Mucosal Surfaces: Immunological Protection

Abstract

The mucosal surfaces of the body are protected against pathogens and other environmental antigens by the mucosal immune system. This is functionally separate from the circulatory immune system, and represents by far the largest part of the entire immune system. Components include innate and adaptive immune cells and molecules. Specific T and B cells induced by antigens in the major immune inductive sites located in the gastrointestinal and upper respiratory tract are programmed to relocate in remote mucosal effector sites where secretory IgA antibodies and effector T cells are generated. Regulatory mechanisms including regulatory T cells and cytokines maintain a hypo‐responsive, non‐inflammatory state that prevents over‐reaction to the large mass of antigenic material consisting of food and other environmental antigens as well as the commensal microbiota. However, the mucosal immune system can respond vigorously with localised and disseminated responses when stimulated by aggressive pathogens.

Key Concepts

  • The mucosal immune system protects the large surface areas of the oro‐gastrointestinal, respiratory and genital tracts, the conjunctivae, their associated glands and the mammary glands.
  • The mucosal immune system discriminates between pathogens that elicit a vigorous response, commensals that are regulated but not eliminated and harmless antigens such as food components that are tolerated.
  • Innate components of mucosal immunity include physicochemical barriers such as mucus and low pH, and an array of antimicrobial molecules and cells that defend the mucosae against pathogenic attack and initiate recognition by the adaptive immune system.
  • Adaptive components of mucosal immunity include locally produced secretory IgA antibodies, and both effector and regulatory T cells.
  • Mucosal immune inductive sites such as intestinal Peyer's patches and other mucosa‐associated lymphoid tissues take up luminal antigens and disseminate induced, antigen‐specific T and B cells to remote effector sites in the ‘common’ mucosal immune system.
  • Dendritic cells and other antigen‐presenting cells are located within the mucosal immune inductive sites and in the lamina propria underlying the epithelium.
  • Mucosal trafficking of antigen‐induced T and B cells is determined by a set of vascular addressins, mucosal chemokines and receptors imprinted on lymphocytes during their induction.
  • Mucosal epithelial cells have an integral role in antigen recognition and uptake, interaction with the cells of the immune system and delivery of the cells and molecules involved in immune defence.
  • Innate defence cells including mast cells, macrophages, neutrophils and eosinophils are recruited to the mucosae, and display phenotypic profiles distinct from equivalent cells in systemic locations or the circulation.

Keywords: mucosal immunology; common mucosal immune system; tolerance; regulatory T cells; TH1/TH2/TH17

Figure 1. Secretory IgA (S‐IgA) is the predominant immunoglobulin present on mucosal surfaces and is formed by two IgA monomer subunits attached together by the J chain. S‐IgA contains secretory component (SC) derived from polymeric immunoglobulin receptor (pIgR), which transports it across the epithelial cells and protects it from digestion by luminal proteases. Illustrated here is S‐IgA1, which bears O‐linked glycans in the hinge region, as well as N‐linked glycans in the Cα domains, J chain and SC. The antigen‐binding sites in the Fab arms are marked with asterisks (*). Reproduced from Mestecky et al. (2015) © Elsevier.
Figure 2. Polymeric immunoglobulin receptor (pIgR)‐mediated transport of polymeric IgA. pIgR binds to J chain‐containing polymeric IgA (or IgM) on the basolateral surface of the epithelial cell and this complex is taken up into endocytic vesicles. During transcytosis, pIgR becomes covalently coupled to IgA by the formation of disulfide links and is cleaved at the membrane surface, forming S‐IgA which enters the lumen. The remaining trans‐membrane portion of pIgR is non‐functional and undergoes intra‐cellular degradation. SC protects S‐IgA (and S‐IgM) from luminal degradation.
Figure 3. Gut‐associated lymphoid tissue (GALT). Peyer's patches (PP) are the major inductive sites present in GALT. The PP contains three distinct regions: the sub‐epithelial dome populated by lymphocytes and DC, distinct B cell‐containing follicles organised into germinal centres and parafollicular zones containing T cells and high endothelial venules (HEV). Overlying the dome is the follicle‐associated epithelium (FAE) containing M cells whose numerous microfolds and invaginated membranes increase the surface area of antigen sampling. Antigen‐activated, IgA‐switched B cells as well as antigen‐activated T cells emigrate via lymphatics to the draining mesenteric lymph nodes where further differentiation occurs, enter the circulation through the thoracic duct and finally ‘home’ to mucosal effector sites (IEC, intestinal epithelial cell).
Figure 4. TH1, TH2, TH17 and iTreg cytokine regulation. (a) In TH1 cells, IL‐12 activates STAT4, which will induce production of IFNγ and the IL‐12 receptor. Upon binding of IL‐12 to this receptor, STAT4 is activated and IFNγ is produced. (b) In TH2 cells, IL‐4 induces cytokine production via activation of STAT6 followed by activation of the master transcription factor GATA‐3. (c) In TH17 cells, TGF‐β and IL‐6 induce cytokine production via STAT3 activation and activation of the master transcription factor RORγt/RORα. (d) In iTreg cells, TGF‐β and retinoic acid induce the expression of the master transcription factor Foxp3.
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Further Reading

Mestecky J, Strober W, Russell MW, et al. (eds) (2015) Mucosal Immunology, 4th edn. Amsterdam: Academic Press/Elsevier.

Smith PD, MacDonald TT and Blumberg RS (eds) (2013) Principles of Mucosal Immunology, New York: Garland Science.

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Wohlfert, Elizabeth A, and Russell, Michael W(Feb 2016) Mucosal Surfaces: Immunological Protection. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000942.pub2]