B cells generate non-inflammatory immune protection in the intestinal mucosa by undergoing class switch recombination (CSR) from IgM to IgA. Growing evidence indicates that IgA CSR involves engagement of transmembrane activator and calcium-modulating cyclophilin-ligand interactor (TACI) on B cells by B cell activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two factors released by intestinal epithelial cells (lECs) and dendritic cells in response to microbial Toll-like receptor (TLR) ligands. The goal of this proposal is to elucidate the mechanisms by which BAFF and APRIL induce IgA CSR and somatic hypermutation (SHM), a process required for affinity maturation. The proposal will also explore the contribution of BAFF and APRIL to intestinal homeostasis, a dynamic process required to develop immunity without causing inflammation. Our preliminary data indicate that BAFF and APRIL activate the CSR machinery and elicit IgA CSR and IgA production through a B cell signaling pathway involving interaction of TACI with MyD88, an adaptor protein usually required for the generation of signals by TLRs. Additional preliminary results show that TACI activates mammalian target of rapamycin (mTOR), a signal integrator with an emerging role in adaptive immunity. Further findings show that lECs express TACI and respond to BAFF and APRIL by enhancing the expression of mucin, an IgA-interacting protein endowed with immunoprotective and immunoregulatory functions. Thus, we hypothesize that BAFF and APRIL promote non-inflammatory immunity in the intestine by linking B cells with lECs through a TACI-dependent IgA inducing pathway comprising MyD88 and mTOR.
Three specific aims are proposed.
Aim 1 is to identify the mechanisms by which TACI activates IgA-inducing transcription factors in intestinal B cells.
Aim 2 is to dissect the mechanisms by which TACI triggers IgA CSR, SHM and production in intestinal B cells.
Aim 3 is to determine the mechanisms by which TACI induces transcytosis of IgA and production of IgA-interacting homeostatic factors in intestinal epithelial cells. The proposed studies (Project 2) will take advantage of the unique resources including cells and tissues made available by this consortium and of the complementary and integrative expertise of the Cunningham-Rundles group, which evaluates the role of TACI in B cell proliferation and differentiation (Project 1), the Meffre group (Project 3), which explores the role of TACI and other key antibody-regulating molecules in B cell tolerance, and the Casanova group (Project 4), which studies B cell genes involved in primary antibody deficiencies.

Public Health Relevance

Primary immunodeficiencies can be regarded as experiments of nature that can help us to better understand the in vivo relevance, function and regulation of specific immune processes and signaling pathways. In this application, we will take advantage of multiple primary immunodeficiencies with known gene defects to better understand the mechanisms by which B cells produce IgA, the most abundant antibody isotype in our body. The proposed studies may also elucidate the mechanisms by which IgA generates immune protection in the intestinal mucosa without causing inflammation-induced disruption of the epithelial barrier.

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Icahn School of Medicine at Mount Sinai
New York
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