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（由申请方提供）：常见变异性免疫缺陷是一种已充分描述的原发性免疫缺陷，其特征为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易感性增加。只有大约5-10%的病例是由于ICOS或TACI中的遗传可识别缺陷，使得大多数病例成为病因不明的异质性组。理论上，CVID的发病机制可能涉及B细胞成熟、T细胞辅助和/或抗原呈递缺陷。虽然CVID中描述了T细胞功能的几种缺陷，但已知的唯一特异性共刺激缺陷是ICOS 1缺陷，ICOS 1是一种T细胞共刺激分子，其功能对B细胞免疫球蛋白类别转换很重要1，2。考虑到ICOS对于T细胞辅助的阐述是重要的，并且CVID可能是一种多基因疾病，可能存在T细胞共刺激的其他缺陷，无论是通过共刺激分子本身的遗传缺陷，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）在初始刺激后通过CD 3/CD 28暂时表达，其促进T细胞记忆应答和寿命，这两者对于T细胞辅助的阐述都很重要。本项目将从T细胞辅助的角度探讨常见可变型免疫缺陷病的发病机制，特别是研究T细胞共刺激的缺陷。CVID中的几个其他发现也表明T细胞帮助中的可能缺陷，包括：在一些患者中存在相对扩增的CD 28-/CD 8 + T细胞群体（“耗尽的”效应细胞，也见于慢性HIV感染），血清IL 7（一种T细胞存活因子）降低，以及类别转换记忆B细胞数量较少3 -10。该项目的中心假设是：T细胞共刺激缺陷导致T细胞帮助缺陷，并导致CVID的发病机制。这将使用具有人工抗原呈递细胞（aAPC）系统的功能测定来探索，用于分析对T细胞增殖和功能的影响，包括共刺激的下游影响（目标#1），来自CVID样品的全基因组SNP分析和使用aAPC系统刺激的T细胞的微阵列基因表达分析（目标#2）。该项目的初步数据将用于开发一项研究计划，探索原发性免疫缺陷疾病中的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发病机制的促成因素。肿瘤坏死因子超家族（TNFSF）的T细胞共刺激分子已在小鼠模型中进行了大量研究，但在人类中的表征尚未完全了解。待研究的人群是一组在生命的前20年出现的常见变异性免疫缺陷（CVID）患者，而不是后来出现的传统CVID人群。研究这一人群将导致重要的发现CVID的发病机制，在一个年轻的年龄组和开发的治疗靶向TNFSF成员，这有希望操纵免疫反应的免疫缺陷疾病的治疗。