Authors
Simon Thebault, Ana-Luiza Abdalla, Samantha S Soldan, Adil Harroud, Jack P Antel
Published in
Neurology(R) neuroimmunology & neuroinflammation. Volume 14. Issue 1. Pages e200680. Epub Nov 11, 2026.
Abstract
Classical autoimmune postulates were developed for diseases driven by a dominant antigen or transferable effector mechanism. Multiple sclerosis (MS), despite compelling evidence of immune-mediated pathogenesis, has never mapped cleanly onto these classical frameworks. We propose that in complex autoimmune diseases such as MS, the proximate cause of sustained tissue injury may instead be a disease-defining immune state: a self-sustaining network of immune interactions that emerges when host susceptibility and environmental exposures converge to overcome tolerance, bridging peripheral immune dysregulation and tissue injury. The evolving Epstein-Barr virus (EBV) literature provides an informative test case for this concept. EBV exposure shows compelling epidemiologic evidence of temporality in relation to MS and may seed autoreactivity through molecular mimicry. Its lifelong persistence in antigen-experienced B cells also provides a plausible mechanism for sustaining pathogenic antigen-presentation circuits. In susceptible hosts, EBV may promote atypical antigen-presenting B-cell states, engage autoreactive and antiviral T-cell responses, and become enriched within compartmentalized CNS inflammation. Fluctuations in viral activity and antiviral immune surveillance may further modulate this state across disease stages. However, whether an EBV-conditioned immune state consistently precedes disease, quantitatively tracks disease activity, and drives tissue injury remains unresolved, and EBV-targeted interventions have not yet produced predictable clinical benefit. We therefore propose 5 postulates for causality in complex autoimmunity centered on host susceptibility, temporal precedence, establishment of a disease-defining immune state, mechanistic and anatomical linkage to tissue injury, and predictable response to intervention. Applied to EBV and MS, this framework distinguishes established evidence from remaining uncertainty, identifies the key unanswered questions, and provides a general approach for evaluating causality in complex autoimmune disease.
PMID:
43013799
Bibliographic data and abstract were imported from PubMed on 12 Nov 2026.
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