HLA*B Associated Genes and Memory B cells in patients with CVID

描述（由申请人提供）：常见变异性免疫缺陷（CVID）是对患有不明原因的血清免疫球蛋白缺乏的患者的临床诊断。大多数CVID患者的主诉是复发性肺感染。最近的研究表明，记忆B细胞区室的减少可能是该疾病发病机制的一个关键特征，特别是在编码ICOS或TACI的基因功能突变丧失的患者中，这两种基因都是促进抗原反应性B细胞及其免疫球蛋白分泌浆细胞后代长期存活的因素。然而，在我们美国东南部的临床CVID患者群体中，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），几乎一半的人继承了HLA*B44。我们最近在我们的临床人群中描述了一组单独的患者，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诊断的阈值。HLA*B44在该人群中的患病率与CVID人群相似。在CVID患者的一级和二级亲属中识别出符合RESPI类别的患者，这使我们提出了这样的假设，即这些RESPI患者患有与经典CVID患者更严重的免疫功能障碍相同的遗传易感性的影响。由于HLA*B44及其邻近基因与常见的ICOS或TACI通路之间没有明显联系，因此B细胞数量减少与mhc相关的RESPI和CVID之间的相关性程度尚不清楚。在本应用中，我们拟检测HLA* b44相关的CVID和RESPI中记忆B细胞数量是否减少。如果是这样，那么这将支持记忆B细胞测定在不明原因复发性肺感染患者的临床评估中的应用。我们进一步建议使用这些信息来帮助绘制假定的RESPI/CVID的共同易感基因。在美国临床免疫学家的护理下，MHC中一个或多个基因的特征可以用来预测对RESPI的易感性和改变记忆B细胞数量，这有助于定义和扩展已经是最常见的原发性免疫缺陷的范围。鉴定一个易感基因将有助于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：目前的一种假设认为，共同可变免疫缺陷（CVID）反映了无法产生或维持记忆B细胞。在我们的诊所中，几乎一半的CVID患者，以及几乎一半的血清抗体水平正常且肺部和鼻窦反复感染（RESPI）的患者都遗传了HLA*B44，这表明MHC等位基因与感染易感性之间存在联系。我们建议使用这些患者群体来检测血清免疫球蛋白水平正常的感染患者是否也具有低记忆B细胞数量，并确定与HLA*B44相关的易感基因，这将有助于阐明这种感染易感性背后的机制。

DESCRIPTION (provided by applicant): Common variable immunodeficiency (CVID) is a clinical diagnosis given to patients who suffer with an unexplained deficiencies of serum immunoglobulins. The presenting complaint for most CVID patients is recurrent sinopulmonary infections. Recent work suggests that a reduction in the memory B cell compartment may be a key feature in the pathogenesis of the disease, especially among patients with loss of function mutations in the genes that encode ICOS or TACI, both of which are factors involved in promoting the long term survival of antigen-responsive B cells and their immunoglobulin-secreting, plasma cell progeny. However, among our clinic population of CVID patients in the Southeastern US, the greatest genetic linkage is to the major histocompatibility complex (MHC) on chromosome 6, with almost half inheriting HLA*B44. We recently characterized a separate group of patients within our clinic population who presented with adult-onset recurrent sinopulmonary infections (RESPI) and serum immunoglobulin levels above the threshold for diagnosis with CVID. The prevalence of HLA*B44 in this population proved similar to that in CVID. Recognition of patients who fit into the RESPI category among first and second degree relatives of CVID patients led us to the hypothesis that these RESPI patients are suffering from the effects of the same genetic susceptibility to immune dysfunction that manifests more severely in classic CVID. With no obvious link as yet between HLA*B44 and neighboring genes to a common ICOS or TACI pathway, the extent of correlation between reduced B cell numbers and MHC-associated RESPI and CVID remains unclear. In the present application, we propose to test whether memory B cell numbers are reduced in HLA*B44-associated CVID and RESPI. If so, then this would support use of memory B cell determinations in the clinical evaluation of patients with unexplained recurrent sinopulmonary infection. We further propose to use this information to help map the putative common susceptibility gene for RESPI/CVID. Characterization of a gene or genes within the MHC that can be used to predict susceptibility to RESPI and alter memory B cell numbers 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. Identification of a susceptibility gene would help to elucidate the mechanism(s) that underlie susceptibility to infection, facilitate diagnosis, and point to new avenues for prevention and treatment. PUBLIC HEALTH RELEVANCE: One current hypothesis holds that common variable immune deficiency (CVID) reflects an inability to produce or maintain memory B cells. In our clinic, almost one-half of our CVID patients, as well as almost one-half of patients with normal serum antibody levels and repeated infections of the lungs and sinuses (RESPI), have inherited HLA*B44, suggesting linkage between this MHC allele and susceptibility to infection. We propose to use these patient populations to test whether the patients with infections in spite of normal serum immunoglobulin levels also have low memory B cell numbers and to identify the susceptibility gene linked to HLA*B44, which should help elucidate the mechanism behind this susceptibility to infections.