HLA Region and KIR Genomics in Common Variable Immune Deficiency

常见变异性免疫缺陷病中的 HLA 区域和 KIR 基因组学

基本信息

批准号：
8115993
负责人：
Harry William Schroeder
金额：
$ 57.06万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115993
关键词：
Adult Alleles B-Lymphocytes Cell physiology Chromosomes, Human, Pair 6 Clinic Clinical Clinical Immunology Common Variable Immunodeficiency Coupled DNA Depressed mood Diagnosis Disease Evaluation Event Genetic Epistasis Genetic Predisposition to Disease Genomics HLA-B Antigens Haplotypes Immune Immune System Diseases Immunogenetics Immunoglobulins Immunologist Individual Infection Inherited Institutional Review Boards Ligands Lymphocyte Subset Major Histocompatibility Complex Maps Mediating Molecular Epidemiology Monozygotic twins Natural Killer Cells Pathogenesis Patients Pattern Phenotype Population Population Study Predisposition Prevention Recurrence Reporting Retinal Cone Risk Factors Role Second Degree Relative Serum Sorting - Cell Movement Specimen Study Subject Susceptibility Gene T-Cell Receptor T-Lymphocyte TNFRSF10A gene Techniques Time case control clinical Diagnosis clinical care cost genetic linkage public health relevance

项目摘要

DESCRIPTION (provided by applicant): Common variable immunodeficiency (CVID) is a clinical diagnosis given to patients who suffer with unexplained deficiencies of serum immunoglobulins. Most CVID patients present with recurrent sinopulmonary infections. Among our clinic population, the greatest genetic linkage is to the major histocompatibility complex (MHC) on chromosome 6, with more than 80% of our patients inheriting either HLA*B08 or HLA*B44. We recently characterized a separate group of clinic patients who presented with adult-onset recurrent sinopulmonary infections (RESPI) and serum immunoglobulin levels above the threshold for diagnosis with CVID, but with the same distribution of HLA*B08 and HLA*B44 as that seen in CVID. Recognition of RESPI patients among first and second degree relatives of CVID patients, including two identical twins discordant for RESPI and CVID, led us to the hypothesis that RESPI patients are suffering from the effects of the same genetic susceptibility to immune dysfunction that manifests more severely in classic CVID. Careful analysis has shown a variety of abnormalities in either the number or function of a number of different lymphocyte subsets in both RESPI and CVID patients. For example, NK cells have been reported to be depressed in number, but the role of factors that can mediate NK cell function, including the role of KIR and MHC ligands, remains unknown. We propose to use our population of RESPI/CVID patients to map the putative common susceptibility gene for RESPI/CVID within the MHC, to characterize HLA/KIR interactions, and to evaluate the expressed B cell and T cell antigen receptor repertoires in these patients. This comprehensive analysis of the MHC, KIR, BCR and TCR could help define and extend the spectrum of what is already the most common primary immune deficiency under the care of clinical immunologists in the US, as well as to elucidate the mechanism(s) that underlie susceptibility to infection, facilitate diagnosis, and point to new avenues for prevention and treatment. PUBLIC HEALTH RELEVANCE (provided by applicant): Findings from this proposal will be used to define the relationships between the MHC, KIR, the BCR and TCR repertoires and their functional relevance to the pathogenesis and clinical course of CVID and RESPI.

描述（由申请人提供）：普通变异性免疫缺陷（CVID）是对患有不明原因的血清免疫球蛋白缺乏的患者进行的临床诊断。大多数 CVID 患者出现复发性鼻窦肺部感染。在我们的临床人群中，最大的遗传连锁是 6 号染色体上的主要组织相容性复合体 (MHC)，我们超过 80% 的患者遗传 HLA*B08 或 HLA*B44。我们最近对另一组临床患者进行了特征分析，这些患者患有成人复发性鼻窦肺部感染 (RESPI)，血清免疫球蛋白水平高于 CVID 诊断阈值，但 HLA*B08 和 HLA*B44 的分布与CVID。在 CVID 患者的一级和二级亲属中识别出 RESPI 患者，包括 RESPI 和 CVID 不一致的两个同卵双胞胎，使我们得出这样的假设：RESPI 患者遭受相同的免疫功能障碍遗传易感性的影响，这种影响在 CVID 患者中表现得更严重。经典CVID。仔细分析表明，RESPI 和 CVID 患者中许多不同淋巴细胞亚群的数量或功能存在多种异常。例如，据报道 NK 细胞数量减少，但介导 NK 细胞功能的因子的作用，包括 KIR 和 MHC 配体的作用，仍然未知。我们建议利用我们的 RESPI/CVID 患者群体来绘制 MHC 内 RESPI/CVID 假定的常见易感基因，以表征 HLA/KIR 相互作用，并评估这些患者中表达的 B 细胞和 T 细胞抗原受体库。对 MHC、KIR、BCR 和 TCR 的全面分析可以帮助定义和扩展美国临床免疫学家治疗下最常见的原发性免疫缺陷的范围，并阐明其机制是感染易感性的基础，有助于诊断，并指出预防和治疗的新途径。公共卫生相关性（由申请人提供）：本提案的研究结果将用于定义 MHC、KIR、BCR 和 TCR 全部之间的关系及其与 CVID 和 RESPI 的发病机制和临床病程的功能相关性。