The naive B cell repertoire predisposes to antigen-induced systemic lupus erythematosus.
It is clear that the development of an autoimmune disease usually depends on both a genetic predisposition and an environmental trigger. In this study, we demonstrate that BALB/c mice develop a lupus-like serology following immunization with a peptide mimetope of DNA, while DBA/2 mice do not. We further demonstrate that the critical difference resides within the B cell compartment and that the naive B cell repertoire of DBA/2 mice has fewer B cells specific for the DNA mimetope. Differences in the strength of B cell receptor signaling exist between these two strains and may be responsible for the difference in disease susceptibility. BALB/c mice possess more autoreactive cells in the native repertoire; they display a weaker response to Ag and exhibit less Ag-induced apoptosis of B cells. DBA/2 mice, in contrast, display a stronger B cell receptor signal and more stringent central tolerance. This correlates with resistance to lupus induction. Thus, the degree to which autoreactive B cells have been eliminated from the naive B cell repertoire is genetically regulated and may determine whether a nonspontaneously autoimmune host will develop autoimmunity following exposure to Ag.
Wang
Chuansheng
C
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Khalil
Magi
M
Ravetch
Jeffrey
J
Diamond
Betty
B
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000941:Antigens / Q000008:administration & dosage*; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000276:immunology; D007399:Interphase / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology; D013045:Species Specificity
D000888:Antibodies, Anti-Idiotypic; D000941:Antigens; D001323:Autoantibodies; D003432:Cross-Linking Reagents; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009842:Oligopeptides; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D004247:DNA; D002118:Calcium