [ "[33] Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects.", "[34] Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[36] Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort.", "[37] Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription.", "[38] Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity.", "[39] Human FOXP3 mutations segregate with IPEX immune dysregulation.", "[40] Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology.", "[41] CD25-cell removal permits autoimmune disease and timely reconstitution prevents it.", "[42] Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[46] Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation." ], "what_would_cross_it": "Prospective genotype/functional thresholds accurately predict tolerance failure and therapeutic rescue across populations while retaining unaffected carriers." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[2] Patient-derived antibody cross-binds EBNA1 and GlialCAM; peptide immunization aggravates PLP-induced EAE.", "[14] EBV reprograms HLA-DR15 B-cell presentation of MBP peptides recognized by MS T cells.", "[17] LMP1 or CD40L overrides death of antigen-capturing myelin-reactive B cells and enables lesions.", "[18] Open-label EBV-specific T-cell treatment is feasible and clinical improvement tracks product reactivity.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[48] Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "[49] Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "[50] Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "[53] TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "[56] Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "[60] Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "[61] E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "[62] L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "[63] Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "[64] Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "[65] One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "[66] SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "[67] Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "[68] Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "[69] HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology." ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[2] Patient-derived antibody cross-binds EBNA1 and GlialCAM; peptide immunization aggravates PLP-induced EAE.", "[14] EBV reprograms HLA-DR15 B-cell presentation of MBP peptides recognized by MS T cells.", "[17] LMP1 or CD40L overrides death of antigen-capturing myelin-reactive B cells and enables lesions.", "[18] Open-label EBV-specific T-cell treatment is feasible and clinical improvement tracks product reactivity.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[48] Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "[49] Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "[50] Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "[53] TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "[56] Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "[60] Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "[61] E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "[62] L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "[63] Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "[64] Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "[65] One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "[66] SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "[67] Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "[68] Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "[69] HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology." ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "no", "supporting_evidence": [ "[2] Patient-derived antibody cross-binds EBNA1 and GlialCAM; peptide immunization aggravates PLP-induced EAE.", "[14] EBV reprograms HLA-DR15 B-cell presentation of MBP peptides recognized by MS T cells.", "[17] LMP1 or CD40L overrides death of antigen-capturing myelin-reactive B cells and enables lesions.", "[18] Open-label EBV-specific T-cell treatment is feasible and clinical improvement tracks product reactivity.", "[30] LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology.", "[48] Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "[49] Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "[50] Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "[53] TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "[56] Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "[60] Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "[61] E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "[62] L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "[63] Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "[64] Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "[65] One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "[66] SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "[67] Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "[68] Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "[69] HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology." ], "what_would_cross_it": "Selective infection prevention or clearance before disease in baseline-tolerance-characterized people, with incident autoimmune disease and mediator-specific readouts." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[48] Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "[49] Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "[50] Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "[53] TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "[56] Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "[60] Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "[61] E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "[62] L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "[63] Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "[64] Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "[65] One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "[66] SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "[67] Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "[68] Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "[69] HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology." ], "what_would_cross_it": "" }, { "subclaim_id": "SC5", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[48] Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "[49] Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "[50] Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "[53] TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "[56] Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "[60] Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "[61] E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "[62] L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "[63] Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "[64] Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "[65] One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "[66] SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "[67] Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "[68] Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "[69] HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology." ], "what_would_cross_it": "" }, { "subclaim_id": "SC5", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "no", "supporting_evidence": [ "[23] Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy.", "[32] Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes.", "[35] Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance.", "[43] Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation.", "[44] PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss.", "[45] BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it.", "[48] Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells.", "[49] Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease.", "[50] Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect.", "[53] TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls.", "[54] Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis.", "[56] Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis.", "[60] Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it.", "[61] E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality.", "[62] L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease.", "[63] Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns.", "[64] Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient.", "[65] One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease.", "[66] SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis.", "[67] Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis.", "[68] Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1.", "[69] HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology." ], "what_would_cross_it": "Independent prespecified disease cohorts and interventions establish which pathogen, mechanism and host state explain onset; preserve negative and protective contexts." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "CMV does not show the EBV-MS seroconversion risk pattern.", "Healthy controls also show EBV-expanded CNS-reactive T cells.", "BENEFIT post-CIS EBV titres do not predict activity; this is a progression-stage negative context.", "Original Godschalk orf11 does not alter LOS structure or eliminate GD1a responses; asialo-GM1 responses persist in sialylation mutants.", "Normal GD1a mice resist antibody injury while engineered high-antigen terminals are damaged.", "Healthy CTLA4 variant carriers are retained; full penetrance is not asserted.", "MyD88-null germ-free NOD develop diabetes while colonized counterparts are protected.", "SFB promotes K/BxN arthritis but associates with female NOD protection.", "DiViD insulin-dose and 12-month HbA1c contrasts are null despite C-peptide benefit." ], "note": "Boundaries are mapped prospectively by bacterial LOS genotype, HLA/tolerance genotype, disease/stage, animal strain, microbial housing, antigen and intervention timing. Outcomes do not define susceptibility. C. jejuni axonal GBS cannot stand for all GBS; MS seroconversion cannot identify a unique mimic; gnotobiotic RA/lupus and protective NOD contexts refute a common microbial sign. The formal overall Β is especially sensitive to inclusion of a descriptive association row in a conjunctive rule; primary-gate Ε is displayed rather than silently changing the preregistration." }, "falsification_patterns_met": [ { "pattern": "Microbes need not initiate autoimmune disease and can protect", "evidence": "Germ-free MyD88-null NOD still develop diabetes; defined colonization attenuates it. Acute tolerance loss and sterile oligodendrocyte injury provide other model routes.", "downgrade_applied": false }, { "pattern": "Cross-reactivity does not uniquely identify affected individuals or onset", "evidence": "Healthy-control EBV T-cell autoreactivity, partial mimic seropositivity and discordant GlialCAM/CRYAB cohort signatures remain in scope.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "EBV upstream risk substituted for a proved initiating epitope", "where": "SC1 versus SC2b/SC4; original induced-EAE design." }, { "pitfall": "Mutant antibody induction treated as clinical disease prevention", "where": "Godschalk deficient recipient and adjuvant Methods." }, { "pitfall": "Genetic tolerance necessity treated as proof of infectious initiation", "where": "SC3 is rival support." }, { "pitfall": "Antiviral benefit after diagnosis treated as prevention", "where": "DiViD timing, PCR-negative cohort and two-drug specificity." }, { "pitfall": "HBV transgene called acquired infection or human protection", "where": "PMID27125291 actual experiment." }, { "pitfall": "Formal weakest-link letter obscures stronger causal subclaims", "where": "SC1 descriptive Β controls overall; primary and scope-matched Ε sensitivities must accompany publication." }, { "pitfall": "Provider retrieval counts or substituted thesis treated as primary validation", "where": "Consensus Godschalk/Krogvold failed matches and penetrance correction." } ], "causal_tally_audit": { "tally_claimed_by_document": 47, "tally_after_audit": 47, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "The strongest case for Γ or above for the assembled scientific hypothesis combines GBS causal convergence, EBV temporal specificity and model infection/sensor perturbations. It is scientifically compelling for bounded contexts. Under the retained weakest-link protocol, it cannot raise the descriptive SC1 above Β merely by relabelling associations. Primary-gate Ε is a legitimate sensitivity, and the protocol limitation must remain visible rather than implying the entire causal set is associational.", "case_one_rung_lower": "An Α narrative-only assessment is untenable: prospective antecedence, defined molecular mimics, specific subtraction, neuropathic outcomes and tolerance loss/rescue are actual primary evidence. The hypothesis merits formal causal adjudication even though its broad initiating mechanism is unresolved.", "which_rejected": "Preserve the preregistered formal Β while exposing the aggregation artifact and stronger disease-specific causal conclusions. Neither universal infection primacy nor infection-as-passive-marker explains the examined evidence. A future review should prospectively treat the descriptive existence row separately from causal conjunction grading.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In baseline infection-negative, genotype- and tolerance-function-characterized cohorts, prevent a specific pathogen before seroconversion or selectively block a prespecified cross-reactive epitope while preserving antiviral immunity. Follow incident disease and matched antigen-specific clones, with independently replicated infection exposure and disease ascertainment; in parallel use physiological pathogen mimic-loss and restored-mimic rescue with functional pathology." }, "final_score": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the Campylobacter/ganglioside and inherited-tolerance literatures are replicated across independent laboratories and instrument classes, while much of the remaining mimicry evidence rests on induced or engineered systems, the microbial results change sign with strain, sex, diet and housing, the abatacept cohort is nonrandomized, and recurrence of the same serorepositories and clinical isolate platforms is only partly audited.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered weakest-link rule returns Β because the descriptive antecedence subclaim SC1 is associational. This is an aggregation limitation, not a finding that all infection causality is merely correlational: defined Campylobacter/ganglioside GBS convergence reaches Ζ, intrinsic tolerance necessity Η, and broader context-dependent initiation Ε. Primary-subclaim and scope-matched sensitivities return Ε. Human MS mimic-specific initiation remains Γ. Do not publish the overall letter without this subclaim explanation or interpret it as refuting EBV risk causality." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "For the broad class, infections can amplify, license or maintain self-reactivity; evidence does not identify one required and rate-limiting initiating mechanism. C. jejuni mimicry can initiate a defined axonal neuropathy and EBV is an upstream MS risk factor, so this class-level role is not imposed on every disease-specific route. Disease in germ-free settings does not by itself mean microbes are downstream consequences.