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Pathogenic autoantibodies in multiple sclerosis — from a simple idea to a complex concept

Abstract

The role of autoantibodies in multiple sclerosis (MS) has been enigmatic since the first description, many decades ago, of intrathecal immunoglobulin production in people with this condition. Some studies have indicated that MS pathology is heterogeneous, with an antibody-associated subtype — characterized by B cells (in varying quantities), antibodies and complement — existing alongside other subtypes with different pathologies. However, subsequent evidence suggested that some cases originally diagnosed as MS with autoantibody-mediated demyelination were more likely to be neuromyelitis optica spectrum disorder or myelin oligodendrocyte glycoprotein antibody-associated disease. These findings raise the important question of whether an autoantibody-mediated MS subtype exists and whether pathogenic MS-associated autoantibodies remain to be identified. Potential roles of autoantibodies in MS could range from specific antibodies defining the disease to a non-disease-specific amplification of cellular immune responses and other pathophysiological processes. In this Perspective, we review studies that have attempted to identify MS-associated autoantibodies and provide our opinions on their possible roles in the pathophysiology of MS.

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Fig. 1: Potential mechanisms of antibody pathogenicity in multiple sclerosis.
Fig. 2: Neuropathology of tumefactive MS and MOGAD.

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Acknowledgements

The research of R.H. is supported by research grants from the Austrian Science Funds (FWF; project I4685-B SYNABS; DOC 33-B27 and I3334-B27 SILENCE). The research of M.R. is supported by research grants from FWF (project P32699) and the Austrian Research Promotion Agency (FFG, COMET Centre VASCage).

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Correspondence to Markus Reindl.

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The University Hospital and Medical University of Innsbruck, Austria (M.R.) and Vienna, Austria (R.H. and T.B.) receive payments for antibody assays (MOG, AQP4 and other autoantibodies) and for MOG and AQP4 antibody validation experiments organized by Euroimmun (Lübeck, Germany). H.L. declares no competing interests.

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Höftberger, R., Lassmann, H., Berger, T. et al. Pathogenic autoantibodies in multiple sclerosis — from a simple idea to a complex concept. Nat Rev Neurol (2022). https://doi.org/10.1038/s41582-022-00700-2

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