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  • Review Article
  • Published:

The regulation of IgA class switching

Nature Reviews Immunology volume 8, pages 421–434 (2008)Cite this article

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 (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.

Abstract

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.

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Figure 1: Recombinatorial and transcriptional events underlying IgA class switching.
Figure 2: Signalling events leading to T-cell-dependent IgA class switching.
Figure 3: Signalling events leading to T-cell-independent IgA class switching.
Figure 4: Map of IgA class switching in the gut.
Figure 5: Cellular interactions causing IgA class switching in the gut.

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Acknowledgements

The author is supported by US National Institutes of Health (NIH) research grants AI057653, AI057653-S1 and AI074378, and by an Irma T. Hirschl Career Scientist Award.

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  1. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, and Weill Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, 10021, New York, USA

    Andrea Cerutti

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Glossary

Non-homologous end-joining

The process that joins broken DNA ends independently of extended homology. Components of this pathway include the proteins Ku70, Ku80, ARTEMIS, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).

Membrane-bound IgA

IgA protein expressed on the surface of B cells that have undergone IgA class switching. Membrane IgA works as a transmembrane antigen receptor in that it delivers activating signals to effector memory B cells on secondary exposure to antigen.

Secreted IgA

(sIgA). IgA protein secreted by early plasmacytoid B cells (or plasmablasts) and terminally differentiated plasma cells. sIgA exists in monomeric, dimeric or oligomeric forms that target local or distant antigens.

Biofilm

A population of aggregated microorganisms, typically concentrated at an interface (usually solid–liquid), that is held together by a protective self-produced extracellular polymeric substance matrix.

M cells

(Microfold or membrane cells). Specialized epithelial cells that deliver antigens by transepithelial vesicular transport from the gut lumen to intraepithelial dendritic cells and lymphocytes.

Peyer's patches

Large lymphoid follicles positioned in the antimesenteric wall of the small intestine and containing a large germinal centre. Each follicle is capped by a dome area and is flanked by a T-cell-rich perifollicular area.

Follicular DCs

Specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells have long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface.

Kupffer cells

Large, stellate- or pyramidal-shaped, specialized macrophages that line the sinusoidal vessels of the liver. They regulate local immune responses, and remove microbial particles, endotoxin and other noxious substances that penetrate the portal venous system.

Asialoglycoprotein receptor

A C-type lectin receptor that mediates endocytosis of desialylated glycoproteins and clearance of circulating IgA2 by hepatocytes.

Transferrin receptor

Also known as CD71, this receptor regulates the cellular import of iron by binding the iron-carrier protein transferrin. In addition, it mediates clearance of circulating IgA1 by renal mesangial cells.

Portal venous system

The venous system responsible for directing blood from parts of the gastrointestinal tract to the liver.

APOBEC

(Apolipoprotein B RNA-editing, catalytic component). A cytidine deaminase enzyme family including APOBEC1, an RNA editor involved in lipid metabolism, APOBEC3G and APOBEC3F, two DNA editors with antiretroviral activity, and activation-induced cytidine deaminase, a DNA editor mediating immunoglobulin gene diversification.

Hyper-IgM syndrome

(HIGM). Congenital immunodeficiency with defective immunoglobulin heavy chain class switching and increased IgM production. The underlying molecular defect involves CD40 ligand (HIGM1), activation-induced cytidine deaminase (HIGM2), CD40 (HIGM3), uracil DNA glycosylase (HIGM4) or other unknown B-cell proteins (HIGM5).

Isolated lymphoid follicles

Small lymphoid aggregates located in the antimesenteric wall of the small intestine and containing B cells, dendritic cells, stromal cells and some T cells. They may contain germinal centres.

VIP

(Vasoactive intestinal peptide). A peptide hormone released by mucosal postsynaptic parasympathetic nerve fibres and intrinsic neurons of the intestinal lamina propria. In addition to stimulating water and electrolyte secretion and intestinal wall motility, VIP activates lymphocytes via a constitutive VIPR1 receptor and an inducible VIPR2 receptor.

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Cerutti, A. The regulation of IgA class switching. Nat Rev Immunol 8, 421–434 (2008). https://doi.org/10.1038/nri2322

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