Identification of novel Inhibitory receptors Involved In B cell tolerance

项目摘要 在自身免疫性疾病的早期阶段，遗传和环境因素共同作用破坏免疫。 宽容。几个与系统性红斑狼疮发病风险增加相关的风险等位基因 系统性红斑狼疮(SLE)和其他自身免疫性疾病的靶点是Src家族酪氨酸激酶Lyn的功能。林恩扮演一个 通过在自身反应性B细胞中启动抑制信号而在免疫耐受中发挥重要作用，从而导致 没有反应或无能为力。介导这一抑制信号的重要下游磷酸酶有 Ship-1和SHP-1。目前尚不清楚Lyn如何促进无能B细胞中SHIP-1和SHP-1的激活。 LYN使抑制性受体(ITIM或ITSM)上的特定基序磷酸化，使这些受体能够 招募和激活磷酸酶。这一建议的目的是识别LYN依赖的抑制 激活无能B细胞SHIP-1(Aim 1)和SHP-1(Aim 2)所需的受体我们将用一本小说 抑制性受体陷阱(IRT)技术，以识别这些抑制性受体。IRT使用来自 SHIP-1或SHP-1特异性分离磷酸化抑制受体(表明受体是 活动)。分离的受体将通过质谱学进行鉴定。我们将评估已确定的 人和小鼠无能B细胞的受体。了解抑制作用的分子途径 信号通路在自身反应性B细胞中被激活是很重要的。许多风险等位基因与 患自身免疫性疾病的风险增加会影响这些抑制回路。勾画路径 相关关系将允许更准确地预测哪些风险等位基因将发挥协同作用。这将是 使我们能够识别高风险的个人，并将允许更早的干预和可能的预防性 关心。识别的受体也是治疗干预的潜在新靶点，这可能允许我们 恢复B细胞耐受性。

Project Summary Both genetic and environmental factors conspire during early stages of autoimmune disease to break immune tolerance. Several risk alleles associated with an increased risk of developing systemic lupus erythematosus (SLE), and other autoimmune diseases, target the function of the Src-family tyrosine kinase Lyn. Lyn plays an important role in immune tolerance by initiating inhibitory signaling in autoreactive B cells, leading to a state of unresponsiveness or anergy. Important downstream phosphatases that mediate this inhibitory signaling are SHIP-1 and SHP-1. It is still unclear how Lyn facilitates the activation of SHIP-1 and SHP-1 in anergic B cells. Lyn phosphorylates specific motifs on inhibitory receptors (ITIM or ITSM) that enables these receptors to recruit and activate phosphatases. The aims of this proposal are to identify the Lyn-dependent inhibitory receptors required to activate SHIP-1 (Aim 1) and SHP-1 (Aim 2) in anergic B cells. We will use a novel technique, Inhibitory Receptor Trap (IRT), to identify these inhibitory receptors. IRT uses SH2 domains from SHIP-1 or SHP-1 to specifically isolate phosphorylated inhibitory receptors (indicating that the receptors are active). Isolated receptors will be identified by mass spectrometry. We will evaluate the relevance of identified receptors in anergic B cells from man and mouse. Understanding the molecular pathways by which inhibitory signaling circuits are activated in autoreactive B cells is important. Many risk alleles associated with an increased risk to develop autoimmune disease affect these inhibitory circuits. Delineating pathway relationships will allow for more accurate predictions of which risk alleles will act synergistically. This will enable us to identify individuals at heightened risk and will allow for earlier intervention and possible preventive care. Identified receptors are also potential novel targets for therapeutic intervention which may allow us to restore B cell tolerance.