Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from Ig V region-specific T cells.
B cells present BCR V region-derived Id-peptides on their MHC class II molecules to Id-specific CD4+ T cells. Prolonged Id-driven T-B collaboration could cause autoimmune disease, but this possibility is difficult to test in normal individuals. We have investigated whether mice doubly transgenic for an Id+ Ig L chain and an Id-specific TCR develop autoimmune disease. Surprisingly, T cell tolerance was not complete in these mice because a low frequency of weakly Id-reactive CD4+ T cells accumulated with age. These escapee Id-specific T cells provided chronic help for Id+ B cells, resulting in a lethal systemic autoimmune disease including germinal center reactions, hypergammaglobulinemia, IgG autoantibodies, glomerulonephritis, arthritis, skin affection, and inflammatory bowel disease. Inflamed tissues contained foci of Id-driven T-B collaboration, with deposition of IgG and complement. The disease could be transferred with B and T cells. The results demonstrate a novel mechanism for development of autoimmune disease in which self-reactive Id+ B cells receive prolonged help from Id-specific T cells, thus bypassing the need for help from T cells recognizing conventional Ag.
Munthe
Ludvig André
LA
Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway. l.a.munthe@medisin.uio.no
Corthay
Alexandre
A
Os
Audun
A
Zangani
Michael
M
Bogen
Bjarne
B
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003108:Colonic Diseases / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000502:physiology*; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007130:Immunoglobulin Idiotypes / Q000096:biosynthesis / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D008211:Lymphocyte Cooperation / Q000276:immunology*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D007130:Immunoglobulin Idiotypes; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region