The regulation of IgA class switching

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Abstract
IgA is the most abundant isotype antibody in the intestinal mucosa, where it provides a first line of immune protection against commensal, ingested and sexually transmitted agents. IgA uses a high-affinity binding system to neutralize toxins and pathogens and a low-affinity binding system to confine commensal bacteria to the intestinal lumen. B cells acquire the capability to produce IgA by undergoing class-switch recombination (CSR), a process that requires germline transcription of the heavy chain constant α gene (Cα) and expression of activation-induced cytidine deaminase (AID), an essential component of the CSR machinery. Together with post-IgA CSR modifications, IgA CSR generates multiple molecular forms of IgA proteins, each endowed with distinct topography and functions. In vivo and in vitro studies show that B cells undergo IgA class switching through both T-cell-dependent and T-cell-independent pathways, which generate high- and low-affinity IgA antibodies, respectively. T-cell-dependent IgA class switching requires T-cell help to B cells via CD40 ligand (CD40L) and the cytokine transforming growth factor-β1 (TGFβ1), whereas T-cell-independent IgA class switching involves innate signals provided by microbial Toll-like receptor (TLR) ligands and CD40L-related dendritic cell (DC) mediators, including B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). TGFβ1 induces germline Cα gene transcription through SMAD (mothers against decapentaplegic) proteins, whereas CD40L triggers AID expression through nuclear factor-κB (NF-κB). BAFF and APRIL activate B cells by engaging transmembrane activator and calcium-modulating cyclophilin-ligand interactor (TACI), a receptor that triggers AID expression via NF-κB and germline Cα gene transcription through a signalling pathway that remains poorly understood. In the gut, T-cell-dependent IgA class switching takes place in the germinal centres of organized lymphoid structures, including Peyer's patches, whereas T-cell-independent IgA class switching occurs in the non-organized lymphoid tissue of the lamina propria. Nitric oxide from a subset of mucosal DCs enhances T-cell-dependent IgA class switching by upregulating the expression of TGFβ1 receptor on B cells, and T-cell-independent IgA class switching by augmenting the production of BAFF and APRIL by DCs. Intestinal epithelial cells produce APRIL and thymic stromal lymphopoietin (TSLP), a DC-activating cytokine with APRIL-inducing activity, after sensing bacteria through TLRs. APRIL triggers sequential class switching to IgA2 in human IgA1-expressing B cells arriving from Peyer's patches, thereby enriching the distal intestinal tract in IgA2, which is more resistant to bacterial degradation than IgA1.