Primary Immuno-Deficiencies Affecting Specific Stages of the Immune Response

影响免疫反应特定阶段的原发性免疫缺陷

• 批准号: 7560933
• 负责人: CORNELIS P TERHORST
• 金额: $ 182.21万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7560933
• 关键词: Primary; Immuno; Deficiencies; Affecting; Specific

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.

描述（由申请人提供）：我们的新计划项目拨款的修订申请汇集了一组研究人员，他们是分子和细胞免疫学以及人类和小鼠遗传学领域的专家。我们建议在题为“影响适应性免疫反应特定阶段的原发性免疫缺陷”的申请中研究单基因在 X 连锁淋巴增殖综合征 (XLP)、常见变异免疫缺陷 (CVID)、Omenn 综合征和严重联合免疫缺陷 (SCID) 发病机制中的作用。由于对患者材料的成功初步分析，令人兴奋 该应用旨在确定 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 细胞依赖性和/或 T 细胞非依赖性免疫球蛋白反应。我们将在以下四个相互关联的项目和管理核心中利用我们最近获得的对这些疾病原因的见解：项目#1 SAP (SH2D1A) 基因在 T 细胞依赖性抗体反应中的作用。考克斯·特霍斯特，贝斯以色列女执事医疗中心。项目 #2 TACI 突变在常见变异性免疫缺陷中的作用 Raif Geha，波士顿儿童医院。项目 #3 Omenn 综合征和渗漏 SCID 的基因敲入模型。 Luigi Notarangelo，波士顿儿童医院。项目#4 严重联合免疫缺陷小鼠模型。弗雷德·阿尔特，波士顿儿童医院。核心 A 行政核心 Cox Terhorst，贝斯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个基因突变引起的复杂且经常交替的疾病表现。这些研究的结果应该提出可应用于这些 PID 患者的治疗策略，并可能揭示通常与免疫失调、自身免疫和癌症有关的分子和细胞机制。 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（由申请人提供）：X 连锁淋巴增殖综合征 (XLP) 具有三种常见表型的特征：1) 暴发性传染性单核细胞增多症，2) 恶性 B 细胞淋巴瘤和 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 的三种主要表型在一个具有相同突变的家族中被发现，因此遗传背景和/或环境因素必定在该疾病的发病机制中发挥作用。 FIM 患者的 T 细胞和 B 细胞发生剧烈、不受控制的多克隆扩增，不可避免地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），这是一种单一的游离 SH2 结构域蛋白，控制 CD4 和 CD8 T 淋巴细胞、NK 细胞、血小板以及可能的 B 细胞子集中不同的关键信号转导途径。 SAP 充当适配器，将 SLAM 受体家族六个成员的细胞质尾部桥接至信号转导途径，例如Fyn 和其他酪氨酸激酶。先前的研究表明，XLP 患者和 SAP 缺陷小鼠中获得性免疫反应的多个部分受到影响，并且 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，这些机制对于控制体液免疫至关重要。本申请中提出的实验将检验以下假设：#1) 不同的 SAP-/- CD4+ T 细胞亚群和/或 NKT 细胞导致 SAP-/- 小鼠的丙种球蛋白异常血症，#2) SAP 基因的破坏影响滤泡 B 细胞亚群，这些亚群参与体液反应和生发中心反应，#3) EAT-2A/B 和 SAP 在 抗体反应的控制。这些实验共同阐明了 SAP 和 EAT-2 在 T 细胞依赖性 B 细胞反应中的作用，以及 SAP 功能缺失导致丙种球蛋白异常血症的原因。这些研究的结果应提出可应用于 XLP 患者的治疗策略。