B Cell-Specific MHC Class II Deletion Reveals Multiple Nonredundant Roles for B Cell Antigen Presentation in Murine Lupus.
B cells have both Ab-dependent and Ab-independent functions in systemic autoimmune diseases, including systemic lupus erythematosus (SLE). Ab-independent functions are known to be important, because mice with B cells but no secreted Ig have severe disease. These functions could include roles in lymphoid development, cytokine secretion, and Ag presentation; however, these possibilities have not been directly tested in SLE models. In this study, we show by lineage-specific ablation of MHC class II (MHCII) that B cell Ag presentation plays a nonredundant role in CD4(+) T cell activation and effector differentiation in the MRL.Fas(lpr) mouse model of SLE. MHCII-mediated interactions between B and T cells further promote B cell proliferation and differentiation, and, in fact, inefficient MHCII deletion on B cells led to strong selection of escaped cells in activated and plasmablast compartments, further underscoring the central role of B cell Ag presentation. Despite the leakiness in the system, B cell-specific MHCII deletion resulted in substantially ameliorated clinical disease. Hence, B cell Ag presentation is critical for T and B cell activation and differentiation, as well as target organ damage.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Josephine R
JR
Giles
Department of Pathology, Yale University School of Medicine, New Haven, CT 06519;
Michael
M
Kashgarian
Cancer Research Center, Georgia Regents University, Augusta, GA 30192; and Department of Medicine, Georgia Regents University, Augusta, GA 30192.
Pandelakis A
PA
Koni
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; mshlomch@pitt.edu.
Mark J
MJ
Shlomchik
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic
D001323:Autoantibodies; D016207:Cytokines; D000949:Histocompatibility Antigens Class II