Autoimmunity risk alleles compromising B cell anergy

自身免疫是由遗传易感性和环境因素共同作用引起的，如 损伤、感染和微生物群构成。虽然多个遗传基因座影响易感性，但在大多数情况下 每一种隔离都只有很小的影响，这表明疾病只有在多重风险引发时才会发生。 功能一致的等位基因是由单个个体遗传的。我们假设这种情况是存在的 在自身反应性B细胞中，多个SLE风险等位基因编码的分子似乎具有信号传递功能 正常发挥作用以限制/终止抗原受体信号的通路。在本申请中，我们建议 验证这一假设，分析这组基因/蛋白质的功能相互作用及其引发的风险 等位基因。“精准”医学治疗方法的未来发展和实施 自身免疫需要了解遗传变异共同作用的机制。 增加疾病风险，这里提出的研究是实现这些努力的关键的第一步。 许多自身免疫风险等位基因编码的分子以前被认为是人类免疫的中介。 参与调节B细胞活化的信号通路。因此，他们可能是重要的保持 自身反应性B细胞被激活并有助于自身免疫。在本申请中，我们请求 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，这些基因的变体 增加了自身免疫的风险。以往的报道表明，编码基因的B细胞靶向缺失 Ship-1、PTEN、SHP-1或Lyn，PTPN22(PEP-R619W)的表达，或CSK的表达增加， 推动自身免疫发展。然而，这种情况发生的机制尚不清楚。我们 假设这些蛋白质在分叉通路中起中介作用，其中最终效应器 肌醇脂磷酸酶SHIP-1和酪氨酸磷酸酶SHP-1。此外，我们建议，无论是 末端效应器是维持无能B细胞抗原无反应性所必需的。这些研究将 采用简化论遗传模型，其中风险等位基因模拟蛋白质表达/功能的变化 可在无能B细胞中急性诱导，随后细胞激活、增殖、分化和 监测自身抗体的产生。目标1将检验PTPN22、CSK和LYN呈线性作用的假设 SHIP-1和SHP-1上游的通路，以及带来风险的基因变异通过以下方式损害无能 削弱了它们的监管职能。目标2将定义紧急引入的下游后果 在自身免疫性疾病的发展方面的风险等位基因模拟条件，并将测试候选 治疗用的激酶抑制剂。AIM 3将翻译研究结果，研究SHIP-1和SHP-1的作用 磷酸酶在人类B细胞维持无能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，其无能受到自身免疫风险等位基因的影响。

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.