Molecular Pathogenesis of Immune Dysfunction In Wiskott-Aldrich-Syndrome

描述（由申请人提供）：Wiskott-Aldrich综合征（WAS）是一种X连锁免疫缺陷，由WAS蛋白（WASp）基因突变引起，是辅助性T细胞（Th）正常功能所需，对形成适应性免疫应答很重要。疾病的临床严重程度可以从轻度到重度不等，即使在具有相同WASp突变的患者中也是如此。这种适应性免疫功能障碍的生物学基础尚不清楚。Th：DC相互作用启动了多种特异于Th 1分化的信号通路。经典的Th 1信号通路需要在Th免疫突触（ThIS）处形成成熟的Th 1-信号体（IFN 3R + TCR 2）以及下游STAT 1和T-bet的激活，从而导致IFN-3的转录。同时，T-bet的ITK依赖性磷酸化是Th 2转录因子加塔-3失活所必需的。最后，Notch信号通路对Th 1和Th 2分化都有影响。这些看似不同的信号通路是如何组织成一个功能性Th 1发育范式的？在这项提案中，我们将测试的假设，WASp是关键的TCR依赖性和Notch依赖性途径的Th 1激活，并提出WASp的适配器功能组织Th 1发育反应，通过促进Notch，ITK和T-bet之间的相互作用。我们认为WAS临床表型的严重程度反映了WASp突变破坏这些相互作用所引起的Th功能障碍的程度。在目标1中，我们将测试的假设，即WASp是关键的TCR依赖性途径的Th 1分化的正常运作。目的2将检验WASp在Th 1分化中对Notch信号传导至关重要的假设。最后，目标3将测试WAS临床表型的严重程度反映在Th功能障碍的程度的假设。这些研究将为WASp在健康和疾病适应性免疫反应发展中的功能提供新的见解，这可能对开发新的治疗靶点具有价值。术语摘要：Wiskott-Aldrich综合征（WAS）是一种遗传性全身免疫缺陷，由一种称为WASP的蛋白质缺陷引起，临床表现为严重的复发性感染、容易瘀伤和出血、自身免疫和癌症。本提案中的研究将在分子水平上检查WASP的功能，以确定WAS上述临床并发症的原因。这些研究应该为未来设计新的治疗方法奠定基础，针对这种危及生命的儿童衰弱疾病。

DESCRIPTION (provided by applicant): Wiskott-Aldrich syndrome (WAS) is an X-linked immune deficiency arising from mutations in the WAS protein (WASp) gene, required for the proper functioning of T helper cell (Th), important for shaping the adaptive immune response. The clinical severity of disease can range from mild to severe, even in patients with the identical WASp mutation. The biological basis for this range of adaptive immune dysfunction is not known. The Th:DC interaction initiates multiple signaling pathways specific for Th1 differentiation. The classical Th1 signaling pathway requires the formation of a mature Th1-signalosome (IFN3R+TCR2) at the Th immune synapse (ThIS) and downstream activation of STAT1 and T-bet, leading to transcription of IFN-3. In parallel, ITK-dependent phosphorylation of T-bet is required for deactivation of GATA-3, the Th2 transcription factor. Finally, the Notch signaling pathway has effects on both Th1 and Th2 differentiation. How are these seemingly disparate signaling pathways organized into a functional Th1 developmental paradigm? In this proposal we will test the hypothesis that WASp is critical for both TCR-dependent and Notch-dependent pathways of Th1 activation, and propose that the adaptor function of WASp organizes Th1 developmental responses by fostering interactions between Notch, ITK and T-bet. We posit that the severity of WAS clinical phenotype mirrors the degree of Th dysfunction imparted by WASp mutations that disrupt these interactions. In Aim 1, we will test the hypothesis that WASp is critical for the proper functioning of the TCR-dependent pathway of Th1 differentiation. Aim 2 will test the hypothesis that WASp is critical for Notch-signaling in Th1 differentiation. Finally, Aim 3 will test the hypothesis that the severity of WAS clinical phenotype is mirrored in the degree of Th dysfunction. These studies should provide new insights into the function of WASp in the development of the adaptive immune response in health and disease, which may be of value in developing new therapeutic targets. Lay-term summary: Wiskott-Aldrich syndrome (WAS) is a genetically transmitted systemic immune deficiency resulting from a defect in a protein called WASP and manifesting clinically in severe recurrent infections, easy bruising and bleeding, autoimmunity, and cancers. The studies in this proposal will examine the function of WASP at the molecular level to determine the causes of the above clinical complications of WAS. These studies should lay the foundation for designing novel therapies in the future, for this life-threatening, debilitating disease of the childhood.