Molecular and Cellular Analysis of Autoreactive B Cell Elimination from Germinal

生殖细胞中自身反应性 B 细胞消除的分子和细胞分析

• 批准号: 8524161
• 负责人: Deepta Bhattacharya
• 金额: $ 6.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524161
• 关键词: Antibodies; Antigens; Autoantigens; Autoimmune Diseases; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Survival; Data; Dendritic Cells; Development; Genes; Genetic Recombination; Germ Lines; Height; Helper-Inducer T-Lymphocyte; Immunization; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Individual; Measures; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mouse Strains; Mus; Ovalbumin; Ovum; Pathway interactions; Patients; Peptides; Phosphotransferases; Reaction; Receptor Signaling; Receptors, Antigen, B-Cell; Rheumatism; Serum; Signal Transduction; Somatic Mutation; Specificity; Structure of germinal center of lymph node; T-Lymphocyte; Wild Type Mouse; anti-dsDNA antibodies; autoreactive B cell; prevent; promoter; recombinase; scavenger receptor

Self-reactivity in antibodies isolated from patients with autoimmune disorders is often imparted by somatic mutations. Indeed, reversion of immunoglobulin genes to germ line sequences typically eliminates reactivity against self-antigens. These data suggest that many autoreactive B cells are derived from the germinal center reaction, in which somatic hypermutation of immunoglobulin variable genes occurs. The mechanisms by which self-reactive B cells are eliminated during early development are well-understood. In contrast, very little is known about how somatic mutation-induced self-reactivity is normally prevented in healthy individuals, and which of these pathways fail in patients with autoimmune disorders. In this proposal, we will identify the survival pathways downstream of B cell receptor (BCR) signals and CD4+ T cell help that allow autoreactive B cells to survive.

从自身免疫性疾病患者中分离出的抗体的自我反应性通常通过体细胞突变赋予。实际上，将免疫球蛋白基因重新转换为种系序列通常会消除针对自我抗原的反应性。这些数据表明，许多自动反应性B细胞源自生殖中心反应，其中发生了免疫球蛋白可变基因的体细胞超名。在早期发育过程中消除了自我反应性B细胞的机制是充分理解的。相比之下，关于健康个体通常会阻止体细胞突变诱导的自我反应性的知之甚少，并且自身免疫性疾病患者中哪种途径失败。在此提案中，我们将确定B细胞受体信号（BCR）信号和CD4+ T细胞下游的生存途径，从而使自动反应性B细胞能够生存。