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.

自身免疫性疾病的自身抗体特征已显示出通过其可变区域的体细胞过度过度的亲和力成熟。尚未阐明经历亲和力成熟的自我反应性B细胞与没有躯体突变的自我调节。我们已经证明，CD40信号传导会阻止抗原介导的B细胞凋亡，从而从克隆缺失中拯救了自反应性B细胞。实际上，据报道，患有全身性红斑狼疮（SLE）和易于SLE的BXSB小鼠的患者在T细胞上过表达CD40配体（CD40L），并在B细胞上表达CD40L。为了评估CD40L在自反应性B细胞产生中的作用，我们建立了在B细胞上表达CD40L的转基因小鼠。 CD40L - 肥大小鼠会产生自身抗体并发展出SLE样肾小球肾炎。表达CD40L和低亲和力抗DNA抗体的转基因小鼠在B细胞耐受性中确实存在缺陷。但是，那些同时表达CD40L和高亲和力抗DNA抗体的人在自反应性B细胞的克隆缺失中显示出缺陷并产生自身抗体。这些结果表明，CD40介导的B细胞耐受性的分解需要对自我抗原具有高亲和力的B细胞。在免疫球蛋白中获取体细胞突变的自反应性B细胞可能与在耐受性分解时没有体细胞突变的人不同。

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)

Adachi T.: "The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 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）。

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）。