Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis

Abstract

The neuroinflammatory disease multiple sclerosis is driven by autoimmune pathology in the central nervous system. However, the trigger of the autoimmune pathogenic process is unknown. MS models in immunologically naïve, specific‐pathogen‐free bred rodents support an exogenous trigger, such as an infection. The validity of this outside–in pathogenic concept for MS has been frequently challenged by the difficulty to translate pathogenic concepts developed in these models into effective therapies for the MS patient. Studies in well‐validated non‐human primate multiple sclerosis models where, just like in humans, the autoimmune pathogenic process develops from an experienced immune system trained by prior infections, rather support an endogenous trigger. Data reviewed here corroborate the validity of this inside–out pathogenic concept for multiple sclerosis. They also provide a plausible sequence of events reminiscent of Wilkin’s primary lesion theory: (i) that autoimmunity is a physiological response of the immune system against excess antigen turnover in diseased tissue (the primary lesion) and (ii) that individuals developing autoimmune disease are (genetically predisposed) high responders against critical antigens. Data obtained in multiple sclerosis brains reveal the presence in normally appearing white matter of myelinated axons where myelin sheaths have locally dissociated from their enwrapped axon (i.e., blistering). The ensuing disintegration of axon–myelin units potentially causes the excess systemic release of post‐translationally modified myelin. Data obtained in a unique primate multiple sclerosis model revealed a core pathogenic role of T cells present in the normal repertoire, which hyper‐react to post‐translationally modified (citrullinated) myelin–oligodendrocyte glycoprotein and evoke clinical and pathological aspects of multiple sclerosis.

Lyso-Lipid-Induced Oligodendrocyte Maturation Underlies Restoration of Optic Nerve Function

“…Two paradigms for the pathogenesis of demyelinating diseases propose an initial event triggering an autoimmune response occurring outside the CNS (outside-in) or inside the CNS (inside-out; ‘t Hart et al, 2021 ). Consensus between these two paradigms has yet to be reached, with evidence supporting both hypotheses.…”

The Neuroimmunology of Multiple Sclerosis: Fictions and Facts

“…These two types of pathogenesis are, of course, not mutually exclusive, but the predominance of one hypothesis vs. the other has considerable significance for research directions and possible therapeutic targeting. The arguments for these two contrasting hypotheses are extensive and beyond the scope of this review but have been summarized in multiple recent review articles ( 24 – 26 ).…”

Relevance of Pathogenetic Mechanisms to Clinical Effectiveness of B-Cell-Depleting Monoclonal Antibodies in Multiple Sclerosis

“…On the other hand, the “inside-out” model suggests that the autoimmune reaction is triggered by an “internal event” occurring within the CNS and generating myelin debris. CNS-derived soluble antigens may then be drained via lymphatic pathways to peripheral lymphoid organs, where they might be presented to T and B cells eliciting the autoimmune reaction [ 33 , 34 ]. Different hypotheses suggest that the CNS-intrinsic event might be triggered by a CNS viral infection or by primary neurodegeneration [ 11 ].…”