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

• 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
• 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

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）：常见可变免疫缺陷（CVID）是对患有无法解释的血清免疫球蛋白缺乏症的患者进行的临床诊断。大多数CVID患者都有复发性肺部感染。在我们的诊所人群中，最大的遗传联系是6号染色体上的主要组织相容性复合物（MHC），其中80％以上的患者遗传了HLA*B08或HLA*B44。我们最近对一组单独的临床患者进行了表征，这些临床患者呈现成人发作的中性肺部感染（RESSI）和血清免疫球蛋白水平高于CVID诊断的阈值，但在CVID中所见，HLA*B08和HLA*B44的分布相同。 CVID患者一级和二级亲属的认识，包括两个与RESPI和CVID不一致的双胞胎，这使我们提出了这样的假设：Respi患者正患有相同遗传易感性对免疫功能障碍的影响，在经典CVID中表现出更严重的免疫功能障碍。仔细的分析表明，在RESPI和CVID患者中，许多不同淋巴细胞亚群的数量或功能各种异常。例如，据报道，NK细胞的数量降低，但是可以介导NK细胞功能（包括KIR和MHC配体的作用）的因素的作用仍然未知。我们建议利用我们的RESSI/CVID患者群体绘制MHC内respI/CVID的假定共同敏感性基因，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细胞抗原受体谱。对MHC，KIR，BCR和TCR的这种全面分析可以帮助定义和扩展美国在美国临床免疫学家的照顾下最常见的原发性免疫缺陷的观点，并阐明了对感染的敏感性的机制，以促进诊断，并促进诊断，并指向新的诊断和治疗。 公共卫生相关性（由申请人提供）：该提案的发现将用于定义MHC，KIR，BCR和TCR曲目之间的关系及其与CVID和RESSI的发病机理和临床过程的功能相关性。