Reframing Multiple Sclerosis as a Failure of Repair Permissiveness: A Systems-Level Hypothesis Integrating Immune Trafficking, Immune Restraint, and Innate Inflammatory Timing

Multiple sclerosis (MS) is traditionally managed through disease-modifying therapies (DMTs) that primarily suppress immune-mediated damage. While effective at reducing relapse frequency and inflam- matory activity, these approaches have limited impact on long-term disability progression. Importantly, pathological and imaging studies demonstrate that endogenous repair, including remyelination, occurs in a subset of patients, indicating that repair is biologically possible but frequently blocked. Here, we propose a systems-level hypothesis reframing MS not solely as a disease of immune overactivity, but as a failure of repair permissiveness driven by persistent immune trafficking, insufficient immune re- straint, and dysregulated innate inflammatory timing. Coordinated modulation of these axes may enable endogenous repair mechanisms to proceed.