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: 9121221
• 负责人: John C Cambier
• 金额: $ 45.51万
• 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/9121221
• 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; 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; Therapeutic; 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

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.

自身免疫是由遗传易感性和环境因素的共同作用引起的， 损伤、感染和微生物组构成。虽然多个遗传位点影响易感性，但在大多数情况下， 每一种单独的作用都很小，这表明疾病只有在多种风险因素共同作用下才会发展。 协同作用的等位基因由单个个体遗传。我们假设这样的情况存在 在自身反应性B细胞中，多个SLE风险等位基因编码似乎在信号传导中起作用的分子， 正常发挥功能以限制/终止抗原受体信号传导的途径。在本申请中，我们提出 测试这一假设，分析这组基因/蛋白质的功能相互作用及其风险赋予 等位基因。未来发展和实施“精确”医疗方法治疗 自身免疫需要了解遗传变异的机制， 增加疾病风险，这里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出的在免疫调节中起中介作用的分子。 参与调节B细胞活化的信号通路。因此，他们可能是重要的， 自身反应性B细胞被激活并导致自身免疫。在本申请中，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 增加自身免疫的风险。先前的报道表明，B细胞靶向缺失编码 SHIP-1、PTEN、SHP-1或林恩、PTPN 22（PEP-R619 W）的表达或CSK的表达增加， 促进自身免疫的发展。然而，这种情况发生的机制尚不清楚。我们 假设这些蛋白质在最终效应物被 肌醇脂质磷酸酶SHIP-1和酪氨酸磷酸酶SHP-1。此外，我们建议双方 维持无反应性B细胞的抗原无反应性需要末端效应物。这些研究将 采用简化的遗传模型，其中风险等位基因模拟蛋白质表达/功能的变化 可在无反应性B细胞中急性诱导，随后的细胞活化、增殖、分化和 监测自身抗体产生。目的1将检验PTPN 22、CSK和林恩以线性方式起作用的假设。 SHIP-1和SHP-1上游途径，以及带来风险的遗传变异通过以下方式损害无反应性 削弱其监管功能。目标2将定义急性引入 在自身免疫性疾病的发展方面具有风险等位基因模拟条件，并将测试候选人 治疗性激酶抑制剂。目标3将翻译研究结果，检查SHIP-1和SHP-1的作用 磷酸酶在维持人B细胞无反应性中的作用拟议的研究将提供重要的新见解 关于自身反应性B细胞的体内生活方式，其无反应性受到自身免疫风险等位基因的损害。