Myelin-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner.

Abstract

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered a T cell-mediated disease. However, accumulating evidence points to a crucial role for B cells in disease processes. IgH[MOG] mice possess a transgenic immunoglobulin heavy chain derived from a monoclonal antibody specific to myelin oligodendrocyte glycoprotein (MOG), a key target for autoimmune responses. Here, using the experimental autoimmune encephalomyelitis (EAE) model of MS, we investigated the susceptibility of IgH[MOG] mice to CD4+ T cell-driven disease that was induced by active immunization with MOG[35-55] autoantigen. We found that immunized IgH[MOG] mice rapidly developed severe EAE, characterized by the aggregation of T and B cells in the CNS meninges. We observed an increased presence of class-switched and inflammatory cytokine-positive B cells in the IgH[MOG] CNS, as well as a greater frequency of IL-17- and GM-CSF-producing CD4+ T cells. Production of the Th17 maintenance factor IL-23 was increased from IgH[MOG] CNS-infiltrating B cells, and in vivo blockade of IL-23p19 strongly attenuated disease severity in IgH[MOG] mice. Strikingly, we observed an increased frequency of PD-1+CXCR5- T peripheral helper (Tph)-like cells in the CNS parenchyma and dura mater of IgH[MOG] mice. Both Tph accumulation in the CNS, as well as meningeal inflammation, were again sharply reduced upon IL-23p19 blockade in vivo. Notably, CNS-infiltrating B and Tph cells from IgH[MOG] mice showed an upregulation of genes related to neurodegeneration and oxidative phosphorylation, and IL-23 blockade reduced ROS production from these cells in vivo. Altogether, these data show that MOG-specific B cells contribute to severe CD4+ T cell-driven EAE by promoting CNS accumulation of Th17 and Tph cells, as well as tertiary lymphoid organs in the CNS meninges, in an IL-23 dependent manner.