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

描述(由申请人提供)： 免疫球蛋白是人类合成的主要免疫球蛋白类。大部分IgA是由粘膜相关淋巴组织合成的。正常的黏膜免疫球蛋白A反应对于防止细菌和病毒通过呼吸道和胃肠道的入侵非常重要。选择性IgA缺乏症是最常见的免疫缺陷，影响1/300至1/700人，其中约一半人患有反复感染。(S)免疫球蛋白A缺乏症的原因不明。APRIL和BAFF是表达在树突状细胞上的相关的肿瘤坏死因子家族成员，树突状细胞共享两个受体TACI和BCMA，而BAFF还有一个额外的受体BAFF-R，它们都表达在B细胞上。TACI-/-小鼠和4月-/-小鼠患有选择性IgA缺乏症，而BAFF-/-和BAFF-R-/-实际上缺乏成熟的B细胞。APRIL和BAFF在体外诱导IgA类转换。我们推测，APRIL/BAFF驱动的IgA转换可能解释了CD40L和CD40缺陷患者血清IgA水平正常的原因。 我们的目标是确定APRIL、BAFF及其受体在黏膜免疫球蛋白A抗体应答和人类免疫球蛋白A缺乏症中的作用。我们将验证假设：(目的I)APRIL和BAFF在体外通过TACI的参与引起IgA同型转换；(目的II)APRIL和BAFF由肠道和呼吸道粘膜中的树突状细胞(DC)和巨噬细胞表达，并在与装入共生菌的肠道DC培养的B细胞中介导IgA转换。我们还将测试APRIL和BAFF是否在保护肠道细菌入侵、对这些细菌的IgA抗体反应和粘膜抗原免疫方面发挥重要作用。我们将调查(目标III)4月和TACI的突变是否是人类IgA缺乏症的基础。建议的研究对于我们理解黏膜免疫球蛋白A反应和设计更有效的口服疫苗很重要。识别IgA缺陷患者的突变基因对于设计提高他们的IgA抗体反应的治疗方法至关重要。

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.