title: MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies.
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; 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.
authors: Department of Neurology and 2 Program in Immunology, University of California, San Francisco, San Francisco, CA 94158.
authors: Nicolas
authors: N
authors: Molnarfi
authors: Ulf
authors: U
authors: Schulze-Topphoff
authors: Martin S
authors: MS
authors: Weber
authors: Juan C
authors: JC
authors: Patarroyo
authors: Thomas
authors: T
authors: Prod'homme
authors: Michel
authors: M
authors: Varrin-Doyer
authors: Aparna
authors: A
authors: Shetty
authors: Christopher
authors: C
authors: Linington
authors: Anthony J
authors: AJ
authors: Slavin
authors: Juan
authors: J
authors: Hidalgo
authors: Dieter E
authors: DE
authors: Jenne
authors: Hartmut
authors: H
authors: Wekerle
authors: Raymond A
authors: RA
authors: Sobel
authors: Claude C A
authors: CC
authors: Bernard
authors: Mark J
authors: MJ
authors: Shlomchik
authors: Scott S
authors: SS
authors: Zamvil
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002469:Cell Separation; D002490:Central Nervous System / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D007136:Immunoglobulins / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D015850:Interleukin-6