Role of TACI mutations in CVID

常见可变型免疫缺陷(CVID)是人类最常见的原发免疫缺陷。病人 患有CVID的患者反复感染，自身免疫性疾病的发生率增加， 淋巴样恶性肿瘤。TacI是BAFF和APRIL的受体，主要表达在B细胞上，并在 在B细胞分化和产生针对II型T非依赖性(TL)抗原的抗体中起重要作用。TACI是 在CVID患者的亚组中发生突变。两个错义突变，胞外区的C104R， 破坏配体结合的A181E，以及跨膜结构域中的A181E，它废除了信号转导 对于CVID中的大多数TACI突变。大多数具有这两种突变的CVID患者都是杂合子。 该项目的中心主题是确定在CVID中观察到的TACI突变的功能相关性。 我们的初步数据表明，TACI在细胞表面寡聚，TACI连接起协同作用 与CD40和TLRs共同诱导B细胞分化。TACI+/“小鼠表达突变的初步数据 TACI转基因支持单倍体不足是C104R突变的作用机制，并提示 A181E突变可能产生显性负面(DN)效应我们的总体假设是 CVID中发现的杂合子TACI突变因单倍体功能不全或糖尿病肾病而损害TACI功能 这些突变与B细胞活化的其他途径的缺陷一起导致了 CVID的发展。为了检验这一假设，我们建议： 1.检查后续配体是否需要非配体依赖的配体TACI齐聚 诱导信号转导，映射介导hTACI组装的结构域(S)，并探讨hTACI的功能 HTACI的短、长两种亚型。 2.分析A181E TACI突变体是否在体外对转染者和患者B细胞产生糖尿病肾病效应， 在转基因小鼠体内也是如此。 3.检测TACI基因突变对其与CD40、TLRs协同作用的影响 突变小鼠，并研究TACI突变是否与CD40和TLR4突变协同作用 在CVID中观察到的严重损害B细胞功能的途径。 提出的研究将帮助我们理解TACI突变可能通过的分子机制 导致CVID中的B细胞功能障碍。它们对于了解CVID的病因和其 用于治疗并发症(自身免疫和淋巴瘤)以及为受影响的患者设计新的治疗方法。 相关性(请参阅说明)： 常见可变型免疫缺陷(CVID)是人类最常见的原发免疫缺陷。患有疾病的患者 CVID反复感染，自身免疫性疾病和淋巴系统疾病的发生率增加 恶性肿瘤。建议的研究对于了解脑血管病及其并发症的病因学至关重要。 (自身免疫和淋巴瘤)和为受影响的患者设计新的治疗方法。

Common variable immunodeficiency (CVID) is the most common human primary immunodeficiency. Patients with CVID suffer from recurrent infections and have an increased incidence of autoimmune disorders and lymphoid malignancies. TACI is a receptor for BAFF and APRIL expressed mainly on B cells, and plays an important role in B cell differentiation and antibody production to type II T independent (Tl) antigens. TACI is mutated in a subgroup of patients with CVID. Two missense mutations, C104R in the extracellular domain, which disrupts ligand binding, and A181E in the transmembrane domain, which abolishes signaling, account for the majority of TACI mutations in CVID. Most CVID patients with these two mutations are heterozygous. The central theme of this project is to establish the functional relevance of TACI mutations observed in CVID. Our preliminary data suggests that TACI oligomerizes on the cell surface and that TACI ligation synergizes with CD40 and TLRs to cause B cell differentiation. Preliminary data in TACI+/" mice that express mutant TACI transgenes support haploinsufficiency as the mechanism of action of the C104R mutation, and suggest that the A181Emutation could exert a dominant negative (DN) effect Our overall hypothesis is that heterozygous TACI mutations found in CVID impair TACI function because of haploinsufficiency or a DN effect and that these mutations contribute together with defects in other pathways of B cell activation to the development of CVID. To test this hypothesis we propose to: 1. Examine whether ligand-independent ligand TACI oligomerization is required for subsequent ligand induced signaling, map the domain(s) that mediates the assembly of hTACI and probe the function of the short and long isoforms of hTACI. 2. Analyze whether the A181E TACI mutant exerts a DN effect in vitro in transfectants and patient B cells, and in vivo in knock-in mice. 3. Determine the effect of TACI mutations on its synergy with CD40 and TLRs in vitro and in vivo in TACI mutant mice, and investigate whether TACI mutations cooperate with mutations in the CD40 and TLR4 pathways to severely impair B cell function as observed in CVID. The studies proposed will help us understand the molecular mechanisms by which TACI mutations may contribute to B cell dysfunction in CVID. They are also critical for understanding the etiology of CVID and its complications (autoimmunity and lymphoma) and for devising novel therapies for affected patients. RELEVANCE (Seeinstructions): Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in humans. Patients with CVID suffer from recurrent infections and have an increased incidence of autoimmune disorders and lymphoid malignancies. The studies proposed are critical for understanding the etiology of CVID and of its complications (autoimmunity and lymphoma) and for devising novel therapies for affected patients.