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

描述（由申请人提供）：

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.