APRIL-TACI: Role in mucosal IgA and human IgA deficiency

APRIL-TACI：在粘膜 IgA 和人类 IgA 缺乏中的作用

• 批准号: 6956844
• 负责人: EMANUELA CASTIGLI
• 金额: $ 25.31万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956844
• 关键词: CD40 molecule; antigen antibody reaction; bacteria infection mechanism; bacterial genetics; bactericidal immunity; blood tests; clinical research; enzyme linked immunosorbent assay; flow cytometry; gastrointestinal infection; gene mutation; gene rearrangement; genetic mapping; growth factor receptors; human subject; immunodeficiency; immunoglobulin A; immunoglobulin genes; laboratory mouse; mucosal immunity; polymerase chain reaction; receptor expression; tissue /cell culture; tumor necrosis factor beta

DESCRIPTION (provided by applicant): IgA is the predominant immunoglobulin class synthesized in humans. The majority of IgA is synthesized by mucosa-associated lymphoid tissue. A normal mucosal IgA response is important for protection against invasion by bacteria and viruses via the airways and gastrointestinal tract. Selective IgA deficiency is the most common immunodeficiency affecting 1/300 to 1/700 individuals, approximately half of whom suffer from recurrent infections. The cause(s) of IgA deficiency is (are) unknown. APRIL and BAFF are related TNF family members expressed on dendritic cells (DCs) which share two receptors TACI and BCMA with BAFF having an additional receptor BAFF-R, all expressed on B cells. TACI-/- mice and APRIL-/- mice have selective IgA deficiency, whereas BAFF-/- and BAFF-R-/- virtually lack mature B cells. APRIL and BAFF induce IgA class switching in vitro. We postulate that APRIL/BAFF driven IgA switching may explain the normal serum IgA levels in CD40L and CD40 deficiencies. Our objective is to define the role of APRIL, BAFF and their receptors in the mucosal IgA antibody response and in human IgA deficiency. We will test the hypotheses: (Aim I) APRIL and BAFF cause IgA isotype switching in vitro via engagement of TACI; (Aim II) APRIL and BAFF are expressed by dendritic cells (DCs) and macrophages in intestinal and airway mucosa and mediate IgA switching in B cells cultured with intestinal DCs loaded with commensal bacteria. We will also test whether APRIL and BAFF play an important role in protection from invasion by intestinal bacteria, in the IgA antibody response to these bacteria and to mucosal immunization with antigen. We will investigate (Aim III) whether mutations in APRIL and TACI underlie cases of human IgA deficiency. The proposed studies are important for our understanding of the mucosal IgA response and for devising more effective oral vaccines. Identification of genes mutated in IgA deficient patients is critical for devising therapies that boost their IgA antibody response.

描述（由申请人提供）： 伊加是人类中合成的主要免疫球蛋白类别。大部分伊加由粘膜相关淋巴组织合成。正常的粘膜伊加应答对于防止细菌和病毒通过气道和胃肠道侵入是重要的。选择性伊加缺乏症是最常见的免疫缺陷，影响1/300至1/700的个体，其中约一半患有复发性感染。而这一点，也是众所周知的。APRIL和BAFF是在树突状细胞（DC）上表达的相关TNF家族成员，其与BAFF共享两种受体TACI和BCMA，BAFF具有另外的受体BAFF-R，所有受体均在B细胞上表达。TACI-/-小鼠和APRIL-/-小鼠具有选择性伊加缺乏，而BAFF-/-和BAFF-R-/-实际上缺乏成熟的B细胞。APRIL和BAFF在体外诱导伊加类别转换。我们推测，APRIL/BAFF驱动的伊加转换可以解释正常的血清伊加水平在CD 40 L和CD 40缺陷。 我们的目的是确定的作用，APRIL，BAFF和它们的受体在粘膜伊加抗体反应和人类伊加缺乏症。我们将测试假设：（目的I）APRIL和BAFF通过TACI的参与在体外引起伊加同种型转换;（目的II）APRIL和BAFF由肠和气道粘膜中的树突状细胞（DC）和巨噬细胞表达，并介导与负载有肠道细菌的肠DC一起培养的B细胞中的伊加转换。我们还将测试是否APRIL和BAFF发挥重要作用，在保护肠道细菌的入侵，在伊加抗体应答这些细菌和粘膜免疫抗原。我们将研究（目的III）APRIL和TACI突变是否是人类伊加缺乏症的基础。这些研究对于我们理解粘膜伊加反应和设计更有效的口服疫苗具有重要意义。识别伊加缺陷患者中突变的基因对于设计增强其伊加抗体应答的疗法至关重要。