Regulatory mechanisms for self-reactive B cells with somatic mutations in the immunoglobulin genes
| Project/Area Number |
09470092
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Immunology
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
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)
|
|---|
| Project Period (FY) |
1997 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 1999: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1998: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1997: ¥5,200,000 (Direct Cost: ¥5,200,000)
|
|---|
| Keywords | self-reactive B cells / autoantibody / somatic mutation / CD40 / CD40L / SLE / transgenic mice / anti-DNA antibody / トレランス / クローン除去 / 分化停止 / 誘導的発現 / Cre / loxP / テトラサイクリンオペロン / KRAB / エストロゲン受容体 / 融合タンパク |
|---|
| 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.
|
Report
(4 results)
Research Products
(16 results)
