Uncovering co-stimulatory T cell help defects in common variable immunodeficiency

发现共刺激 T 细胞有助于常见变异免疫缺陷的缺陷

• 批准号: 7939826
• 负责人: ELENA E PEREZ
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939826
• 关键词: Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; B-Lymphocytes; BLR1 gene; Bacterial Infections; Biological Assay; CCL19 gene; CCL21 gene; CCR5 gene; CD28 gene; CD4 Positive T Lymphocytes; Cell Communication; Cell Maturation; Cell Size; Cell Survival; Cell physiology; Chronic; Coculture Techniques; Common Variable Immunodeficiency; Data; Databases; Defect; Development; Disease; Effector Cell; Etiology; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic Polymorphism; Genomics; Growth; HIV Infections; Human; IL7 gene; Immune response; Immunoglobulin Class Switching; Immunoglobulins; Immunologic Deficiency Syndromes; Immunophenotyping; Lead; Left; Length; Life; Ligands; Longevity; Memory; Mutation; Pathogenesis; Pathway interactions; Patients; Polymorphism Analysis; Population; Population Study; Predisposition; Production; Property; Research; Sampling; Serum; Signal Transduction; System; Systems Analysis; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF4 gene; Time; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; age group; cell motility; cellular engineering; chemokine; cytokine; exhaust; genome-wide; member; mouse model; programs; public health relevance; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Common variable immunodeficiency is a well described primary immunodeficiency characterized by low serum immunoglobulin concentrations, defective specific antibody production and increased susceptibility to bacterial infections. Only approximately 5-10% of cases are due to genetically identifiable defects in ICOS or TACI, leaving the majority of cases as a heterogeneous group of unknown etiology. Theoretically, the pathogenesis of CVID could involve defects in B cell maturation, T cell help, and/or antigen presentation. While several defects in T cell function have been described in CVID, the only specific co-stimulation defect known is deficiency of ICOS1, a T cell co-stimulatory molecule whose function is important for B cell immunoglobulin class switching1,2. Given that ICOS is important for the elaboration of T cell help, and that CVID is likely a polygenic disease, other defects of T cell co-stimulation probably exist, whether manifested by genetic defects in the co-stimulatory molecules themselves, or in the pathways that they promote. There are many co-stimulatory molecules, (members of the Immunoglobulin or TNFR superfamilies), that are temporally expressed after initial stimulation via CD3/CD28, which promote T cell memory responses and longevity, both important for the elaboration of T cell help. This project will explore the pathogenesis of Common Variable Immunodeficiency Disease from a T cell help perspective, specifically investigating defects of T cell co-stimulation. Several other findings in CVID also suggest a possible defect in T cell help including: the presence in some patients of a relatively expanded population of CD28-/CD8+ T cells ("exhausted" effector cells, also seen in chronic HIV infection), decreased serum IL7, a T cell survival factor, and low numbers of class switched memory B cells3-10. The central hypothesis of this project is: Defects in T cell co-stimulation result in faulty T cell help, and contribute to the pathogenesis of CVID. This will be explored using functional assays with an artificial antigen presenting cell (aAPC) system for analysis of effects on T cell proliferation and function including downstream effects of co-stimulation (Aim #1), genome wide SNP analysis from CVID samples and microarray gene expression analysis of T cells stimulated using the aAPC system (Aim #2),. Preliminary data from this project will be used to develop a research program exploring T cell co-stimulation defects in primary immunodeficiency diseases. PUBLIC HEALTH RELEVANCE: This study aims to discover contributing factors to the pathogenesis of CVID from a T cell help perspective. The T cell co-stimulatory molecules of the Tumor Necrosis Factor Superfamily (TNFSF) have been avidly studied in mouse models, yet characterization in humans is not yet completely understood. The population to be studied is a group of patients with common variable immunodeficiency (CVID) who presented in the first two decades of life, rather than the traditional population of CVID that presents later. Studying this population will lead to important discoveries regarding the pathogenesis of CVID in a younger age group and to the development of therapeutics targeting TNFSF members which holds promise for manipulating immune responses for the treatment of immunodeficiency diseases.

描述（由申请人提供）：普通变量免疫缺陷是一种充分描述的主要免疫缺陷，其特征是血清免疫球蛋白浓度低，特异性抗体产生缺陷和对细菌感染的敏感性增加。仅大约5-10％的病例是由于ICOS或TACI的遗传鉴定缺陷引起的，因此大多数病例是一个未知病因的异质群。从理论上讲，CVID的发病机理可能涉及B细胞成熟，T细胞帮助和/或抗原表现的缺陷。尽管在CVID中描述了T细胞功能中的几个缺陷，但唯一的特定共同刺激缺陷已知是ICOS1的缺陷，ICOS1的缺陷是T细胞的共刺激分子，其功能对B细胞免疫球蛋白类切换至关重要1,2。鉴于ICO对于阐述T细胞帮助很重要，并且CVID可能是一种多基因疾病，因此T细胞共刺激的其他缺陷可能存在，无论是由共刺激分子本身的遗传缺陷表现出来还是在它们促进的途径中。有许多共刺激分子（免疫球蛋白或TNFR超家族的成员）在通过CD3/CD28初始刺激后暂时表达，这促进了T细胞的记忆反应和寿命，这对T细胞的阐述都很重要。该项目将从T细胞帮助的角度探索常见可变免疫缺陷疾病的发病机理，特别研究T细胞共刺激的缺陷。 CVID中的其他几个发现还表明，T细胞帮助的可能缺陷，包括：在相对扩大的CD28-/CD8+ T细胞中的某些患者中的存在（“耗尽”的效应细胞，在慢性HIV感染中也可见），血清IL7降低，T细胞IL7，T细胞存活因子和较低的Class Chessect Switch Memory B细胞3-10。该项目的中心假设是：T细胞共刺激的缺陷导致T细胞的故障，并有助于CVID的发病机理。将使用具有人造抗原呈现细胞（AAPC）系统的功能测定方法来探讨这一点，以分析对T细胞增殖和功能的影响，包括共刺激的下游效应（AIM＃1），CVID样品中的基因组宽SNP分析以及使用AAPC系统刺激的T细胞分析的CVID SNP分析（AIM＃2）。该项目的初步数据将用于制定一项研究计划，探讨原发性免疫缺陷疾病中T细胞共刺激缺陷。公共卫生相关性：本研究旨在从T细胞帮助的角度发现CVID发病机理的贡献。肿瘤坏死因子超家族（TNFSF）的T细胞共刺激分子已经在小鼠模型中进行了广泛研究，但尚未完全了解人类的表征。要研究的人群是一群具有常见可变免疫缺陷（CVID）的患者，他们在生命的前二十年中提出，而不是后来出现的CVID人群。研究该人群将导致有关年龄段CVID发病机理的重要发现，以及针对TNFSF成员的治疗剂的发展，这有望操纵免疫反应以治疗免疫缺陷疾病。