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "2025 SLE EBV reprogramming and 2026 ANO2/HLA-DR15/LMP1 studies examine specific routes. The examined CVB vaccine phase I tests safety/immunogenicity and DiViD treats established disease; no verified ongoing incidence-result programme is claimed here.", "justification": "2025 SLE EBV reprogramming and 2026 ANO2/HLA-DR15/LMP1 studies examine specific routes. The examined CVB vaccine phase I tests safety/immunogenicity and DiViD treats established disease; no verified ongoing incidence-result programme is claimed here." }, "stability": { "value": "Stable", "trigger": "No named verified pending result is asserted likely to move the full class-wide initiation score imminently. A selective pre-onset pathogen/epitope intervention with incident disease would change SC4/SC2b.", "justification": "No named verified pending result is asserted likely to move the full class-wide initiation score imminently. A selective pre-onset pathogen/epitope intervention with incident disease would change SC4/SC2b." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Β", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Editorial categorical verdict and index guidance visible; no blinded grading claimed.", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Β", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "In baseline infection-negative, genotype- and tolerance-function-characterized cohorts, prevent a specific pathogen before seroconversion or selectively block a prespecified cross-reactive epitope while preserving antiviral immunity. Follow incident disease and matched antigen-specific clones, with independently replicated infection exposure and disease ascertainment; in parallel use physiological pathogen mimic-loss and restored-mimic rescue with functional pathology.", "readout": "Incident adjudicated autoimmune disease, onset time, organ function, pathogen acquisition/clearance, antigen-specific autoreactivity and baseline-to-onset tolerance function", "critical_control": "Genotype, age, prior infection, vaccination, baseline autoantibodies/tolerance, tissue injury, clinical stage, target engagement and antiviral competence; pathogen variants with matched fitness", "supporting_result": "Preventing or subtracting the defined infectious mediator reduces incident disease and restored mimic rescues the matched phenotype in the predicted baseline context", "falsifying_result": "Verified infection or mimic suppression leaves onset unchanged, or genotype/tissue injury explains disease without the proposed infectious route" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Separate EBV exposure causality from which mimic, viral program or B-cell route mediates human MS onset.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Measure baseline tolerance before disease rather than infer a genetic deficiency from post-onset inflammation.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Test physiological infection-time mimic subtraction with neurological outcomes, retaining normal-host resistance and bacterial fitness controls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Replicate stage-specific antiviral effects and link benefit to verified tissue viral engagement; new-onset preservation is distinct from prevention.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Map protective and harmful microbial effects by baseline genotype, sex, diet and disease; do not treat all commensals as pathogens.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Reconcile recurring cohort and isolate-platform overlap before claiming independent convergence.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Before public comparison, state the weakest-link sensitivity created by a descriptive existence subclaim; prospectively improve future decomposition rather than silently adjust this review.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-07", "reviewer": "Codex", "evidence_base_note": "70 primary reports; literature cutoff 2026-10-07; source examination UTC date 2026-10-07; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Inborn tolerance errors plus acute conditional manipulation and aligned therapeutic trajectory change make Η reachable for SC3. GBS exposure/strain differences plus molecular manipulation and neuropathy support Ζ in defined scope. EBV seroconversion is a strong temporal causal argument, and no RCT is demanded in principle. The nominal class-wide infection initiation link lacks selective pre-onset mediation; T1D C-peptide preservation, vaccine immunogenicity and uncontrolled progressive-MS cell therapy do not fill that gap." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Inborn tolerance errors plus acute conditional manipulation and aligned therapeutic trajectory change make Η reachable for SC3. GBS exposure/strain differences plus molecular manipulation and neuropathy support Ζ in defined scope. EBV seroconversion is a strong temporal causal argument, and no RCT is demanded in principle. The nominal class-wide infection initiation link lacks selective pre-onset mediation; T1D C-peptide preservation, vaccine immunogenicity and uncontrolled progressive-MS cell therapy do not fill that gap." }, { "kind": "dose_response_across_populations", "available": true, "why_not_sufficient": "Inborn tolerance errors plus acute conditional manipulation and aligned therapeutic trajectory change make Η reachable for SC3. GBS exposure/strain differences plus molecular manipulation and neuropathy support Ζ in defined scope. EBV seroconversion is a strong temporal causal argument, and no RCT is demanded in principle. The nominal class-wide infection initiation link lacks selective pre-onset mediation; T1D C-peptide preservation, vaccine immunogenicity and uncontrolled progressive-MS cell therapy do not fill that gap." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Inborn tolerance errors plus acute conditional manipulation and aligned therapeutic trajectory change make Η reachable for SC3. GBS exposure/strain differences plus molecular manipulation and neuropathy support Ζ in defined scope. EBV seroconversion is a strong temporal causal argument, and no RCT is demanded in principle. The nominal class-wide infection initiation link lacks selective pre-onset mediation; T1D C-peptide preservation, vaccine immunogenicity and uncontrolled progressive-MS cell therapy do not fill that gap." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Inborn tolerance errors plus acute conditional manipulation and aligned therapeutic trajectory change make Η reachable for SC3. GBS exposure/strain differences plus molecular manipulation and neuropathy support Ζ in defined scope. EBV seroconversion is a strong temporal causal argument, and no RCT is demanded in principle. The nominal class-wide infection initiation link lacks selective pre-onset mediation; T1D C-peptide preservation, vaccine immunogenicity and uncontrolled progressive-MS cell therapy do not fill that gap." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 70, "claims_total": 77, "claims_verified": 77, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 70, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "EBV seroconversion precedes incident MS and neurofilament rise; CMV provides an exposure negative control. Prospective natural exposure strongly constrains reverse causation but does not isolate mimicry or baseline tolerance mediation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C2", "text": "Patient-derived antibody cross-binds EBNA1 and GlialCAM; peptide immunization aggravates PLP-induced EAE. Selected Results show induced EAE amplification rather than spontaneous MS initiation or selective human mimic necessity.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:Molecular mimicry between EBNA1AA386–405 and GlialCAM, 5:Phosphorylation of GlialCAMAA370–389 at pSer376 enables MS CSF-derived MS39p2w174 binding, 7:Immunization with EBNA1AA386–405 aggravates EAE. