Primary Immuno-Deficiencies Affecting Specific Stages of the Immune Response

描述(由申请人提供)：我们新项目资助的修订申请汇集了一群在分子和细胞免疫学以及人类和老鼠遗传学领域的专家的研究人员。我们建议研究单基因在X连锁淋巴增殖性综合征(XLP)、常见变量免疫缺陷(CVID)、Omenn综合征和严重联合免疫缺陷(SCID)的发病机制中的作用。在一项题为“初级免疫缺陷影响适应性免疫反应的特定阶段”的应用中，由于对患者材料的成功的初步分析，在转基因小鼠中的令人兴奋的发现，该应用试图定义SH2D1A、SH2D1B/C、TACI、RAG-1/2、DNA Ligase IV或Cernunnos基因的突变如何影响T和B细胞发育以及T细胞依赖和/或T细胞非依赖的免疫球蛋白反应。我们将在以下四个相互关联的项目和一个管理核心中使用我们最近获得的对这些疾病的原因的见解：项目1 SAP(SH2D1A)基因在T细胞依赖抗体反应中的作用。考克斯·特霍斯特，贝丝以色列女执事医疗中心。项目2在常见变量免疫缺陷的TACI突变中的作用，波士顿儿童医院Raif Geha。项目#3 Omenn综合征和漏洞性SCID的基因敲入模型。Luigi Notarangelo，波士顿儿童医院。项目4严重联合免疫缺陷的小鼠模型。弗雷德·阿尔特，波士顿儿童医院。管理核心考克斯·特霍斯特，贝丝以色列女执事医疗中心。拟议研究的结果应该有助于更好地理解由单基因突变引起的复杂且往往是交替的疾病表现。这些研究的结果应该会建议可以应用于这些盆腔炎患者的治疗策略，并可能解开通常涉及免疫失调、自身免疫和癌症的分子和细胞机制。

DESCRIPTION (provided by applicant): This revised application for our new Program Project Grant brings together a group of investigators who are experts in the areas of molecular and cellular immunology and human and mouse genetics. We propose to study the role of single genes in the pathogenesis of X-linked Lymphoproliferative syndrome (XLP), Common variable immunodeficiency (CVID), Omenn syndrome and Severe Combined Immunodeficiencies (SCID) in an application, entitled: "Primary Immunodeficiencies Affecting Specific Stages of the Adaptive Immune Response" Because of successful preliminary analyses of patient materials, exciting findings in genetically altered mice, this application seeks to define how mutations in the SH2D1A, SH2D1B/C, TACI, RAG-1/2, DNA Ligase IV or Cernunnos genes affect T and B cell development and T cell dependent and/or T cell-independent immunoglobulin responses. We will use our recently acquired insights into the causes of these diseases in the following four interlinked projects and an Administrative Core: Project #1 Role of the SAP (SH2D1A) gene in T cell-dependent antibody responses. Cox Terhorst, Beth Israel Deaconess Medical Center. Project #2 Role of in TACI mutations in Common Variable Immunodeficiency Raif Geha, Children's Hospital of Boston. Project #3 Gene knock-in models for Omenn syndrome and leaky SCID. Luigi Notarangelo, Children's Hospital of Boston. Project #4 Mouse Models of Severe Combined Immunodeficiencies. Fred Alt, Children's Hospital of Boston. Core A Administrative Core Cox Terhorst, Beth Israel Deaconess Medical Center. The outcomes of proposed studies should lead to better understanding of the complex and often alternate disease manifestations that are caused by mutations in a single gene. The results of these studies should suggest therapeutic strategies that can be applied to these PID patients and may unravel molecular and cellular mechanisms that are generally involved in immune dysregulation, autoimmunity and cancer.