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

Nicolas Molnarfi, Ulf Schulze-Topphoff, Martin S. Weber, Juan C. Patarroyo, Thomas Prod'homme, Michel Varrin-Doyer, Aparna Shetty, Christopher Linington, Anthony J. Slavin, Juan Hidalgo, Dieter E. Jenne, Hartmut Wekerle, Raymond A. Sobel, Claude C.A. Bernard, Mark J. Shlomchik, Scott S. Zamvil

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Abstract

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; IgHMOG-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, IgHMOG-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 IgHMOG-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. © 2013 Molnarfi et al.
Original languageEnglish
Pages (from-to)2921-2937
JournalJournal of Experimental Medicine
Volume210
DOIs
Publication statusPublished - 1 Dec 2013

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    Molnarfi, N., Schulze-Topphoff, U., Weber, M. S., Patarroyo, J. C., Prod'homme, T., Varrin-Doyer, M., Shetty, A., Linington, C., Slavin, A. J., Hidalgo, J., Jenne, D. E., Wekerle, H., Sobel, R. A., Bernard, C. C. A., Shlomchik, M. J., & Zamvil, S. S. (2013). MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. Journal of Experimental Medicine, 210, 2921-2937. https://doi.org/10.1084/jem.20130699