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C3", "text": "Prediagnostic EBV peptidome responses are increased without one selectively targeted peptide. Small military nested cohort shares a repository with other reports; adjusted estimates and wide intervals limit unique epitope inference.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2b" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C4", "text": "HLA-DR15 presents self and foreign peptides to cross-reactive patient T-cell clones. Immunopeptidomics and ex vivo recognition do not establish which antigen first caused human onset.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C5", "text": "GlialCAM/EBNA1 reciprocal blocking confirms cross-reactivity and HLA-associated risk patterns. Established-case serology and overlapping mimic cohorts cannot establish onset mediation.", "carries_number": true, "load_bearing_for": [ "SC2b" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C6", "text": "EBNA1/CRYAB reciprocal blocking and mouse responses support cross-reactive immunity. Risk serology and immunization do not isolate CRYAB as a necessary initiator of MS.", "carries_number": true, "load_bearing_for": [ "SC2b" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C7", "text": "ANO2 pre-immunization and transferred CD4 cells exacerbate EAE; human clones cross-recognize EBNA1. Induced EAE enhancement is a phenotype but does not establish spontaneous human onset necessity.", "carries_number": true, "load_bearing_for": [ "SC2b" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C8", "text": "EBV-expanded T-cell lines recognize CNS antigens in both MS and healthy controls. Cross-reactivity also in controls limits disease-specific sufficiency; peripheral viral load is unchanged.", "carries_number": false, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C9", "text": "BENEFIT antibody titres do not predict CIS conversion or subsequent clinical/MRI activity. A post-CIS titre null does not test preventing EBV infection before initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C10", "text": "ANO2/EBNA1 blocking and genotype combinations link cross-reactivity to MS risk. Case-control antibody positivity occurs in a minority and does not demonstrate individual causal initiation.", "carries_number": true, "load_bearing_for": [ "SC2b" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C11", "text": "ANO2 differs in MS but GlialCAM/CRYAB responses and disease-phase signatures do not distinguish consistently. Cross-sectional assay/cohort heterogeneity qualifies universal mimic or reactivation narratives.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C12", "text": "Late EBV exposure and recalled mononucleosis associate with MS in a high-prevalence region. Recall and geographic contrasts do not isolate infection timing from correlated exposures.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C13", "text": "Prediagnostic maternal/offspring EBV antibody associations recur with CMV comparison. Maternal antibodies are not the child's measured infection; observational confounding remains.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C14", "text": "EBV reprograms HLA-DR15 B-cell presentation of MBP peptides recognized by MS T cells. Human tissue alignment and infected-cell experiments support a route distinct from proving onset through molecular mimicry.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C15", "text": "MS CD4 responses preferentially target late-lytic EBV antigens and fall after anti-CD20 treatment. B-cell depletion changes multiple immune functions; reduced responses or shedding do not isolate viral initiation.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C16", "text": "Expanded CSF CD8 clonotypes include functionally EBV-reactive receptors; many mimotopes fail functional response. Established-disease antigen specificity and the updated preprint are one report lineage, not prospective onset proof.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C17", "text": "LMP1 or CD40L overrides death of antigen-capturing myelin-reactive B cells and enables lesions. Engineered viral-protein signaling tests a bounded route; ectopic expression cannot establish endogenous human primacy alone.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C18", "text": "Open-label EBV-specific T-cell treatment is feasible and clinical improvement tracks product reactivity. Small uncontrolled progressive-MS phase I trial does not prove efficacy or prevention; linked erratum details unexamined.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C19", "text": "Recent Campylobacter infection is enriched in incident GBS and links to motor/axonal severity. Case-control antecedence does not alone prove mimicry or explain non-Campylobacter GBS.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2a", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C20", "text": "Bacterial LOS class and sialyltransferase genotype distinguish neuropathy from uncomplicated enteritis isolates. Isolate ascertainment and linked strain features limit attributing clinical risk to one gene alone.", "carries_number": false, "load_bearing_for": [ "SC2a" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C21", "text": "GBS isolates preferentially express GD1a-like mimicry with relevant biosynthesis genes. Strain association is not a selective onset intervention.", "carries_number": true, "load_bearing_for": [ "SC2a" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C22", "text": "Anti-GM1 positivity associates with recent Campylobacter and a severe motor phenotype. Antibody-positive disease subgroups are not all GBS and observational treatment differences are not randomized mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2a" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C23", "text": "Serial conduction studies reclassify transient Campylobacter-related demyelinating patterns as axonal neuropathy. Clinical classification depends on timing; this limits broad demyelination transfer but does not refute axonal mimicry.", "carries_number": false, "load_bearing_for": [ "SC2a", "SC5" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C24", "text": "GBS-strain LPS immunization induces GM1-cross-reactive rabbit antibodies. Antibody induction alone is not demonstrated neuropathic functional injury.", "carries_number": true, "load_bearing_for": [ "SC2a" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C25", "text": "Cloned glycosyltransferases synthesize defined ganglioside-like structures with linkage confirmation. Biochemical biosynthesis establishes the molecular mimic rather than human disease necessity.", "carries_number": false, "load_bearing_for": [ "SC2a" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C26", "text": "GBS/MFS LPS induces matched antibody specificity; control-strain LPS lacks ganglioside reactivity. Immunization establishes antigen specificity without showing spontaneous infection produces neuropathy in every host.", "carries_number": false, "load_bearing_for": [ "SC2a" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C27", "text": "cst-II polymorphism aligns bacterial mimic, patient autoantibody and neurological phenotype. Same clinical isolate platform can share failure modes with other genotype association reports.", "carries_number": false, "load_bearing_for": [ "SC2a" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C28", "text": "NMR and chemical analysis identify a GM1-identical terminal bacterial oligosaccharide. Structural identity is not alone a causal neurological experiment.", "carries_number": true, "load_bearing_for": [ "SC2a" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C29", "text": "Anti-GD1a antibody plus complement injures high-antigen motor terminals and blocks function. Tolerance bypass and ganglioside-overexpressing recipients are engineered; normal mice resist the same exposure.", "carries_number": true, "load_bearing_for": [ "SC2a" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C30", "text": "LOS-sensitized rabbits develop anti-GM1 antibodies, weakness and GBS-like peripheral pathology. Patient/mouse antibody blocks coculture potentials but does not itself induce paralysis; selected full body unavailable.", "carries_number": true, "load_bearing_for": [ "SC2a", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C31", "text": "cst-II/orf10 loss removes sialylated mimics and anti-GD1a induction while orf11 is a negative control. Original publisher Methods use ganglioside-deficient mice and repeated adjuvant immunization; asialo-GM1 responses remain and neuropathy was not measured.", "carries_number": true, "load_bearing_for": [ "SC2a" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph62, 0:Publisher HTML paragraphs:paragraph65, 0:Publisher HTML paragraphs:paragraph70, 0:Publisher HTML paragraphs:paragraph82, 0:Publisher HTML paragraphs:paragraph92. