Immune Responses at Mucosal Surfaces

Abstract

The mucosal surfaces of the gastrointestinal or respiratory tracts form vast interfaces of the host organism with the environment and constitute major entry ports for pathogens. Strategies to defend mucosal surfaces have developed early in evolution and in mammals engage the innate as well as the adaptive arms of the immune system. This article depicts aspects of anatomy, development and function of the mucosa‐associated lymphoid tissues (MALT) with a focus on the intestinal immune system. The intestinal epithelium is continuously exposed to large amounts of foreign antigens. Thus, one of the key challenges of the intestinal immune system is to tolerate harmless food derived antigen and to keep peace with the commensal microbiota populating the gut tube, while efficiently combating pathogens and their toxins.

Key Concepts:

  • Innate and adaptive immunity synergise to protect mucosal surfaces.

  • Adaptive immune responses at mucosal sites are initiated in Mucosa associated lymphoid tissues (MALT), such as the gut‐associated lymphoid tissue (GALT), the bronchus‐associated lymphoid tissue (BALT) and the nasal‐associated lymphoid tissue (NALT).

  • The intestinal immune system is continuously challenged by innocuous antigen derived from food and the commensal microbiota.

  • Interaction of the host with the commensal microbiota is required for the full maturation of the intestinal immune system whereas in turn the intestinal immune system restricts the growth and controls the composition of our commensal microbiota.

  • Secretory IgA (SIgA) is the predominant Immunoglobulin at mucosal surfaces.

  • Dysbiosis of the commensal microflora promotes diseases such as inflammatory bowel disease (IBD), diabetes and obesity and enhances the susceptibility to infection with enteropathogenic bacteria.

  • Failure to induce oral tolerance towards food derived antigens manifests in allergy or coeliac disease.

Keywords: mucosa; intestinal barrier; gut‐associated lymphoid tissue; immunoglobulin A; oral tolerance; microbiota; inflammatory bowel disease; Peyer's Patches; isolated lymphoid follicles

Figure 1.

Architecture of the gut epithelium. The mucosal epithelium lining the gut tube is heavily unfolded, thereby creating villi protruding into the gut lumen as well as a basal crypt zone. The majority of cells are absorptive enterocytes, however, mucus secreting Goblet cells and Paneth cells producing anti‐microbial compounds are also present in high numbers. Intraepithelial lymphocytes (IEL) are located at the basement membrane. Intestinal epithelial cells rapidly proliferate and derive from stem cells located at the crypt zone. Although newly generated enterocytes and Goblet cells migrate towards the villus tip, Paneth cells migrate downwards and settle close to the crypt zone.

Figure 2.

Secretory Immunoglobulin A (SIgA). Plasma cells in the Lamina propria mucosae produce huge amounts of IgA. Two IgA monomers and a joining J chain assemble into the secretory SIgA dimer. The J chain binds to the poly Ig receptor (pIgR) expressed on the basolateral side of the epithelial cells, facilitating the transport of the SIgA molecule across the epithelium into the gut lumen. SIgA protects the epithelium by neutralising bacteria and their toxins.

Figure 3.

The Lamina propria mucosae contains a plethora of innate and adaptive immune cells. Intraepithelial lymphocytes (IEL) sit above the basement membrane. Gut resident macrophages are also in intimate contact to the epithelium and capable of extending dendrites into the gut lumen to sample luminal antigens. In contrast, classical dendritic cells and Lamina propria T cells locate to the core of the villus.

Figure 4.

Peyer's patches – architecture and vascularisation. Peyer′s patches (PP) are the most prominent structures of the gut‐associated lymphoid tissue (GALT) and the main inductive sites of adaptive intestinal immune responses. PP consist of several B cell follicles containing a germinal centre, fringed by an interfollicular T cell zone. Antigens delivered from the gut lumen via M cells in the overlying epithelium are readily taken up by dendritic cells (DC) located in the subepithelial dome. Upon antigen contact activated T cells migrate into the B cell follicle and help in the induction of antigen specific B cells. B cells undergo class switch recombination and start differentiating into IgA producing plasma cells. Via efferent lymphatics (blue lines) activated B and T cells migrate via the gut draining mesenteric lymph nodes (mLN) into the thoracic duct and finally home back into the intestinal Lamina propria via the blood (red lines).

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References

Bouskra D, Brezillon C, Berard M et al. (2008) Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456: 507–510.

Coombes JL, Siddiqui KR, Arancibia‐Carcamo CV et al. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF‐beta and retinoic acid‐dependent mechanism. Journal of Experimental Medicine 204: 1757–1764.

Coutinho HB, da Mota HC, Coutinho VB et al. (1998) Absence of lysozyme (muramidase) in the intestinal Paneth cells of newborn infants with necrotising enterocolitis. Journal of Clinical Pathology 51: 512–514.

Deplancke B and Gaskins HR (2001) Microbial modulation of innate defense: goblet cells and the intestinal mucus layer. American Journal of Clinical Nutrition 73: 1131S–1141S.

Fagarasan S, Muramatsu M, Suzuki K et al. (2002) Critical roles of activation‐induced cytidine deaminase in the homeostasis of gut flora. Science 298: 1424–1427.

Gaboriau‐Routhiau V, Rakotobe S, Lecuyer E et al. (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31: 677–689.

Hadis U, Wahl B, Schulz O et al. (2011) Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34: 237–246.

