Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA

Abstract

Humoral immune responses at mucosal surfaces have historically focused on IgA. Growing evidence highlights the complexity of IgA-inducing pathways and the functional impact of IgA on mucosal commensal bacteria. In the gut, IgA contributes to the establishment of a mutualistic host-microbiota relationship that is required to maintain homeostasis and prevent disease. This Review discusses how mucosal IgA responses occur in an increasingly complex humoral defence network that also encompasses IgM, IgG and IgD. Aside from integrating the protective functions of IgA, these hitherto neglected mucosal antibodies may strengthen the communication between mucosal and systemic immune compartments.

Fig. 1 |. Inductive pathways and protective strategies of intestinal IgA and IgM.

Gut IgA emerges from highly complementary T cell-dependent (TD) and T cell-independent (TI) pathways. In the TD pathway, microfold cells from the follicle-associated epithelium of Peyer’s patches capture naked or secretory IgA (SIgA)-coated commensals, which are then transferred to subepithelial dendritic cells (DCs) or B cells. These cells establish cognate interactions with T follicular helper (T_FH) cells in the subepithelial dome (SED) underneath the follicle-associated epithelium. After initiating IgM-to-IgA class switch recombination (CSR) in the SED, T_FH cell-activated B cells enter germinal centres (GCs) from Peyer’s patches to undergo IgA somatic hypermutation. In addition to plasma cells, this GC reaction generates memory B cells with high affinity for highly penetrant members of the microbiota. Although GCs from young individuals recruit de novo activated naive B cells, GCs from adults with a stable microbiota mainly recruit pre-existing memory B cells to generate ‘IgA-edited’ plasma cells. This second strategy permits intestinal GCs to continually adjust IgA responses to small changes of the microbiota. While memory B cells re-enter intestinal GCs, plasma cells home to the gut lamina propria to release dimeric IgA, which then translocates across the gut epithelium via the polymeric immunoglobulin receptor (pIgR). The resulting SIgA binds to intraluminal commensals. In humans, the TD pathway also generates secretory IgM (SIgM) clonally affiliated with some SIgA and both target a fraction of commensals. SIgA mediates immune exclusion but also immune inclusion and selection by anchoring some bacteria to metabolically regulated competitive niches via mucus-associated functional factors (MAFF), which exclude less beneficial microorganisms. Moreover, SIgA quenches the motility, growth and pro-inflammatory properties of commensals, regulates their metabolic output and promotes their sampling by M cells. In the TI pathway, extrafollicular B cells generate additional polyreactive and low-affinity SIgA that recognizes a broad spectrum of commensals. FDC, follicular dendritic cell; ILF, isolated lymphoid follicle.

Fig. 2 |. Impact of gut metabolites on gut IgA and systemic IgG responses.

Fermentation of dietary fibres by gut bacteria generates short-chain fatty acids (SCFAs), including acetate (C2), propionate (C3) and butyrate (C4). Engagement of G protein-coupled receptor 43 (GPR43) on T cells or GPR109A on dendritic cells (DCs) as well as inhibition of histone deacetylase (HDAC) in T cells by SCFAs elicits anti-inflammatory immune responses poised on enhancing gut homeostasis. These responses include induction of DCs with enhanced ability to prime FOXP3⁺ regulatory T (T_reg) cells, increased differentiation and expansion of IgA-inducing FOXP3⁺ T_reg cells and augmented conversion of T_reg cells into professional IgA-inducing T follicular helper (T_FH) cells. Aside from increasing gut IgA responses by shaping the B cell-activating function of T cells, SCFAs augment gut IgA production by modulating B cells. Indeed, SCFAs increase the differentiation of IgA-secreting plasma cells by augmenting B cell expression of the class switch-inducing enzyme activation-induced cytidine deaminase (AID) and by increasing IgA synthesis as well as plasma cell differentiation. Due to their small molecular size, SCFAs can also reach systemic lymphoid organs via the general circulation after being absorbed by the gut mucosa. In systemic lymphoid organs, SCFAs enhance IgG responses by supporting the formation of IgG class-switched plasma cells that secrete IgG. In addition to SCFAs, the gut microbiota as well as gut host cells release ATP, which engages the ATP-gated purinergic receptor P2X₇ on T_FH cells. Engagement of P2X₇ by ATP constraints the expansion of T_FH cells in intestinal germinal centres, thereby increasing the stringency of the selection of IgA-expressing B cells specific to commensals. BCR, B cell receptor; CSR, class switch recombination; SIgA, secretory IgA; TGFβ, transforming growth factor-β.

Fig. 3 |. IgG in the neonatal gut mucosa and IgD in the aerodigestive mucosa.

a | Transfer of circulating maternal IgG across the placenta occurs via the neonatal Fc receptor (FcRn) on syncytiotrophoblasts and protects the fetus against microorganisms in addition to promoting gut immune maturation. b | Transfer of circulating maternal IgG into breast milk also occurs via the FcRn. This IgG derives from commensal-reactive plasma cells induced in the gut-associated lymphoid tissue (GALT). In addition to IgG, GALT-derived plasma cells release secretory IgA (SIgA) and secretory IgM (SIgM) into milk via polymeric immunoglobulin receptor (pIgR). Milk-derived IgG, SIgA and SIgM promote gut homeostasis and immunity in suckling neonates. c | Mucosal IgD mostly emerges from a follicular T cell-dependent pathway in the human aerodigestive tract. In this pathway, a fraction of IgM⁺IgD⁺ B cells undergo IgM-to-IgD class switch recombination (CSR) and very extensive IgD somatic hypermutation. The resulting IgM⁻IgD⁺ B cells are highly polyreactive and autoreactive, and further differentiate into IgD-secreting plasmablasts and plasma cells. While some of these cells release IgD locally, others colonize distal respiratory or glandular districts via the general circulation. Very few IgD-secreting cells home to or emerge from systemic organs, at least in humans. In addition to undergoing transcytosis by an unknown mechanism, secreted IgD binds to myeloid effector cells such as basophils and mast cells through a receptor comprised of galectin 9 and CD44. Soluble IgD recognizes aerodigestive commensals, pathogens and food proteins. In addition, engagement of basophil-bound and mast cell-bound IgD by antigen amplifies humoral IgG and IgE responses while constraining IgE-mediated basophil and mast cell degranulation. These responses may enhance mucosal homeostasis and immunity in cooperation with SIgA and IgG. Also, an extrafollicular IgD-inducing T cell-independent pathway may exist. Indeed, mice generate short-lived IgD responses very early after immunization. BAFF, B cell activating factor; T_H2 cell, T helper 2 cell; TNF, tumour necrosis factor.