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C32", "text": "Some neuropathy-associated isolates lack detectable ganglioside mimics or have frameshifted biosynthesis genes. Post-isolation phase variation may differ from infection-time expression; these are boundaries rather than definitive mimic absence at onset.", "carries_number": false, "load_bearing_for": [ "SC2a", "SC5" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C33", "text": "Foxp3-lineage neuritin loss causes abnormal germinal-center/plasma-cell autoimmunity with reconstitution effects. Rescue primarily changes cellular/antibody endpoints and does not establish infection initiation.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C34", "text": "Treg-specific CTLA4 loss causes spontaneous fatal autoimmune disease. Conditional lineage specificity supports tolerance function; developmental/immune interactions do not establish a universal trigger.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C35", "text": "Independent human CTLA4 variants impair regulatory function and produce immune dysregulation with incomplete penetrance. Unaffected carriers invalidate complete-penetrance claims; no measured infectious mimic is required by the proposed genotype mechanism.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C36", "text": "Abatacept controls manifestations in a genotype-defined LRBA/CTLA4 cohort. Nonrandomized treatment allocation and disease-duration differences limit comparative superiority estimates.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C37", "text": "Engineered dominant AIRE mutations disrupt central tolerance and alter chromatin/transcription. Mutant-line developmental biology and expression changes do not prove ordinary sporadic autoimmunity is AIRE-deficient.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C38", "text": "Aire-deficient thymic stroma loses tissue-antigen transcription and supports defined autoimmunity. Constitutive loss has developmental confounds; thymic localization narrows but does not remove them.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C39", "text": "Human FOXP3 mutations segregate with IPEX immune dysregulation. Rare syndromic causality is not a class-wide requirement for pathogenic FOXP3 variants.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C40", "text": "Independent IPEX sequencing finds forkhead-domain FOXP3 variants matching scurfy biology. Genetic identification alone does not measure a specific infection or explain all polygenic disease.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C41", "text": "CD25-cell removal permits autoimmune disease and timely reconstitution prevents it. Athymic transfer and imperfect CD25 lineage specificity constrain physiology; adult conditional depletion is an orthogonal follow-up.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C42", "text": "Acute neonatal/adult Foxp3-Treg ablation causes autoimmunity without lifelong gene-loss dependence. Mouse induced depletion establishes ongoing regulatory necessity, not that human infection always removes Tregs.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C43", "text": "Human CTLA4 haploinsufficiency causes cellular dysregulation and wild-type complementation corrects ex vivo proliferation. Original text preserves healthy carriers and culture rescue; common disease initiation is a separate scope.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph3, 1:Main text:paragraph5, 1:Main text:paragraph6, 1:Main text:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C44", "text": "PD1 loss produces background-dependent lupus-like autoimmunity accelerated by Fas loss. Constitutive immune development and genetic background limit generalization.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C45", "text": "BALB/c PD1 loss causes autoimmune cardiomyopathy while RAG2 deficiency prevents it. B/T-cell dependency and strain context do not identify an infectious initiator.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C46", "text": "Inherited human PD1 deficiency impairs antimycobacterial immunity and causes immune dysregulation. Single affected child with TB cannot independently determine whether infection or tolerance loss initiated each lesion.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C47", "text": "Incident T1D follows checkpoint therapy with regimen and baseline-disease risk contrasts. Administrative coding and nonrandomized therapy comparisons constrain incidence attribution; survival analysis is vulnerable to time-dependent selection.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C48", "text": "Established-SLE EBV-positive B cells encode nuclear autoreactivity and transformed chromatin-loaded cells activate autologous helper/B cells. Original Results use diagnosed patients and cell-line genomic datasets; no prediagnostic onset sequence or selective in vivo viral depletion is established.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph1, 0:Results:paragraph10, 0:Results:paragraph11, 0:Results:paragraph17, 0:Results:paragraph18, 0:Results:paragraph19, 0:Results:paragraph20. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C49", "text": "Oligodendrocyte ablation precedes delayed adaptive demyelination; transfer and MOG tolerization change disease. Engineered tissue injury establishes an alternative route in a model, not proof that human MS routinely begins without EBV.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C50", "text": "Sensing the same diabetogenic virus differently through MDA5/TLR3 changes diabetes risk and can protect. Sensor, local interferon and host state determine sign; this is not a universal infection-to-disease rule.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C51", "text": "TEDDY prolonged enterovirus-B shedding associates with islet autoimmunity but not T1D incidence. Repeated stools measure exposure patterns and surrogate seroconversion, not necessary clinical initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C52", "text": "Virome changes precede autoimmunity but common enterovirus sequences do not associate in this small cohort. Small sample and linked correction details unexamined limit precise diversity inference.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C53", "text": "TLR3 knockout protects female NOD from CB4 diabetes and reduces insulitis versus matched uninfected controls. Constitutive receptor loss and forced viral challenge establish model-specific causal contribution.