MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies

• Published in: The Journal of experimental medicine 2013-12, Vol.210 (13), p.2921-2937
• Main Authors: Molnarfi, Nicolas, Schulze-Topphoff, Ulf, Weber, Martin S, Patarroyo, Juan C, Prod'homme, Thomas, Varrin-Doyer, Michel, Shetty, Aparna, Linington, Christopher, Slavin, Anthony J, Hidalgo, Juan, Jenne, Dieter E, Wekerle, Hartmut, Sobel, Raymond A, Bernard, Claude C A, Shlomchik, Mark J, Zamvil, Scott S
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; B-Lymphocytes - immunology; Cell Proliferation; Cell Separation; Central Nervous System - immunology; Cytokines - metabolism; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Flow Cytometry; Gene Expression Regulation; Genes, MHC Class II; Genetic Predisposition to Disease; Immunoglobulins - immunology; Interleukin-6 - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myelin Sheath - immunology; Th1 Cells - immunology; Th17 Cells - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20130699

Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B-MHC II(-/-)), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)-specific B cell receptor (BCR; IgH(MOG-mem)) but cannot secrete antibodies. B-MHC II(-/-) mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell- and B cell-dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B-MHC II(-/-) mice. In the absence of antibodies, IgH(MOG-mem) mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle-like structures were observed in IgH(MOG-mem) mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell-targeted therapies.