Epitope spreading in multiple sclerosis is shaped by the spatial organisation of immune responses

Epitope spreading has long been proposed as a mechanism contributing to the progression of multiple sclerosis (MS), yet its role in human disease remains incompletely defined. Traditionally viewed as a consequence of antigen release during tissue damage, epitope spreading is often considered independently of the anatomical context in which immune responses occur. Here, I re-examine epitope spreading in MS by integrating evidence from experimental models and human studies with recent advances in neuroimmunology. I propose that the diversification of autoreactive responses is not solely driven by antigen availability but is shaped by the spatial organisation of immune cells within the central nervous system (CNS), CNS-draining lymph nodes, and peripheral lymphoid tissues. In particular, I highlight EBI2 (GPR183) as a candidate regulator of immune-cell positioning that may influence the cellular interactions required for the emergence of new antigen specificities. This spatial framework links epitope spreading with germinal-centre dynamics, B-cell-mediated immunity, and Epstein-Barr virus-associated mechanisms in MS, while emphasising that direct evidence connecting EBI2 to epitope spreading remains limited. Defining how autoreactive diversification is controlled may help explain disease progression and guide strategies aimed at limiting the evolution of pathogenic immune responses.