HLA Region and KIR Genomics in Common Variable Immune Deficiency

描述（由申请人提供）：常见可变免疫缺陷（CVID）是一种临床诊断给患有不明原因的血清免疫球蛋白缺乏的患者。大多数CVID患者表现为复发性肺感染。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*B08或HLA*B44。我们最近描述了一组临床患者，他们表现为成人发作的复发性肺感染（RESPI），血清免疫球蛋白水平高于CVID的诊断阈值，但HLA*B08和HLA*B44的分布与CVID相同。在CVID患者的一级和二级亲属中识别出RESPI患者，包括两个RESPI和CVID不一致的同卵双胞胎，使我们假设RESPI患者遭受相同的遗传易感性对免疫功能障碍的影响，而在经典CVID中表现得更严重。仔细分析表明，在RESPI和CVID患者中，许多不同淋巴细胞亚群的数量或功能都存在各种异常。例如，据报道NK细胞数量下降，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。我们建议使用我们的RESPI/CVID患者群体来绘制MHC中RESPI/CVID的假定共同易感基因，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。这项对MHC、KIR、BCR和TCR的综合分析可以帮助定义和扩展美国临床免疫学家护理下最常见的原发性免疫缺陷的范围，并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。

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.