Autoimmunity risk alleles compromising B cell anergy

损害 B 细胞无反应性的自身免疫风险等位基因

• 批准号: 9568080
• 负责人: John C Cambier
• 金额: $ 11.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9568080
• 关键词: Acute; Affect; Alleles; Antigen Receptors; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Cells; Chromatin; Complement; Constitution; Development; Disease; Environmental Risk Factor; Feedback; Fingerprint; Future; Gene Deletion; Gene Proteins; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Glomerulonephritis; Goals; Hot Spot; Human; Immune Tolerance; Immunoglobulin Class Switching; Individual; Infection; Inherited; Injury; Inositol; LYN gene; Lead; Life Style; Lipids; Lupus; Maintenance; Mediating; Medical; Modeling; Molecular; Monitor; Mus; PTEN gene; PTPN22 gene; PTPN6 gene; Pathology; Pathway interactions; Patients; Peripheral; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Predisposition; Prevention; Production; Protein Tyrosine Phosphatase; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Receptor Signaling; Regulation; Regulatory Pathway; Reporting; Request for Applications; Research; Risk; Role; Signal Pathway; Signal Transduction; Site; Specificity; Systemic Lupus Erythematosus; Testing; Translating; Tyrosine Phosphorylation; Work; anergy; autoreactive B cell; central tolerance; disorder risk; gene function; genetic variant; in vivo; insight; kinase inhibitor; knock-down; microbiome; mimetics; new therapeutic target; personalized approach; prevent; protein function; release of sequestered calcium ion into cytoplasm; response; risk variant; therapeutic candidate

Autoimmunity is caused by conspiring effects of genetic predisposition and environmental factors such as injury, infection and microbiome constitution. While multiple genetic loci affect susceptibility, in most cases each in isolation has only a small effect, suggesting that disease develops only when multiple risk-conferring alleles that function in concert are inherited by a single individual. We hypothesize that such a situation exists in autoreactive B cells where multiple SLE risk alleles encode molecules that appear to function in signaling pathways that function normally to limit/terminate antigen receptor signaling. In this application we propose to test this hypothesis, analyzing the functional interplay of this set of genes/protein and their risk conferring alleles. Future development and implementation of “precision” medical approaches for treatment of autoimmunity will require an understanding of the mechanisms by which genetic variations conspire to increase disease risk, and research proposed here represents a critical first step to enable these efforts. A number of autoimmunity risk alleles encode molecules previously proposed to function as intermediaries in signaling pathways involved in regulation of B cell activation. As such they may be important in keeping autoreactive B cells from becoming activated and contributing to autoimmunity. In this application we request support to define the functions and functional interactions of proteins encoded by six genes, variants of which confer increased risk of autoimmunity. Previous reports indicate that B cell-targeted deletion of genes encoding SHIP-1, PTEN, SHP-1 or LYN, expression of PTPN22 (PEP-R619W), or increased expression of CSK, promote the development of autoimmunity. However the mechanism by which this occurs is unknown. We hypothesize that these proteins function as intermediaries in a bifurcating pathway in which final effectors are the inositol lipid phosphatases SHIP-1 and the tyrosine phosphatase SHP-1. Further, we suggest that both terminal effectors are required for maintenance of antigen unresponsiveness of anergic B cells. The studies will employ reductionist genetic models in which risk allele mimetic changes in expression/function of the proteins can be induced acutely in anergic B cells, and subsequent cell activation, proliferation, differentiation and autoantibody production monitored. Aim 1 will test the hypothesis that PTPN22, CSK and LYN act in linear pathways upstream of SHIP-1 and SHP-1, and that genetic variations that confer risk compromise anergy by undermining their regulatory function. Aim 2 will define the downstream consequences of acute introduction of risk allele mimetic conditions in terms of development of autoimmune disease, and will test candidate therapeutic kinase inhibitors. Aim 3 will translate findings, examining the role of SHIP-1 and SHP-1 phosphatases in maintenance anergy of human B cells. Proposed studies will provide important new insight regarding the in vivo lifestyle of autoreactive B cells whose anergy is compromised by autoimmunity risk alleles.

自身免疫性是由遗传易感性的阴谋作用和环境因素（例如 损伤，感染和微生物组构型。虽然多种遗传局部影响敏感性，但在大多数情况下 每个人都只有很小的影响，这表明只有在多个风险限制时才发生疾病的发展 该功能在音乐会上的等位基因由一个人继承。我们假设存在这种情况 在自动反应性B细胞中，多个SLE风险等位基因编码似乎在信号中起作用的分子 正常功能以限制/终止抗原受体信号的途径。在此申请中，我们建议 检验该假设，分析这组基因/蛋白质的功能相互作用及其风险会议 等位基因。未来开发和实施“精确”医学方法 自身免疫将需要了解遗传变异共同促进的机制 增加疾病的风险，此处提出的研究代表了实现这些努力的关键第一步。 许多自身免疫风险等位基因编码先前提议的分子，以作为中间人发挥作用 涉及调节B细胞激活的信号通路。因此，它们可能在保持 自动反应性B细胞受到激活并导致自身免疫性。在此应用程序中，我们要求 支持定义由六个基因编码的蛋白质的功能和功能相互作用，其中的变体 会议增加了自身免疫性的风险。先前的报告表明，B细胞针对编码的基因缺失 Ship-1，PTEN，SHP-1或LYN，PTPN22（PEP-R619W）的表达或CSK的表达增加， 促进自身免疫的发展。但是，发生这种情况的机制尚不清楚。我们 假设这些蛋白质在分叉途径中充当中间体，其中最终影响是 肌醇脂质磷酸酶Ship-1和酪氨酸磷酸酶SHP-1。此外，我们建议 维持厌食B细胞的抗原无反应性需要终端效应。研究会 雇员还原主义遗传模型，其中风险等位基因模拟蛋白质表达/功能的变化 可以在厌食的B细胞中急性诱导，并随后的细胞激活，增殖，分化和 监测自身抗体。 AIM 1将检验PTPN22，CSK和LYN用线性作用的假设 Ship-1和SHP-1上游的途径，以及会议风险损害反对意外的遗传变异 破坏其监管功能。 AIM 2将定义急性引入的下游后果 在自身免疫性疾病的发展方面有可能模仿等位基因的状况，并将测试候选人 治疗激酶抑制剂。 AIM 3将翻译发现，检查Ship-1和SHP-1的作用 维持人B细胞的磷酸酶。拟议的研究将提供重要的新见解 考虑到自动免疫风险等位基因的自动反应性B细胞的体内生活方式。