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MOG-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity

Doss, PMIA;Yeola, AP;Mailhot, B;Baillargeon, J;

BACKGROUND Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered T cell-mediated. However, accumulating evidence points to a crucial role for B cells in disease processes. Experimental autoimmune encephalomyelitis (EAE) is a well-established model to study the immune aspects of CNS autoimmunity. METHODS In order to examine the collaboration of B cells and T cells in EAE, we studied non-obese diabetic (NOD)-background IgH[MOG] mice, whose B cells express a transgenic IgH chain derived from a myelin oligodendrocyte glycoprotein (MOG)-specific antibody. We immunized these and NOD WT controls with the MHC class II-restricted peptide MOG[35-55], which induces a CD4+ T cell-driven response. CNS tissue inflammation and demyelination were assessed histopathologically, and the phenotype of CNS-infiltrating mononuclear cells was studied by flow cytometry. The capacity of IgH[MOG] B cells to present antigen to CD4+ T cells was assessed using in vitro priming assays with MOG[35-55] as the antigen. RESULTS MOG[35-55]-immunized IgH[MOG] mice rapidly developed severe EAE characterized by leukocytic infiltration and demyelination in the brain, spinal cord and optic nerve. Notably, while the frequency of CD4+ T cells was increased in the CNS of IgH[MOG] with severe disease relative to controls, no differences were observed with respect to the frequency of B cells. Further, IgH[MOG] CNS-infiltrating CD4+ T cells produced significantly higher levels of Th17-associated cytokines GM-CSF and IL-17 compared to those from controls. Mechanistically, IgH[MOG] B cells were better able than WT B cells to elicit inflammatory cytokine production from MOG[35-55]-specific CD4+ T cells in in vitro priming assays. CONCLUSION These data show that MOG-specific B cells contribute to CD4+ T cell-driven EAE by promoting CD4+ T cell inflammation and recruitment to the CNS.