Multiple sclerosis and the limits of classical autoimmune theory

Concepts of autoimmune disease have traditionally emphasized genetic susceptibility, antigen-specific immune activation, and inflammation as linear drivers of tissue injury and clinical symptoms. While this framework has been highly successful in explaining disease initiation and guiding the development of immunomodulatory therapies, accumulating evidence indicates important limitations in its capacity to account for long-term disease outcomes. In this review, we use multiple sclerosis (MS) as an illustrative case through which autoimmune theory can be critically examined. MS provides strong support for immune-mediated mechanisms in early disease, yet it also shows that neurodegeneration and disability accumulation often become uncoupled from overt inflammatory activity. These observations challenge linear models and sustained coupling between immune activity, tissue injury, and clinical progression. We use this gap between theoretical expectations and observed disease patterns to examine broader conceptual issues relevant to autoimmune and immune-mediated diseases, particularly the need to distinguish between mechanisms of susceptibility, inflammatory activity, and progressive worsening, and to incorporate temporal dynamics, interactions, and tissue-specific responses into explanatory models. We argue that the main contribution of MS lies not in serving as a generalizable model, but in clarifying the scope and limits of autoimmune theory and in underscoring the importance of theoretical refinement for organizing increasingly complex empirical evidence.