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。 项目1：SAP(SH2D1A)基因在T细胞依赖性抗体反应中的作用(Cornelis Terhorst) 项目1描述(申请人提供)：X连锁淋巴增殖症(XLP)的特征是三种流行的表型：1)暴发性传染性单核细胞增多症，2)恶性B细胞淋巴瘤，3)无传染性单核细胞增多症的获得性低丙种球蛋白血症。由于XLP的三种主要表型是在一个具有相同突变的家族中发现的，遗传背景和/或环境因素肯定在该病的发病机制中发挥了作用。FIM患者对T和B细胞进行了强有力的、不受控制的多克隆扩增，不可避免地会导致肝坏死和骨髓衰竭而死亡。人类XLP的一个主要原因是SH2D1A基因的缺陷，该基因编码SAP(SLAM相关蛋白)，SAP是一种单一的游离SH2结构域蛋白，控制着CD4和CD8 T淋巴细胞、NK细胞、血小板以及可能是B细胞亚群的不同的关键信号转导通路。SAP作为一个适配器，连接SLAM受体家族六个成员的细胞质尾巴与信号转导通路，如Fyn和其他酪氨酸激酶。先前的研究表明，XLP患者和SAP缺陷小鼠的获得性免疫反应的几个臂受到影响，SAP相关分子EAT-2A和-2B具有类似的功能。我们的一般假设是SAP和EAT-2A/B控制部分重叠的机制，这些机制对体液免疫的控制至关重要。本申请中提议的实验将检验这样的假设：1)不同的SAP-/-CD4+T细胞亚群和/或NKT细胞有助于SAP-/-小鼠的丙种球蛋白血症，#2)SAP基因的中断影响毛囊B细胞亚群，后者参与体液反应和生发中心反应，以及#3)EAT-2A/B和SAP在抗体反应控制中相互作用。总之，这些实验应该阐明SAP和EAT-2在T细胞依赖性B细胞反应中的作用，以及为什么SAP功能的缺失会导致丙种球蛋白血症。这些研究的结果应该建议可以应用于XLP患者的治疗策略。

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. PROJECT 1: Role of SAP (SH2D1A) gene in T cell-dependent antibody response (Cornelis Terhorst) PROJECT 1 DESCRIPTION (provided by applicant): X-linked lymphoproliferative syndrome (XLP) is characterized by three prevalent phenotypes: 1) Fulminant Infectious Mononucleosis, 2) malignant B cell lymphoma and 3) acquired hypogammaglobulinemia in the absence of infectious mononucleosis. As the three major phenotypes of XLP are found within one family harboring the same mutation, genetic background and/or environmental factors must play a role in the pathogenesis of the disease. FIM patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells, inevitably leading to death by hepatic necrosis and bone marrow failure. A major cause of XLP in humans is a defect in the SH2D1A gene, which encodes SAP (SLAM Associated Protein), a single free SH2- domain protein that controls distinct key signal transduction pathways in CD4 and CD8 T lymphocytes, NK cells, platelets and probably a subset of B cells. SAP functions as an adapter, which bridges the cytoplasmic tail of six members of the SLAM receptor family to signal transduction pathways, e.g. Fyn and other tyrosine kinases. Previous studies show that several arms of the acquired immune responses are affected in XLP patients and SAP-deficient mice and that the SAP related molecules EAT-2A and -2B subserve similar functions. Our general hypothesis is that SAP and EAT-2A/B control partially overlapping mechanisms that are critical for the control of humoral immunity. The experiments proposed in this application will test the hypothesis that #1) distinct SAP-/- CD4+ T cell subsets and/or NKT cells contribute to the dysgammaglobulinemia of SAP-/- mice, #2) disruption of the SAP gene affects the subsets of follicular B cells, which participate in humoral responses and in the germinal center reaction and #3) EAT-2A/B and SAP interact in the control of antibody responses. Together these experiments should clarify the role of SAP and EAT-2 in T cell dependent B cell responses and why the absence of SAP functions causes dysgammaglobulinemia. The results of these studies should suggest therapeutic strategies that can be applied to XLP patients.