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: 8508841
• 负责人: Harry William Schroeder
• 金额: $ 48.66万
• 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/8508841
• 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（由申请方提供）：常见变异型免疫缺陷（CVID）是对患有原因不明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患者表现为反复鼻窦感染。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），超过80%的患者遗传HLA* B 08或HLA*B44。我们最近对一组临床患者进行了特征分析，这些患者表现为成人复发性鼻窦炎感染（RESPI），血清免疫球蛋白水平高于CVID诊断阈值，但HLA* B 08和HLA*B44的分布与CVID相同。CVID患者的一级和二级亲属中对RESPI患者的识别，包括两对RESPI和CVID不一致的同卵双胞胎，使我们假设RESPI患者遭受着与免疫功能障碍相同的遗传易感性的影响，这种影响在经典CVID中表现得更严重。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各种异常。例如，据报道NK细胞的数量减少，但可以介导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。我们建议使用我们的RESPI/CVID患者群体来绘制MHC内RESPI/CVID的推定共同易感基因，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。这种对MHC、KIR、BCR和TCR的全面分析可以帮助定义和扩展在美国临床免疫学家的护理下已经是最常见的原发性免疫缺陷的范围，以及阐明感染易感性的机制，促进诊断，并指出预防和治疗的新途径。 公共卫生相关性（由申请方提供）：本提案的结果将用于定义MHC、KIR、BCR和TCR库之间的关系及其与CVID和RESPI发病机制和临床病程的功能相关性。