Fig. 2

Immunopathogenesis of multiple sclerosis. Although the antigen responsible for the initiation of the autoimmune reaction in multiple sclerosis (MS) has not yet been described, it is hypothesized that antigens derived from the central nervous system (CNS) would reach the periphery and be presented to autoreactive CD4⁺ T cells in the lymph nodes. Alternatively, other self-antigens, pathogenic or gut microbial peptides sharing high homology with myelin antigens, have been postulated as candidates for autoimmune MS. The pool of autoreactive CD4⁺ T cells, which are enriched in brain-homing clones, circulate inside the CNS upon activation. Peripheral tolerance mechanisms involving the suppressor functionality of regulatory T (Treg) cells, including reduced suppressor function of Treg cells, loss of FoxP3 or resistance of effector T cells to Treg-mediated suppressive mechanisms, have also been shown to be dysregulated in MS patients. Once inside the CNS, autoreactive CD4⁺ T cells are reactivated by local antigen-presenting cells and differentiate into encephalitogenic T helper (Th)1/Th17 effector cells, initiating a series of immunological events that lead to demyelination and neuronal damage. Myeloid cells are the most abundant immune cell type found in MS lesions and are involved in multiple aspects of MS pathogenesis, including the differentiation of CD4⁺ T cells and the recruitment of other immune cells at the lesion site. CD8⁺ T cells are also recruited into the CNS and are clonally expanded, although the heterogeneity of clones is much greater than that of CD4⁺ T-cell clones. The formation of tertiary lymphoid structures similar to germinal centers in the meninges results in the activation of T and B cells, along with the sustained secretion of antibodies. APC, antigen-presenting cell; BCR, B-cell receptor; CNS, central nervous system; IFN- γ, interferon gamma; MHC-II, class II major histocompatibility complex; IgG, immunoglobulin isotype G; TCR, T-cell receptor; Th, T helper cell. Created in https://BioRender.com