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C54", "text": "Affinity-purified recent-onset T1D antibodies cross-bind viral/islet antigens and induce beta-cell apoptosis. Culture killing does not establish the infection-to-human-onset chain; SC2b comparison illustrates mimicry transfer limits, not MS evidence.", "carries_number": true, "load_bearing_for": [ "SC2b", "SC4", "SC5" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C55", "text": "Enterovirus infections precede islet autoantibodies in genetically at-risk children. Formula allocation was randomized; viral infection exposure was not randomized and clinical T1D causality is unproven.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C56", "text": "Randomized new-onset antiviral combination preserves stimulated C-peptide on the primary repeated-measures analysis. Post-diagnosis functional secretion is not prevention; peripheral PCR is negative, drug effects cannot be separated, and insulin-dose/12-month HbA1c contrasts are null.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph14, 1:Results:paragraph15, 2:Discussion:paragraph2, 2:Discussion:paragraph3, 2:Discussion:paragraph5, 2:Discussion:paragraph8, 3:Methods:paragraph11, 3:Methods:paragraph12, 3:Methods:paragraph15, 3:Methods:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C57", "text": "Phase-I CVB vaccine is tolerable and induces neutralizing responses. Healthy-adult safety/immunogenicity without autoimmune incidence outcomes does not prove prevention.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C58", "text": "Prediagnostic islet-autoantibody subgroups differ in transcription and antiviral-response signatures. Cell composition, genotype and response correlates do not isolate infectious initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C59", "text": "TEDDY enterovirus exposure interacts with gluten intake in celiac autoimmunity risk. Nested observational analysis with autoantibody endpoint shares TEDDY data and does not remove the causal dietary antigen.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C60", "text": "Germ-free MyD88-null NOD regain diabetes and defined commensal colonization attenuates it. Original Results show protective microbiota and retained diabetogenic cells, with genotype/housing limits and no human prevention demonstration.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph2, 2:Main text:paragraph4, 2:Main text:paragraph5, 2:Main text:paragraph12, 2:Main text:paragraph13. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C61", "text": "E. gallinarum translocation induces autoimmunity in predisposed mice and pathogen-directed vaccine prevents mortality. Human liver DNA is associative; antibiotic pleiotropy and induced colonization do not establish spontaneous human initiation; correction attached.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C62", "text": "L. reuteri colonization worsens TLR7-linked lupus and resistant starch lowers translocation and disease. Strain, diet and transgenic host set context; human fecal enrichment is not onset mediation.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C63", "text": "Aa leukotoxin causes neutrophil hypercitrullination matching RA antigen patterns. Human exposure/ACPA association and ex vivo toxin action do not establish necessary RA onset.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C64", "text": "Aa endocarditis eradication coincides with sustained arthritis and ACPA resolution in one genetically at-risk patient. One RA-like infection-associated case lacks randomized withdrawal/rechallenge and cannot establish ordinary RA primacy.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C65", "text": "One Subdoligranulum isolate causes arthritic autoimmunity in germ-free mice and lymphocyte depletion eliminates disease. At-risk human antibody selection plus germ-free strain challenge proves a bounded route rather than all RA initiation.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C66", "text": "SFB colonization restores Th17/autoantibodies and arthritis in germ-free K/BxN; IL17 neutralization prevents arthritis. Transgenic host and immune background set context; one commensal can have the opposite sign in NOD diabetes.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C67", "text": "Naturally acquired SFB segregates with diabetes protection in female NOD despite persistent insulitis. Colonization is naturally incomplete and observational within the facility; sex dependence limits mechanistic certainty.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C68", "text": "Early H. microstoma infection suppresses spontaneous lupus manifestations in NZBWF1. Parasitic immune pleiotropy and unsuccessful nematode settlement limit target specificity and human transfer.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C69", "text": "HBV-transgenic mice have reduced pristane-lupus renal and antibody pathology. The actual manipulation is a transgene, not acquired HBV infection; the abstract's human-protection conclusion is unsupported by this experiment.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 69 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C70", "text": "RA oral/gut microbiota vary with disease and partly normalize after treatment. Treatment-associated normalization permits reverse causation and does not show dysbiosis first initiated RA.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 70 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC1", "text": "Prediagnostic EBV seroconversion and C. jejuni antecedence are reproducible with temporal and exposure controls. This registered descriptive existence claim has no selective causal manipulation of its own and is graded Β. Its formal minimum must not re-cap the independent mechanistic evidence assessed separately.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 3, 9, 12, 13, 19, 22, 51, 52, 55, 58, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC2a", "text": "Within defined bacterial/ganglioside genotypes, chemical identity, bacterial mimic subtraction, matched antibody specificity, rabbit neuropathy and clinical isolate/phenotype contrasts converge across errors. Ζ credits the causal set, not the mutant antibody biomarker alone. Host resistance, non-mimicking isolates and absent human selective prevention limit Η and broader GBS sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2a" ], "source_ns": [ 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC2b", "text": "EBNA1/GlialCAM, ANO2 and CRYAB cross-reactivity has human and functional support, but original Lanz Results show enhancement of induced EAE. ANO2 transfer and 2026 B-cell presentation/viral-signaling studies add model support without selective endogenous human mimic necessity at onset. The registered initiation link remains Γ.", "carries_number": false, "load_bearing_for": [ "SC2b" ], "source_ns": [ 2, 3, 4, 5, 6, 7, 8, 10, 11, 14, 15, 16, 17, 54 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC3", "text": "Human FOXP3/CTLA4 inborn errors, lineage-specific CTLA4 loss, acute adult Treg removal and time-dependent reconstitution establish ongoing tolerance causality. Genotype-aligned abatacept changes clinical trajectories. Different failure structures support Η; incomplete penetrance, developmental effects and multiple tolerance routes prevent Θ/Ω for all pathways.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 4, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC4", "text": "A coherent infection-to-autoimmune injury route is established in defined C. jejuni/ganglioside settings, with rare human Aa eradication evidence and model perturbations in other diseases. EBV antecedence strongly supports an upstream MS risk role without identifying the initiating mimic. Prediagnostic baseline tolerance breakdown and onset mediation across human diseases are unresolved, so context-specific Ε is retained.