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）：这项修订的新计划项目赠款的申请将一组研究人员汇集在一起​​，这些研究人员是分子和细胞免疫学领域以及人类和小鼠遗传学领域的专家。我们建议研究单个基因在X连锁淋巴细胞增生综合征（XLP），常见可变免疫缺陷（CVID），OMENN综合征和严重组合免疫缺陷（SCID）的作用中在遗传改变的小鼠中的发现，该应用程序试图定义SH2D1A，SH2D1B/C，TACI，RAG-1/2，DNA连接酶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细胞依赖性免疫球蛋白反应。我们将在以下四个相互联系的项目和管理核心：SAP（SH2D1A）基因在T细胞依赖性抗体反应中的作用：项目＃1的作用。考克斯·特霍斯特（Cox Terhorst），贝丝以色列执事医疗中心。项目＃2在塔西taci突变中的作用在波士顿儿童医院的常见可变免疫缺陷中。 Omenn综合征和SCID泄漏的项目＃3基因敲入模型。波士顿儿童医院Luigi Notarangelo。项目＃4严重合并免疫缺陷的小鼠模型。波士顿儿童医院弗雷德·阿尔特（Fred Alt）。核心行政核心Cox Terhorst，贝丝以色列执事医疗中心。拟议的研究的结果应使人们更好地了解由单个基因突变引起的复杂疾病表现。这些研究的结果应提出可以应用于这些PID患者的治疗策略，并可能揭示通常参与免疫失调，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（Cornelis Terhorst）中的作用 项目1描述（由申请人提供）：X连锁的淋巴增生综合征（XLP）的特征是三种普遍的表型：1）在没有感染单核症的情况下获得降低性低毒素的传染性单核细胞增多症，2）恶性B细胞淋巴瘤和3）获得降低症。由于在一个具有相同突变的家庭中发现了XLP的三种主要表型，因此遗传背景和/或环境因素必须在疾病的发病机理中起作用。 FIM患者在T和B细胞的剧烈，不受控制的多克隆膨胀上，不可避免地因肝坏死和骨髓衰竭而导致死亡。人类XLP的一个主要原因是SH2D1A基因的缺陷，该缺陷编码SAP（SLAM相关蛋白），这是一种单个游离的SH2域蛋白，该蛋白可以控制CD4和CD8 T淋巴细胞，NK细胞，NK细胞，血小板以及B细胞的一个不同的CD4和CD8 T淋巴细胞中的不同键信号转导途径。 SAP充当适配器，它桥接了SLAM受体家族的六个成员的细胞质尾巴，以信号转导途径，例如Fyn和其他酪氨酸激酶。先前的研究表明，获得的免疫反应的几个臂在XLP患者和SAP缺陷型小鼠中受到影响，并且与SAP相关的分子EAT-2A和-2B效果相似。我们的总体假设是，SAP和EAT-2A/B控制了对控制体液免疫至关重要的部分重叠机制。本应用程序中提出的实验将检验以下假设：＃1）不同的SAP - / - CD4+ T细胞集和/或NKT细胞有助于SAP - / - 小鼠的肿瘤性肿瘤 - 甘露素血症，＃2）破坏SAP基因的sap基因会影响柔性B细胞，并在幽默反应中，并在幽默反应中，并在幽默响应中及其中心，并在幽默反应中及其序列中的序列中的序列中心及＃中的序列中的序列中的序列，＃）序列中的序列中的序列中的序列和序列中的序列中的序列中的序列相互作用。抗体反应的控制。这些实验应加在一起阐明SAP和EAT-2在T细胞依赖性B细胞反应中的作用，以及为什么缺乏SAP功能会导致肿瘤性肿瘤性血症。这些研究的结果应提出可以应用于XLP患者的治疗策略。