1999 Fiscal Year Final Research Report Summary
Regulatory mechanisms for self-reactive B cells with somatic mutations in the immunoglobulin genes
| Project/Area Number |
09470092
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
TSUBATA Takeshi Medical Research Institute, Tokyo Medical and Dental University, Dept. Immunology, Professor, 難治疾患研究所, 教授 (80197756)
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| Project Period (FY) |
1997 – 1999
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| Keywords | self-reactive B cells / autoantibody / somatic mutation / CD40 / CD40L / SLE / transgenic mice / anti-DNA antibody |
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| Research Abstract |
Autoantibodies characteristic for autoimmune diseases have been shown to undergo affinity maturation by somatic hypermutations in their variable regions. Whether self-reactive B cells that have undergone affinity maturation are regulated differently from those without somatic mutations has not yet been elucidated. We have demonstrated that CD40 signaling blocks antigen-mediated apoptosis of B cells, resulting in rescuing self-reactive B cells from clonal deletion. Indeed, patients with systemic lupus erythematosus (SLE) and SLE-prone BXSB mice have been reported to overexpress CD40 ligand (CD40L) on T cells and express CD40L ectopically on B cells. To assess the role of CD40L in generation of self-reactive B cells, we established transgenic mice expressing CD40L on B cells. CD40L-trasgenic mice produce autoantibodies and develop SLE-like glomerulonephritis. Transgenic mice expressing both CD40L and low affinity anti-DNA antibodies show do defects in B cell tolerance. However, those expressing both CD40L and high affinity anti-DNA antibodies show defects in clonal deletion of self-reactive B cells and produce autoantibodies. These results indicate that CD40-mediated breakdown of B cell tolerance requires B cells with high affinity to self-antigens. Self-reactive B cells that acquire somatic mutations in immunoglobulin may be differently regulated from those without somatic mutations at tolerance breakdown.
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