B cell class switching in intestinal immunity in health and disease

Abstract

The gastrointestinal tract is colonized by trillions of commensal microorganisms that collectively form the microbiome and make essential contributions to organism homeostasis. The intestinal immune system must tolerate these beneficial commensals, whilst preventing pathogenic organisms from systemic spread. Humoral immunity plays a key role in this process, with large quantities of immunoglobulin (Ig)A secreted into the lumen on a daily basis, regulating the microbiome and preventing bacteria from encroaching on the epithelium. However, there is an increasing appreciation of the role of IgG antibodies in intestinal immunity, including beneficial effects in neonatal immune development, pathogen and tumour resistance, but also of pathological effects in driving chronic inflammation in inflammatory bowel disease (IBD). These antibody isotypes differ in effector function, with IgG exhibiting more proinflammatory capabilities compared with IgA. Therefore, the process that leads to the generation of different antibody isotypes, class-switch recombination (CSR), requires careful regulation and is orchestrated by the immunological cues generated by the prevalent local challenge. In general, an initiating signal such as CD40 ligation on B cells leads to the induction of activation-induced cytidine deaminase (AID), but a second cytokine-mediated signal determines which Ig heavy chain is expressed. Whilst the cytokines driving intestinal IgA responses are well-studied, there is less clarity on how IgG responses are generated in the intestine, and how these cues might become dysfunctional in IBD. Here, we review the key mechanisms regulating class switching to IgA vs IgG in the intestine, processes that could be therapeutically manipulated in infection and IBD.

Keywords: B cells; antibodies; intestinal immunity.

FIGURE 1

Intestinal IgA and IgG in health and disease: During homeostasis (left), sIgA is the predominant antibody present in the gut mucosa. IgA⁺ plasma cells, quiescent MNPs and FoxP3‐expressing regulatory T cells form an immunotolerant triad in the tract, which directs IgA responses mostly against commensal microbes. sIgA is transported from the basolateral side of epithelial cells by the polymeric immunoglobulin receptor (pIgR), which attaches a secretory component to the IgA, releasing it into the intestinal lumen as sIgA. Here, sIgA mediates homeostasis by preventing commensal activation of epithelial cells and warding off potential pathobionts, including by enchaining bacteria. There is a relative paucity of anti‐commensal IgG during homeostasis, some of which is maternallyderived, and functions to prevent systemic spread of potential pathogens. In conditions such as UC and CD (right), IgG‐secreting B cells are induced and appear in large numbers. When gross epithelial barrier breach occurs, IgG can bind both pathogenic and commensal bacteria, causing crosslinking and activation of resident MNPs via FcγR interactions, induction of proinflammatory IL‐1β, and engagement of RORγt‐expressing Th₁₇ cells

FIGURE 2

IgG and IgA cell profiles in the colon: The microbial load of the colon is known to increase from proximal to distal in both mice and man. Memory B cells predominate in the proximal colon, with more plasma cells of both the IgA and IgG variety in the distal colon. This plasma cell–rich profile of the distal colon is accompanied by a decreased Th17:Th1 ratio and increased clonal expansion of CD4⁺ T cells vs the proximal colon. More IgA‐bound microbes can also be found in the lumen of the distal colon, with potentially more IgG‐bound microbes to be found here also

FIGURE 3

Class‐switch recombination: (A) The locus for the heavy chain constant region for both mouse and human DNA is depicted. The genes encoding the heavy chain constant regions are arrayed alongside each other downstream of the VDJ segments, which defines the antigen specificity of the BCR. All the heavy chain constant regions, with the exception of the δ gene, are flanked at their 5′ end by switch (S) regions, which are responsible for governing the AID‐mediated recombination events required to switch isotype class during activation. (B) Naïve B cells that have not encountered their cognate antigen (left) express both membrane‐bound IgM and IgD. Upon antigen encounter and T cell help, class switching begins, substituting these existing transcribed constant domains of the BCR for other isotypes. Mouse B cell isotype switching to IgA or IgG1 is presented as an example of class‐switch recombination. Depending on the cytokine and T cell signals delivered to the B cell during activation, it will preferentially excise intervening constant region genes by a recombination event mediated by S region joining (middle), resulting in the placement immediately downstream of the VDJ segment of the desired isotype (right)

FIGURE 4

IgA vs. IgG generation and maintenance in the intestinal tract: IgA responses, which can be both T cell–dependent and –independent. In T‐dependent responses in the Payer's patches, a variety of cytokines including IL‐10, IL‐6, TGF‐β and retinoic acid (RA) from DCs drive IgA induction via CD4⁺ Tfh cells. BAFF and APRIL can mediate T‐independent responses outside the Peyer's patches via TACI binding on B cells. Once generated, IgA⁺ B cells can migrate from their inductive sites to effector sites via chemokines including epithelial‐derived CCL28, where they express the transcription factor RORα. In mice, intestinal IgG2b/3 CSR in health (middle) has been shown to be largely independent of T cells and dependent on B cell–intrinsic TLR signalling. BAFF and APRIL, released by haematopoietic and stromal cells following microbial stimulation, can promote TI AID expression in B cells, while IL‐17A can support IgG3 CSR. The species of microbes targeted by mucosal IgG responses differ between experimental conditions, suggesting a plastic response highly dependent on the composition of the microbiota. In healthy mice, T cell–dependent IgG responses towards the microbiota that have been identified include IgG1 targeting of Akkermansia muciniphila, as well as cross‐reactive IgG2b/3 responses towards Gram‐negative bacteria that arise following dissemination of intestinal bacteria and provide protection against systemic infection. Inflammatory T cell–dependent IgG responses are also critical for elimination of C rodentium in mice, with similar TD mechanisms likely to be involved in inflammatory bowel disease in humans and mice