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 8, 9, 11, 13, 14, 15, 16, 17, 18, 19, 30, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC5", "text": "Causal microbial routes have positive and protective signs across genotypes and diseases. SFB promotes K/BxN arthritis but associates with female NOD protection; germ-free MyD88-null NOD develop diabetes. Thus bounded causality exists but the class-wide initiation generalization fails: Ε, not a denial that particular infections are causes.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 23, 32, 35, 43, 44, 45, 47, 48, 49, 50, 51, 52, 53, 54, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CH", "text": "Infection can trigger specific autoimmune pathways; a single infection-first account does not explain autoimmunity across diseases.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 30, 31, 2, 35, 60, 48 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-07", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Bjornevik K, Cortese M, Healy BC et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science (New York, N.Y.). 2022.", "tier": "A", "kind": "primary", "pmid": "35025605", "doi": "10.1126/science.abj8222", "url": "https://pubmed.ncbi.nlm.nih.gov/35025605/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "DOD-serorepository-EBV-MS", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC4", "CH" ] }, { "n": 2, "citation": "Lanz TV, Brewer RC, Ho PP et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "35073561", "doi": "10.1038/s41586-022-04432-7", "url": "https://pubmed.ncbi.nlm.nih.gov/35073561/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35073561", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:Molecular mimicry between EBNA1AA386–405 and GlialCAM, 5:Phosphorylation of GlialCAMAA370–389 at pSer376 enables MS CSF-derived MS39p2w174 binding, 7:Immunization with EBNA1AA386–405 aggravates EAE. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2b", "CSC4", "CH" ] }, { "n": 3, "citation": "Cortese M, Leng Y, Bjornevik K et al. Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis. JAMA neurology. 2024.", "tier": "A", "kind": "primary", "pmid": "38497939", "doi": "10.1001/jamaneurol.2024.0272", "url": "https://pubmed.ncbi.nlm.nih.gov/38497939/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "DOD-serorepository-EBV-MS-peptidome", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC2b" ] }, { "n": 4, "citation": "Wang J, Jelcic I, Mühlenbruch L et al. HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis. Cell. 2020.", "tier": "A", "kind": "primary", "pmid": "33091337", "doi": "10.1016/j.cell.2020.09.054", "url": "https://pubmed.ncbi.nlm.nih.gov/33091337/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID33091337", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC2b", "CSC3" ] }, { "n": 5, "citation": "Sattarnezhad N, Kockum I, Thomas OG et al. Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls. Proceedings of the National Academy of Sciences of the United States of America. 2025.", "tier": "A", "kind": "primary", "pmid": "40063790", "doi": "10.1073/pnas.2424986122", "url": "https://pubmed.ncbi.nlm.nih.gov/40063790/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Swedish-EBNA1-mimic-cohorts", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC2b" ] }, { "n": 6, "citation": "Thomas OG, Bronge M, Tengvall K et al. Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Science advances. 2023.", "tier": "A", "kind": "primary", "pmid": "37196088", "doi": "10.1126/sciadv.adg3032", "url": "https://pubmed.ncbi.nlm.nih.gov/37196088/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Swedish-EBNA1-mimic-cohorts", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2b" ] }, { "n": 7, "citation": "Thomas OG, Rykaczewska U, Galešić M et al. Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis. Cell. 2026.", "tier": "A", "kind": "primary", "pmid": "41534529", "doi": "10.1016/j.cell.2025.12.032", "url": "https://pubmed.ncbi.nlm.nih.gov/41534529/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41534529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC2b" ] }, { "n": 8, "citation": "Thomas OG, Haigh TA, Croom-Carter D et al. Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis. PLoS pathogens. 2024.", "tier": "A", "kind": "primary", "pmid": "38843296", "doi": "10.1371/journal.ppat.1012177", "url": "https://pubmed.ncbi.nlm.nih.gov/38843296/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38843296", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC2b", "CSC4" ] }, { "n": 9, "citation": "Munger KL, Fitzgerald KC, Freedman MS et al. No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT. Neurology. 2015.", "tier": "A", "kind": "rct", "pmid": "26453645", "doi": "10.1212/WNL.0000000000002099", "url": "https://pubmed.ncbi.nlm.nih.gov/26453645/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID26453645", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC4" ] }, { "n": 10, "citation": "Tengvall K, Huang J, Hellström C et al. Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. 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Frontiers in immunology. 2024.", "tier": "A", "kind": "primary", "pmid": "39742283", "doi": "10.3389/fimmu.2024.1487523", "url": "https://pubmed.ncbi.nlm.nih.gov/39742283/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39742283", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC2b", "CSC4" ] }, { "n": 12, "citation": "Haahr S, Plesner AM, Vestergaard BF et al. A role of late Epstein-Barr virus infection in multiple sclerosis. 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JCI insight. 2018.", "tier": "A", "kind": "primary", "pmid": "30429369", "doi": "10.1172/jci.insight.124714", "url": "https://pubmed.ncbi.nlm.nih.gov/30429369/", "status_flags": [ "ErratumIn: PMID33055421" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "EBV-T-cell-MS-phase1", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC4" ] }, { "n": 19, "citation": "Rees JH, Soudain SE, Gregson NA et al. Campylobacter jejuni infection and Guillain-Barré syndrome. 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Annals of neurology. 1996.", "tier": "A", "kind": "primary", "pmid": "8773599", "doi": "10.1002/ana.410400209", "url": "https://pubmed.ncbi.nlm.nih.gov/8773599/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID8773599", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC1", "CSC2a" ] }, { "n": 23, "citation": "Kuwabara S, Ogawara K, Misawa S et al. Does Campylobacter jejuni infection elicit \"demyelinating\" Guillain-Barre syndrome? Neurology. 2004.", "tier": "A", "kind": "primary", "pmid": "15304587", "doi": "10.1212/01.wnl.0000133205.05169.04", "url": "https://pubmed.ncbi.nlm.nih.gov/15304587/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID15304587", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC2a", "CSC5" ] }, { "n": 24, "citation": "Ang CW, Endtz HP, Jacobs BC et al. Campylobacter jejuni lipopolysaccharides from Guillain-Barré syndrome patients induce IgG anti-GM1 antibodies in rabbits. 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Infection and immunity. 2001.", "tier": "A", "kind": "primary", "pmid": "11254608", "doi": "10.1128/IAI.69.4.2462-2469.2001", "url": "https://pubmed.ncbi.nlm.nih.gov/11254608/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11254608", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC2a" ] }, { "n": 27, "citation": "Koga M, Takahashi M, Masuda M et al. Campylobacter gene polymorphism as a determinant of clinical features of Guillain-Barré syndrome. 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Infection and immunity. 2007.", "tier": "A", "kind": "primary", "pmid": "17261613", "doi": "10.1128/IAI.00872-06", "url": "https://pubmed.ncbi.nlm.nih.gov/17261613/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Dutch-GBS-Campylobacter-isolate-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C32", "CSC2a", "CSC5" ] }, { "n": 33, "citation": "Gonzalez-Figueroa P, Roco JA, Papa I et al. Follicular regulatory T cells produce neuritin to regulate B cells. 