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

描述(申请人提供)：常见可变型免疫缺陷(CVID)是一种临床诊断，患者患有不明原因的血清免疫球蛋白缺乏。大多数CVID患者的主诉是反复出现的鼻窦肺部感染。最近的研究表明，记忆B细胞室的减少可能是该病发病机制中的一个关键特征，特别是在编码ICOS或TACI的基因发生功能突变的患者中，这两个基因都参与了促进抗原反应性B细胞及其分泌免疫球蛋白的浆细胞后代长期存活的因素。然而，在美国东南部的临床CVID患者中，最大的遗传连锁是与6号染色体上的主要组织相容性复合体(MHC)，几乎一半的人遗传了HL A*B44。我们最近在我们的临床人群中确定了一组单独的患者，这些患者表现为成人起病的复发性鼻窦肺部感染(RESPI)，且血清免疫球蛋白水平高于诊断CVID的阈值。在该人群中，人类白细胞抗原*B44的患病率与CVID相似。在CVID患者的一级和二级亲属中，对符合RESPI类别的患者的认识使我们假设，这些RESPI患者遭受着与经典CVID更严重的相同的免疫功能障碍遗传易感性的影响。到目前为止，由于人类白细胞抗原B44和邻近基因与共同的ICOS或TACI途径之间没有明显的联系，B细胞数量减少与MHC相关的RESPI和CVID之间的相关性仍不清楚。在本应用中，我们建议测试在与HLA*B44相关的CVID和RESPI中记忆B细胞数量是否减少。如果是这样的话，这将支持在不明原因的复发性鼻窦肺部感染患者的临床评估中使用记忆B细胞测定。我们进一步建议利用这一信息来帮助定位RESPI/CVID的推测的共同易感基因。对MHC中可用于预测RESPI易感性和改变记忆B细胞数量的一个或多个基因的特征，可能有助于定义和扩大美国临床免疫学家照顾下的最常见的初级免疫缺陷的范围。识别易感基因将有助于阐明感染易感性的机制(S)，有助于诊断，并为预防和治疗指明新的途径。与公共卫生相关：目前的一种假说认为，共同变量免疫缺陷(CVID)反映了无法产生或维持记忆B细胞。在我们的临床中，几乎一半的CVID患者，以及几乎一半血清抗体水平正常且反复肺部和鼻窦感染(RESPI)的患者都遗传了人类白细胞抗原*B44，这表明这种MHC等位基因与感染的易感性有关。我们建议使用这些患者群体来测试尽管血清免疫球蛋白水平正常的感染患者是否也具有较低的记忆B细胞数量，并识别与人类白细胞抗原*B44连锁的易感基因，这将有助于阐明这种感染易感性的机制。

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.