Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis
Open Access
- 22 June 2021
- journal article
- research article
- Published by Wiley in Annals of Clinical and Translational Neurology
- Vol. 8 (8), 1709-1719
- https://doi.org/10.1002/acn3.51401
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.Keywords
This publication has 70 references indexed in Scilit:
- Chronic autoimmune-mediated inflammation: a senescent immune response to injuryDrug Discovery Today, 2013
- Microglial nodules in early multiple sclerosis white matter are associated with degenerating axonsActa Neuropathologica, 2013
- The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple SclerosisFrontiers in Immunology, 2013
- Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cellsThe Journal of Experimental Medicine, 2011
- How Immune Peptidases Change Specificity: Cathepsin G Gained Tryptic Function but Lost Efficiency during Primate EvolutionThe Journal of Immunology, 2010
- Myelin‐associated glycoprotein and its axonal receptorsJournal of Neuroscience Research, 2009
- The origin and application of experimental autoimmune encephalomyelitisNature Reviews Immunology, 2007
- Positive and Negative Selection of T CellsAnnual Review of Immunology, 2003
- Contra: Evidence Against a Primary Lesion in the Target Organ in Autoimmune DiseaseInternational Archives of Allergy and Immunology, 1994
- Dominance and Crypticity of T Cell Antigenic DeterminantsAnnual Review of Immunology, 1993