Halstensen TS, Scott H and Brandtzaeg P (1989) Intraepithelial T cells of the TcR gamma/delta+ CD8‐ and V delta 1/J delta 1+ phenotypes are increased in coeliac disease. Scandinavian Journal of Immunology 30: 665–672.

Hamada H, Hiroi T, Nishiyama Y et al. (2002) Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. Journal of Immunology 168: 57–64.

Hammerschmidt SI, Ahrendt M, Bode U et al. (2008) Stromal mesenteric lymph node cells are essential for the generation of gut‐homing T cells in vivo. Journal of Experimental Medicine 205: 2483–2490.

Johansen FE, Pekna M, Norderhaug IN et al. (1999) Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component‐deficient mice. Journal of Experimental Medicine 190: 915–922.

Johansson‐Lindbom B, Svensson M, Wurbel MA et al. (2003) Selective generation of gut tropic T cells in gut‐associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. Journal of Experimental Medicine 198: 963–969.

Johansson ME, Phillipson M, Petersson J et al. (2008) The inner of the two Muc2 mucin‐dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences of the USA 105: 15064–15069.

Kanamori Y, Ishimaru K, Nanno M et al. (1996) Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c‐kit+ IL‐7R+ Thy1+ lympho‐hemopoietic progenitors develop. Journal of Experimental Medicine 184: 1449–1459.

Lycke N, Erlandsson L, Ekman L, Schon K and Leanderson T (1999) Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection. Journal of Immunology 163: 913–919.

Mazmanian SK, Liu CH, Tzianabos AO and Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122: 107–118.

Natividad JM, Petit V, Huang X et al. (2011) Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1(‐/‐) ;Nod2(‐/‐) Mice. Inflammatory Bowel Diseases. DOI: 10.1002/ibd. 22848.

Pabst O, Herbrand H, Friedrichsen M et al. (2006) Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. Journal of Immunology 177: 6824–6832.

Pabst O, Ohl L, Wendland M et al. (2004) Chemokine receptor CCR9 contributes to the localization of plasma cells to the small intestine. Journal of Experimental Medicine 199: 411–416.

Sawa S, Cherrier M, Lochner M et al. (2010) Lineage relationship analysis of RORgammat+ innate lymphoid cells. Science 330: 665–669.

Schulz O, Jaensson E, Persson EK et al. (2009) Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. Journal of Experimental Medicine 206: 3101–3114.

Smirnova MG, Guo L, Birchall JP and Pearson JP (2003) LPS up‐regulates mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells. Cellular Immunology 221: 42–49.

Stepankova R, Powrie F, Kofronova O et al. (2007) Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflammatory Bowel Diseases 13: 1202–1211.

Sun CM, Hall JA, Blank RB et al. (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. Journal of Experimental Medicine 204: 1775–1785.

Tsuji M, Suzuki K, Kitamura H et al. (2008) Requirement for lymphoid tissue‐inducer cells in isolated follicle formation and T cell‐independent immunoglobulin A generation in the gut. Immunity 29: 261–271.

Van der Sluis M, De Koning BA, De Bruijn AC et al. (2006) Muc2‐deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131: 117–129.

Wang C, McDonough JS, McDonald KG, Huang C and Newberry RD (2008) Alpha4beta7/MAdCAM‐1 interactions play an essential role in transitioning cryptopatches into isolated lymphoid follicles and a nonessential role in cryptopatch formation. Journal of Immunology 181: 4052–4061.

Worbs T, Bode U, Yan S et al. (2006) Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. Journal of Experimental Medicine 203: 519–527.

Further Reading

Brandtzaeg P (2010) Homeostatic impact of indigenous microbiota and secretory immunity. Benef Microbes 1: 211–227.

Cheroutre H, Lambolez F and Mucida D (2011) The light and dark sides of intestinal intraepithelial lymphocytes. Nature Reviews Immunology 11: 445–456.

Jarchum I and Pamer EG (2011) Regulation of innate and adaptive immunity by the commensal microbiota. Current Opinion in Immunology 23: 353–360.

Koboziev I, Karlsson F and Grisham MB (2010) Gut‐associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. Annals of the New York Academy of Sciences 1207(suppl. 1): E86–E93.

Mantis NJ, Rol N and Corthesy B (2011) Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunology 4: 603–611.

McGuckin MA, Linden SK, Sutton P and Florin TH (2011) Mucin dynamics and enteric pathogens. Nature Reviews Microbiology 9: 265–278.

Newberry RD (2008) Intestinal lymphoid tissues: is variety an asset or a liability? Current Opinion in Gastroenterology 24: 121–128.

Pabst O and Bernhardt G (2010) The puzzle of intestinal lamina propria dendritic cells and macrophages. European Journal of Immunology 40: 2107–2111.

Pabst O and Mowat AM (2012) Oral tolerance to food protein. Mucosal Immunology 5(3): 232–239.

Reading NC and Kasper DL (2011) The starting lineup: key microbial players in intestinal immunity and homeostasis. Frontiers in Microbiology 2: 148.

Suzuki K, Kawamoto S, Maruya M and Fagarasan S (2010) GALT: organization and dynamics leading to IgA synthesis. Advances in Immunology 107: 153–185.

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Herbrand, Heike, and Pabst, Oliver(Jul 2012) Immune Responses at Mucosal Surfaces. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000901.pub2]