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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.

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Fig. 1: Inductive pathways and protective strategies of intestinal IgA and IgM.
Fig. 2: Impact of gut metabolites on gut IgA and systemic IgG responses.
Fig. 3: IgG in the neonatal gut mucosa and IgD in the aerodigestive mucosa.

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Acknowledgements

The authors thank the US National Institutes of Health (NIH) (grant P01 AI61093 to A.C. and grants R21 AI122256, R21 AI138089 and P30 AC22453 to K.C.), the Ministry of Economy and Competitiveness (MINECO) (grants SAF2014-52483-R and RTI2018-093894-B-I00 to A.C.), the Burroughs Wellcome fund preterm birth initiative (1013738 to K.C.), the strategic plan of research and innovation in health (PERIS) 2016–2020 from Generalitat de Catalunya (to G.M.) and the Swedish Research Council 2015-06486 and Swedish Society of Medicine (postdoctoral fellowship to E.K.G.).

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All authors contributed to the review and editing of the manuscript before submission. A.C., G.M. and E.K.G. researched data for the article and discussed the content. A.C., K.C. and G.M. wrote the article.

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Correspondence to Andrea Cerutti.

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Glossary

Immune exclusion

Active impairment of microbial penetration through the gut epithelium that includes anchoring of intraluminal bacteria to mucus as well as attenuation of bacterial motility, growth and adhesion to gut epithelium by secretory IgA.

Immune inclusion

Pro-microbial activity mediated by secretory IgA and mucus that promotes the growth of beneficial bacteria while preventing potentially harmful microorganisms from colonizing the same mucosal niche.

Isolated lymphoid follicles

Single intestinal lymphoid aggregates with or without germinal centres, disseminated along the small intestine in mice and both the small and large intestines in humans, which develop in association with the follicle-associated epithelium and function as dynamic immune reservoirs for T cell-independent or T cell-dependent induction of IgA.

M cells

Specialized antigen-capturing epithelial-like cells from the follicle-associated epithelium that initiate intestinal immune responses by transporting intraluminal antigens into Peyer’s patches and isolated lymphoid follicles with the help of dendritic cells, macrophages and B cells.

Somatic hypermutation

A germinal centre-associated process that promotes antibody affinity maturation by introducing V(D)J gene point mutations through a molecular machinery that includes the DNA-editing enzyme activation-induced cytidine deaminase.

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Chen, K., Magri, G., Grasset, E.K. et al. Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat Rev Immunol 20, 427–441 (2020). https://doi.org/10.1038/s41577-019-0261-1

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