Role of TACI mutations in CVID

TACI 突变在 CVID 中的作用

• 批准号: 8296684
• 负责人: RAIF SALIM GEHA
• 金额: $ 47.76万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296684
• 关键词: Accounting; Affect; Alleles; Antibodies; Antibody Formation; Antigens; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocytes; Binding; Biological Assay; Calcium; Cell physiology; Cell surface; Cells; Collaborations; Common Variable Immunodeficiency; Cyclophilins; Cysteine-Rich Domain; Data; Defect; Dendritic Cells; Development; Dominant-Negative Mutation; Dose; Etiology; Extracellular Domain; Family member; Fluorescence Resonance Energy Transfer; Functional disorder; Genes; Heterozygote; Human; Immune response; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunologic Deficiency Syndromes; In Vitro; Incidence; Infection; Knock-in Mouse; Lateral; Ligand Binding; Ligands; Ligation; Lymphoma; Malignant lymphoid neoplasm; Mediating; Memory B-Lymphocyte; Missense Mutation; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Pathway interactions; Patients; Pediatric Hospitals; Plasma Cells; Play; Polysaccharides; Precipitation; Principal Investigator; Protein Isoforms; Proteins; Recurrence; Reporting; Role; Serum; Signal Transduction; Signaling Protein; Staging; Subgroup; TALL-1 protein; TLR4 gene; TNFRSF5 gene; TNFSF5 gene; TNP-ficoll; Testing; Transgenes; Transgenic Organisms; Transmembrane Domain; Tumor Necrosis Factor Receptor; domain mapping; extracellular; in vivo; macrophage; medical attention; mutant; neutrophil; novel; overexpression; programs; receptor; response; trinitrophenyl-lipopolysaccharide

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.

常见变异型免疫缺陷（CVID）是人类最常见的原发性免疫缺陷。患者 患有CVID的患者患有复发性感染，并且自身免疫性疾病的发病率增加， 淋巴恶性肿瘤TACI是主要在B细胞上表达的BAFF和APRIL的受体，并且在细胞内起作用。 在B细胞分化和针对II型T非依赖性（T1）抗原的抗体产生中起重要作用。TACI是 在CVID患者亚组中发生突变。两个错义突变，胞外区的C104 R， 破坏配体结合，跨膜区的A181 E破坏信号传导， 对于CVID中的大多数TACI突变。大多数具有这两种突变的CVID患者是杂合子。 该项目的中心主题是建立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寡聚化的细胞表面和TACI连接协同 与CD 40和TLR一起引起B细胞分化。在表达突变体的TACI+/-小鼠中的初步数据 TACI转基因支持C104 R突变的作用机制为单倍不足，并提示 A181突变可以产生显性负性（DN）效应。我们的总体假设是， CVID中发现的杂合TACI突变由于单倍不足或DN而损害TACI功能 这些突变与B细胞活化的其他途径中的缺陷一起导致了 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性配体TACI寡聚化 诱导的信号传导，映射介导hTACI组装的结构域并探测hTACI的功能。 hTACI的短和长同种型。 2.分析A181 E TACI突变体是否在转染子和患者B细胞中体外发挥DN效应， 以及在基因敲入小鼠体内。 3.确定TACI突变对其与TACI中的CD 40和TLR的体外和体内协同作用的影响 突变小鼠，并研究TACI突变是否与CD 40和TLR 4突变协同作用 严重损害B细胞功能的途径，如在CVID中观察到的。 这些研究将帮助我们理解TACI突变可能导致的分子机制。 导致CVID中的B细胞功能障碍。它们对于理解CVID的病因及其治疗也是至关重要的。 研究人员还发现，这些药物可以用于治疗并发症（自身免疫和淋巴瘤），并为受影响的患者设计新的治疗方法。 相关性（参见说明）： 常见变异型免疫缺陷（CVID）是人类最常见的原发性免疫缺陷。患者 CVID患有复发性感染，并且自身免疫性疾病和淋巴样疾病的发生率增加。 恶性肿瘤这些研究对于理解CVID的病因及其并发症至关重要 （自身免疫和淋巴瘤）和为受影响的患者设计新的疗法。