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Nature genetics. 2001.", "tier": "A", "kind": "primary", "pmid": "11137992", "doi": "10.1038/83707", "url": "https://pubmed.ncbi.nlm.nih.gov/11137992/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11137992", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C40", "CSC3" ] }, { "n": 41, "citation": "Sakaguchi S, Sakaguchi N, Asano M et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of immunology (Baltimore, Md. : 1950). 1995.", "tier": "A", "kind": "primary", "pmid": "7636184", "doi": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7636184/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID7636184", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C41", "CSC3" ] }, { "n": 42, "citation": "Kim JM, Rasmussen JP, Rudensky AY et al. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. 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Endocrinology. 2015.", "tier": "A", "kind": "primary", "pmid": "25422874", "doi": "10.1210/en.2013-2006", "url": "https://pubmed.ncbi.nlm.nih.gov/25422874/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25422874", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C53", "CSC4", "CSC5" ] }, { "n": 54, "citation": "Bason C, Lorini R, Lunardi C et al. In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells. 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Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial. Diabetologia. 2024.", "tier": "A", "kind": "rct", "pmid": "38369573", "doi": "10.1007/s00125-024-06092-w", "url": "https://pubmed.ncbi.nlm.nih.gov/38369573/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38369573", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C57", "CSC4" ] }, { "n": 58, "citation": "Lin J, Moradi E, Salenius K et al. Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection. 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Science translational medicine. 2022.", "tier": "A", "kind": "primary", "pmid": "36288282", "doi": "10.1126/scitranslmed.abn5166", "url": "https://pubmed.ncbi.nlm.nih.gov/36288282/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID36288282", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C65", "CSC4", "CSC5" ] }, { "n": 66, "citation": "Wu HJ, Ivanov II, Darce J et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. 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No complete-paper or supplement audit claimed.", "carries_claims": [ "C70", "CSC4", "CSC5" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Clinical pathogen-genotype/phenotype alignment", "sources": [ 19, 27, 20 ], "excludes_error": "Tests actual infection-linked clinical patterns independently of induced model adjuvants, while retaining ascertainment confounding." }, { "label": "Bacterial mimic subtraction and structural chemistry", "sources": [ 31, 25, 28 ], "excludes_error": "Changes and verifies the molecular epitope, excluding mere coincidental serology; mutant immunization alone measures antibodies." }, { "label": "Organismal neuropathic outcome", "sources": [ 30, 29 ], "excludes_error": "Links immune specificity to weakness and nerve injury, with species/antigen-density and immunization confounds distinct from patient ascertainment." }, { "label": "Human tolerance natural experiments", "sources": [ 39, 40, 35, 43 ], "excludes_error": "Inherited regulatory lesions exclude infection association as the sole source of self-reactivity; penetrance and rare-genotype scope remain." }, { "label": "Acute lineage depletion and reconstitution", "sources": [ 42, 34, 41 ], "excludes_error": "Adult loss and timed rescue narrow lifelong developmental or familial co-variant explanations." }, { "label": "Genotype-aligned clinical therapy", "sources": [ 36 ], "excludes_error": "CTLA4-Ig trajectory effects support regulator function through a different instrument, with nonrandomized selection retained." } ], "shared_failure_mode_checked": true, "note": "70 primary reports are not 70 causal lines. DOD, TEDDY, Swedish mimic cohorts and clinical Campylobacter isolate platforms recur. GBS, intrinsic tolerance and general infection initiation are different claims: evidence cannot be pooled across them to manufacture convergence for a universal initiator. The GBS Ζ and tolerance Η sets exclude different clinical, molecular and developmental errors; exact cohort overlap remains only partly audited." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the Campylobacter/ganglioside and inherited-tolerance literatures are replicated across independent laboratories and instrument classes, while much of the remaining mimicry evidence rests on induced or engineered systems, the microbial results change sign with strain, sex, diet and housing, the abatacept cohort is nonrandomized, and recurrence of the same serorepositories and clinical isolate platforms is only partly audited.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered weakest-link rule returns Β because the descriptive antecedence subclaim SC1 is associational. This is an aggregation limitation, not a finding that all infection causality is merely correlational: defined Campylobacter/ganglioside GBS convergence reaches Ζ, intrinsic tolerance necessity Η, and broader context-dependent initiation Ε. Primary-subclaim and scope-matched sensitivities return Ε. Human MS mimic-specific initiation remains Γ. Do not publish the overall letter without this subclaim explanation or interpret it as refuting EBV risk causality." }, "score_after": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the Campylobacter/ganglioside and inherited-tolerance literatures are replicated across independent laboratories and instrument classes, while much of the remaining mimicry evidence rests on induced or engineered systems, the microbial results change sign with strain, sex, diet and housing, the abatacept cohort is nonrandomized, and recurrence of the same serorepositories and clinical isolate platforms is only partly audited.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered weakest-link rule returns Β because the descriptive antecedence subclaim SC1 is associational. This is an aggregation limitation, not a finding that all infection causality is merely correlational: defined Campylobacter/ganglioside GBS convergence reaches Ζ, intrinsic tolerance necessity Η, and broader context-dependent initiation Ε. Primary-subclaim and scope-matched sensitivities return Ε. Human MS mimic-specific initiation remains Γ. Do not publish the overall letter without this subclaim explanation or interpret it as refuting EBV risk causality." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\infection-triggered-autoimmunity\\consensus\\broad-browser-snapshot.txt", "sha256": "239cd23999f28151203debe2ae18e119bbeb3569b49d427bbffd8e013b46d87e" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\infection-triggered-autoimmunity\\consensus\\query-ledger.json", "sha256": "a6803eb4c1267f0d7169d2757682c9bf862cce30a910505ec6356416f254b994" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\infection-triggered-autoimmunity\\consensus\\reconciliation.md", "sha256": "07ccc9c06636978cf885e75769a0ef4fb67a6ec42d42c8e214239e67f6521e66" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\infection-triggered-autoimmunity\\consensus\\targeted-browser-snapshot.txt", "sha256": "8ea9a75832f88a3a07b9f6aa7852e0f552aec0ac3494767c601c6a5369f42baf" } ], "limitations": "This verifies documented historical use and links the record to the final edition. It adds no primary-source, full-text, independence or verification credit. Original access remains limited to the source-specific record." } }