Regulatory mechanisms for self-reactive B cells with somatic mutations in the immunoglobulin genes

免疫球蛋白基因体细胞突变的自身反应性 B 细胞的调节机制

• 批准号: 09470092
• 负责人: TSUBATA Takeshi
• 金额: $ 8.45万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470092/
• 关键词: 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

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.

自身免疫性疾病特征的自身抗体已被证明通过其可变区的体细胞超突变而经历亲和力成熟。已经经历亲和力成熟的自身反应性 B 细胞是否受到与没有体细胞突变的细胞不同的调节尚未阐明。我们已经证明，CD40 信号传导可阻断抗原介导的 B 细胞凋亡，从而拯救自身反应性 B 细胞免于克隆缺失。事实上，据报道，系统性红斑狼疮 (SLE) 患者和易患 SLE 的 BXSB 小鼠在 T 细胞上过度表达 CD40 配体 (CD40L)，在 B 细胞上异位表达 CD40L。为了评估 CD40L 在自身反应性 B 细胞生成中的作用，我们建立了在 B 细胞上表达 CD40L 的转基因小鼠。 CD40L 转基因小鼠产生自身抗体并发展成 SLE 样肾小球肾炎。同时表达 CD40L 和低亲和力抗 DNA 抗体的转基因小鼠表现出 B 细胞耐受性缺陷。然而，那些同时表达 CD40L 和高亲和力抗 DNA 抗体的细胞在自身反应性 B 细胞克隆缺失方面表现出缺陷，并产生自身抗体。这些结果表明 CD40 介导的 B 细胞耐受性破坏需要 B 细胞对自身抗原具有高亲和力。在免疫球蛋白中获得体细胞突变的自身反应性 B 细胞在耐受破坏时可能受到与没有体细胞突变的细胞不同的调节。

项目成果

Tubata, T.: "Apoptosis of mature B cells."Int. Rev. Immunol.. 18. 347-365 (1999)

Tubata, T.：“成熟 B 细胞的凋亡。”Int。

Han,H.: "Involvement of the cyclin-dependent kinase inhibitor p27^<kipl> in negative signaling through the antigen-receptor of B lymphocytes." Leukemia. 11(Supp3). 367-369 (1997)

Han,H.：“细胞周期蛋白依赖性激酶抑制剂 p27^<kipl> 参与通过 B 淋巴细胞抗原受体的负信号传导。”

Tsubata,T.: "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" Springer-Verlag, 368 (1997)

Tsubata,T.：“淋巴细胞和神经元信号传导中的激酶和磷酸酶”Springer-Verlag，368 (1997)

Tubata, T.: "Co-receptors on B lymphocytes."Curr. Opin. Immunol. 11・3. 249-255 (1999)

Tubata，T.：“B 淋巴细胞上的辅助受体”。《免疫学》11·3（1999）。

Adachi,T.: "The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-l upon tyrosine phosphorylation." J.Immunol.160・10. 4662-4665 (1998)

Adachi, T.：“B 细胞表面蛋白 CD72 在酪氨酸磷酸化后招募酪氨酸磷酸酶 SHP-1。J.Immunol.160·10 (1998)。