Investigating Blocks to B Cell Memory in CVID

项目总结（见说明）： 普通可变免疫缺陷病（CVID）是临床上最重要的原发性抗体缺乏病，由于患病率，并发症，住院治疗和终身免疫球蛋白治疗的要求。患者的B细胞缺乏正常体细胞超突变和同种型转换的能力，分泌免疫球蛋白差，不能分化为浆细胞。CVID中B细胞功能障碍的遗传原因在很大程度上是未知的。在8- 10%的患者中发现了跨膜激活因子、钙调节因子和亲环素配体相互作用因子（TACI）基因的杂合突变，但在免疫球蛋白水平正常的亲属中也发现了杂合突变，这表明这些不是严重B细胞功能障碍的主要原因。然而，具有TACI突变的CVID受试者，特别是杂合子形式的CVID受试者，更有可能发生显著的淋巴组织增生和自身免疫。使用人B细胞和具有TACI突变的转染子，我们将研究人中的TACI受体功能，检查TACI中的单等位基因或双等位基因突变是否加速BAFF/BAFF-R介导的B细胞生长和分化。TLR激动剂与TACI信号可能会促进自身反应性，以及发挥作用的B细胞分化在人类中，因此，我们将研究如何这些可能会驱动B细胞增殖和自身免疫性CVID，特别是当TACI信号受损。 由于人B细胞具有两种结构不同的TACI同种型，我们将确定功能能力的差异，并探索对这些天然存在的同种型的产生的控制。目前的假设是，TACI突变可能导致单倍不足;我们将通过检查Smith Magenis综合征患者的B细胞功能来研究这一点，这些患者是TACI无效等位基因的杂合子， 染色体缺失在这个项目中，我们假设在CVID受试者及其非免疫缺陷亲属中发现的TACI突变可用于探索TACI受体及其配体BAFF和APRIL如何控制人类B细胞生长和分化。这些数据可能有助于了解这种复杂的受体系统在人类自身免疫性疾病的一般。

PROJECT SUMMARY (See instructions): Common variable immune deficiency (CVID) is the clinically most important primary antibody deficiency disease due to prevalence, complications, hospitalizations and requirement for lifelong immune globulin therapy. B cells of patients lack the capacity for normal somatic hyper-mutation and isotype switch, secrete immune globulins poorly, and fail to differentiate into plasma cells. The genetic causes of B cell dysfunction in CVID are largely unknown. Heterozygous mutations in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene are found in 8-10%, but also in relatives with normal immune globulin levels showing that these are not the main cause of severe B cell dysfunction. However, CVID subjects with TACI mutation especially in heterozygous form are significantly more likely to develop striking lymphoid hyperplasia and autoimmunity. Using human B cells and transfectants with TACI mutations, we will investigate TACI receptor function in humans, examining if monoallellic or biallelic mutations in TACI accelerate BAFF/BAFF-R mediated B cell growth ahd differentiation. TLR agonists with TACI signals may promote self-reactivity as well as play a role in B cell differentiation in humans, thus we will examine how these may drive B cell proliferation and autoimmunity in CVID, especially when TACI signals are impaired. As human B cells have two structurally different TACI isoforms we will determine the differences in functional capacities, and explore the controls on the production of these naturally occurring isoforms. A current hypothesis is that mutations in TACI could lead to haploinsufficiency; we will investigate this by examining B cell function in patients with the Smith Magenis syndrome, who are heterozygous for a null TACI allele due to a chromosomal deletion. In this project we hypothesize that mutations in TACI found in subjects with CVID and their non immune deficient relatives, can be used to explore how the TACI receptor and its ligands, BAFF and APRIL, control B cell growth and differentiation in humans. These data may be of use in understanding this complex receptor system in human autoimmune disease in general.