Fig. 3

Neuropathogenesis of multiple sclerosis. Multiple sclerosis (MS) is caused by demyelination, which begins with microglial activation, macrophage infiltration, and accumulation of CD8⁺ tissue-resident memory T cells, which drive inflammatory changes in astrocytes and microglia. Chronic microglial activation leads to the release of proinflammatory cytokines and reactive oxygen and nitrogen species, which contribute to demyelination, tissue damage and neurodegeneration. Similarly, chronically reactive astrocytes release cytokines and chemokines that recruit additional immune cells, deposit inhibitory chondroitin sulfate proteoglycans that impair remyelination, and contribute to glial scar formation, which further hinders repair. Humoral immunity also plays a role in demyelination through antibody deposition and complement activation. IgG and IgM antibodies trigger the classical complement pathway, leading to opsonization, formation of the membrane attack complex (MAC), and direct damage to oligodendrocytes and neurons. In addition, the C3 component impairs remyelination. The failure of oligodendrocyte progenitor cells to mature into fully functional oligodendrocytes further exacerbates remyelination deficits. Over time, chronically demyelinated neurons experience axonal injury and metabolic stress, causing calcium accumulation within axons, activation of proteases, and consequently axonal degeneration. Additionally, chronic inflammation exacerbates neurodegeneration by exposing neurons to cytotoxic molecules such as nitric oxide and glutamate excitotoxicity. Together, these mechanisms drive progressive tissue damage and disease progression in MS. Created in https://BioRender.com