Details

Autor(en) / Beteiligte

• Cerutti, Andrea

Titel

The regulation of IgA class switching

Ist Teil von

• Nature reviews. Immunology, 2008-06, Vol.8 (6), p.421-434

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• Key Points 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 (C α ) 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 C α 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 C α 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. IgA is the most abundant antibody class and provides a first line of defence at mucosal surfaces. Class switching to IgA occurs through both T-cell-dependent and T-cell-independent pathways, and recent studies reveal a role for commensal bacteria in intestinal IgA responses. IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-cell-dependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.