Multiple sclerosis and autoimmunity: a reappraisal of the evidence

Our understanding of the mechanisms underlying multiple sclerosis (MS) has advanced substantially over recent decades, yet the primary drivers of disease onset and progression remain unclear. Immune dysregulation, particularly antibody-mediated processes and lymphocyte activation, is widely recognised as central to MS pathogenesis, and immune-targeted therapies have improved the management of relapsing disease. However, neither self-antigens nor self-antibodies have been definitively identified. This leaves open a fundamental question: does immune activation initiate MS, or does it arise in response to earlier pathological events? Most of our current knowledge relies on extrapolating findings from artificially induced models, which are mechanistically informative but may be limited in explaining spontaneous onset and responses to neurodegeneration in MS. Furthermore, the recent reclassification of conditions such as MOGAD and NMOSD, previously considered within the MS spectrum, has prompted renewed reflection on longstanding assumptions regarding MS aetiology. In this review, we refine the definition of autoimmune disease (AD) and apply a systematic, criterion-based evaluation of MS, complemented by direct comparison with well-established autoimmune conditions. Unlike previous reviews, which have largely addressed this question in conceptual terms, this paper explicitly examines whether MS fulfils the defining features of autoimmunity. By doing so, we highlight conceptual and evidentiary gaps that remain unresolved. Clarifying whether MS should be defined as autoimmune is not merely semantic, but has important implications for experimental modelling, biomarker discovery, and therapeutic development. By encouraging exploration beyond the conventional autoimmune framework, this review seeks to support a more integrative understanding of disease mechanisms.