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: 7140244
• 负责人: EMANUELA CASTIGLI
• 金额: $ 20.63万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140244
• 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）： IgA 是人类合成的主要免疫球蛋白类别。大部分 IgA 由粘膜相关淋巴组织合成。正常的粘膜 IgA 反应对于防止细菌和病毒通过气道和胃肠道入侵非常重要。选择性 IgA 缺陷是最常见的免疫缺陷，影响 1/300 至 1/700 的个体，其中大约一半患有复发性感染。 IgA 缺乏症的原因尚不清楚。 APRIL 和 BAFF 是在树突状细胞 (DC) 上表达的相关 TNF 家族成员，它们共享两个受体 TACI 和 BCMA，而 BAFF 具有一个额外的受体 BAFF-R，均在 B 细胞上表达。 TACI-/- 小鼠和 APRIL-/- 小鼠具有选择性 IgA 缺陷，而 BAFF-/- 和 BAFF-R-/- 实际上缺乏成熟 B 细胞。 APRIL 和 BAFF 在体外诱导 IgA 类别转换。我们假设 APRIL/BAFF 驱动的 IgA 转换可以解释 CD40L 和 CD40 缺陷的正常血清 IgA 水平。 我们的目标是确定 APRIL、BAFF 及其受体在粘膜 IgA 抗体反应和人类 IgA 缺乏中的作用。我们将测试以下假设：（目标 I）APRIL 和 BAFF 通过 TACI 的参与在体外引起 IgA 同型转换； （目标 II）APRIL 和 BAFF 由肠道和气道粘膜中的树突状细胞 (DC) 和巨噬细胞表达，并介导与负载共生细菌的肠道 DC 培养的 B 细胞中的 IgA 转换。我们还将测试 APRIL 和 BAFF 是否在防止肠道细菌入侵、IgA 抗体对这些细菌的反应以及抗原粘膜免疫中发挥重要作用。我们将调查（目标 III）APRIL 和 TACI 的突变是否是人类 IgA 缺乏病例的基础。拟议的研究对于我们了解粘膜 IgA 反应和设计更有效的口服疫苗非常重要。鉴定 IgA 缺陷患者的突变基因对于设计增强 IgA 抗体反应的疗法至关重要。