Regulation of mucosal IgA responses: lessons from primary immunodeficiencies

Abstract

Adaptive co-evolution of mammals and bacteria has led to the establishment of complex commensal communities on mucosal surfaces. In spite of having available a wealth of immune-sensing and effector mechanisms capable of triggering inflammation in response to microbial intrusion, mucosal immune cells establish an intimate dialogue with microbes to generate a state of hyporesponsiveness against commensals and active readiness against pathogens. A key component of this homeostatic balance is IgA, a noninflammatory antibody isotype produced by mucosal B cells through class switching. This process involves activation of B cells by IgA-inducing signals originating from mucosal T cells, dendritic cells, and epithelial cells. Here, we review the mechanisms by which mucosal B cells undergo IgA diversification and production and discuss how the study of primary immunodeficiencies facilitates better understanding of mucosal IgA responses in humans.

Figure 1

Cellular networks underlying mucosal IgA responses. Intestinal epithelial cells (IECs) “condition” dendritic cells (DCs) by releasing thymic stromal lymphopoietin (TSLP) and retinoic acid (RA) in response to TLR ligands from commensal bacteria. Different subsets of intestinal DCs release TGF-β, IL-10, RA, and nitric oxide (NO) that promote IgA responses in Peyer’s patches and mesenteric lymph nodes (MLNs) by inducing T regulatory (T_reg) and T helper (Th) cells, including T_reg-derived T follicular helper cells, which activate follicular B cells via CD40L, TGF-β, IL-4, IL-10, and IL-21. Follicular DCs further enhance IgA production by releasing B cell–activating factor of the TNF family (BAFF), a proliferation-inducing ligand (APRIL), and TGF-β upon exposure to TLR ligands and RA. Some subsets of intestinal DCs also induce T cell–independent IgA production in mesenteric lymph nodes or the lamina propria by releasing BAFF, APRIL, RA, and NO in response to TLR ligands from commensals or IFN-β from stromal cells. In humans, these T cell–independent signals would induce switching from IgM or IgA1 to IgA2. The IgA antibodies emerging from these pathways undergo transcytosis across IECs via the polymeric Ig receptor.

Figure 2

Signaling pathways emanating from transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI). The TGF-β receptor (TGF-βR) initiates germline C_α gene transcription by activating the I_α promoter via SMA-homologue mothers against decapentaplegic (SMAD) proteins. At the same time, engagement of TACI by BAFF and APRIL triggers the recruitment of myeloid differentiation primary response gene 88 (MyD88) to a TACI highly conserved (THC) motif located in the cytoplasmic domain of TACI receptor. TACI also recruits TNF receptor–associated factor 2 (TRAF2) to a motif located immediately downstream of THC. The THC motif is distinct from the Toll-interleukin-1 receptor (TIR) motif, which mediates the recruitment of MyD88 by Toll-like receptors (TLRs). Recruitment of IL-1 receptor–associated kinase 1 (IRAK-1), IRAK-4, and TRAF6 by TACI and TLRs leads to the activation and nuclear translocation of NF-κB, which initiates transcriptional activation of the AICDA gene encoding activation-induced cytidine deaminase (AID). Together, germline C_α gene transcription and AID induction cause class switch recombination from IgM to IgA in B cells.