Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantibodies / biosynthesis
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Autoantigens / immunology*
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / mortality
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Autoimmune Diseases / pathology
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism
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B-Lymphocyte Subsets / transplantation
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Cell Line
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Cell Line, Tumor
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Cell Proliferation
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Colonic Diseases / immunology
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Colonic Diseases / metabolism
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Epitopes, T-Lymphocyte / physiology*
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Female
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Gastrointestinal Diseases / genetics
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Gastrointestinal Diseases / immunology
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Gastrointestinal Diseases / pathology
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Immunoglobulin Idiotypes / biosynthesis
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Immunoglobulin Idiotypes / genetics
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Immunoglobulin Light Chains / biosynthesis
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Immunoglobulin Light Chains / genetics
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Immunoglobulin Variable Region / physiology*
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Lymphocyte Activation / genetics
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Lymphocyte Cooperation / immunology*
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Lymphocyte Count
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Lymphocyte Depletion
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mice, SCID
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Mice, Transgenic
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Skin Diseases / genetics
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Skin Diseases / immunology
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Skin Diseases / pathology
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
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T-Lymphocytes, Helper-Inducer / transplantation
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Thymus Gland / cytology
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Thymus Gland / immunology
Substances
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Autoantibodies
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Autoantigens
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Epitopes, T-Lymphocyte
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Immunoglobulin Idiotypes
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Immunoglobulin Light Chains
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Immunoglobulin Variable Region