Review Article | Published:

Intestinal mucosal barrier function in health and disease

Nature Reviews Immunology volume 9, pages 799809 (2009) | Download Citation

Subjects

Abstract

Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.

Key points

  • Mucosal barrier function consists of the combined effects of multiple extracellular and cellular processes that may be disrupted globally or in a targeted manner by physiological and pathophysiological stimuli. In the presence of an intact epithelium, mucosal permeability is primarily determined by tight junction barrier function.

  • Intestinal epithelial cells mediate interactions between the mucosal immune system and luminal materials. The mechanisms by which these epithelia regulate and, conversely, are regulated by the immune system are therefore of crucial importance to mucosal homeostasis and disease.

  • In vitro and in vivo studies have indicated that cytokines, including tumour necrosis factor, LIGHT (also known as TNFSF14), interferon-γ, interleukin-13 (IL-13) and IL-17 can modify epithelial barrier function by mechanisms that include new protein synthesis, membrane trafficking, kinase activation, cytoskeletal modulation and epithelial apoptosis. The contributions of these events to acute and chronic barrier regulation are distinct and may complement one another.

  • Increased intestinal permeability is associated with inflammatory bowel disease but can also be present in healthy individuals. Mouse models confirm that intestinal barrier dysregulation alone is insufficient to cause disease, but they also show that enhanced tight junction permeability can accelerate disease onset and increase severity.

  • In addition to activating pro-inflammatory events, intestinal barrier dysfunction initiates immunoregulatory processes. Defects in these processes may be a cause of inflammatory disease.

  • Further investigation of pathways that integrate mucosal barrier function, or dysfunction, and immune regulation will lead to a better understanding of the mechanisms underlying these complex interactions and provide a rational basis for the development of more effective and targeted therapeutic interventions.

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References

  1. 1.

    et al. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J. Am. Soc. Nephrol. 13, 875–886 (2002).

  2. 2.

    , & Permeability of the rat small intestinal epithelium along the villus–crypt axis: effects of glucose transport. Gastroenterology 119, 1029–1036 (2000).

  3. 3.

    , , & Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).

  4. 4.

    et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

  5. 5.

    & Mucosal vaccines: the promise and the challenge. Nature Rev. Immunol. 6, 148–158 (2006).

  6. 6.

    Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nature Rev. Immunol. 8, 411–420 (2008).

  7. 7.

    & Dendritic cells in intestinal immune regulation. Nature Rev. Immunol. 8, 435–446 (2008).

  8. 8.

    et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

  9. 9.

    & Role of CFTR in airway disease. Physiol. Rev. 79, S215–S255 (1999).

  10. 10.

    et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008).

  11. 11.

    & Regulated alkali secretion acts in tandem with unstirred layers to regulate mouse gastric surface pH. Gastroenterology 126, 774–783 (2004).

  12. 12.

    et al. Measurements of the jejunal unstirred layer in normal subjects and patients with celiac disease. Am. J. Physiol. 270, G487–G491 (1996).

  13. 13.

    & In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death. J. Cell Biol. 129, 489–506 (1995).

  14. 14.

    et al. The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J. Cell Sci. 121, 298–305 (2008). This detailed analysis of tight junction size selectivity is the first study to show a role for claudins in the paracellular flux of uncharged solutes.

  15. 15.

    , , , & Interferon-γ selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores. J. Cell Sci. 118, 5221–5230 (2005).

  16. 16.

    et al. Interferon-γ and tumour necrosis factor-α synergize to induce intestinal epithelial barrier dysfunction by upregulating myosin light chain kinase expression. Am. J. Pathol. 166, 409–419 (2005).

  17. 17.

    , , , & Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. J. Clin. Invest. 116, 2682–2694 (2006).

  18. 18.

    et al. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J. Cell Sci. 115, 4969–4976 (2002).

  19. 19.

    , , & Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture. Am. J. Physiol. Cell Physiol. 284, C1346–C1354 (2003).

  20. 20.

    et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285, 103–106 (1999). This is the first description of a human disease caused by tight junction defects.

  21. 21.

    & Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J. Membr. Biol. 100, 149–164 (1987).

  22. 22.

    & Intestinal glucose transport using perfused rat jejunum in vivo: model analysis and derivation of corrected kinetic constants. Clin. Sci. (Lond.) 76, 403–413 (1989).

  23. 23.

    et al. Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. Am. J. Physiol. 273, C1378–C1385 (1997). This is the first report of MLCK-dependent physiological regulation of tight junction permeability.

  24. 24.

    , , , & Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na+–glucose cotransport. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G1487–G1493 (2001).

  25. 25.

    et al. Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J. Cell Sci. 119, 2095–2106 (2006).

  26. 26.

    et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology 136, 551–563 (2009). This is the first in vivo analysis of physiologically relevant barrier dysfunction and consequent immunoregulation.

  27. 27.

    & Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayers. J. Clin. Invest. 83, 724–727 (1989).

  28. 28.

    , & Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumour necrosis factorα. Gastroenterology 114, 657–668 (1998).

  29. 29.

    , , , & Modulation of tumour necrosis factor-induced increase in renal (LLC-PK1) transepithelial permeability. Am. J. Physiol. 263, F915–F924 (1992).

  30. 30.

    & Role of TNF-α in lung tight junction alteration in mouse model of acute lung inflammation. Respir. Res. 8, 75 (2007).

  31. 31.

    et al. Proinflammatory cytokines tumour necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line. Am. J. Physiol. Cell Physiol. 295, C1191–C1201 (2008).

  32. 32.

    , , , & Synergistic effects of tumour necrosis factor-α and thrombin in increasing endothelial permeability. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L958–L968 (2001).

  33. 33.

    et al. Tumour necrosis factor α antibody (infliximab) therapy profoundly downregulates the inflammation in Crohn's ileocolitis. Gastroenterology 116, 22–28 (1999).

  34. 34.

    et al. Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock. Am. J. Physiol. 273, G314–G321 (1997).

  35. 35.

    et al. Tumour necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease. Gastroenterology 116, 593–601 (1999).

  36. 36.

    et al. Anti-tumour necrosis factor treatment restores the gut barrier in Crohn's disease. Am. J. Gastroenterol. 97, 2000–2004 (2002).

  37. 37.

    et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

  38. 38.

    et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J. Clin. Invest. 115, 2702–2715 (2005). This is the first in vivo demonstration of the role of MLCK in TNF-induced tight junction regulation.

  39. 39.

    et al. A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology 123, 163–172 (2002). This is the first report of the role of MLCK in TNF-induced tight junction regulation.

  40. 40.

    , , , & Mechanism of TNF-α modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G422–G430 (2005).

  41. 41.

    & Roles of Rho/ROCK and MLCK in TNF-α-induced changes in endothelial morphology and permeability. J. Cell. Physiol. 213, 221–228 (2007).

  42. 42.

    et al. Tumour necrosis factor-induced long myosin light chain kinase transcription is regulated by differentiation-dependent signalling events. Characterization of the human long myosin light chain kinase promoter. J. Biol. Chem. 281, 26205–26215 (2006).

  43. 43.

    , , & Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab. Invest. 86, 191–201 (2006).

  44. 44.

    et al. LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology 132, 2383–2394 (2007).

  45. 45.

    , , & Mechanism of IL-1β-induced increase in intestinal epithelial tight junction permeability. J. Immunol. 180, 5653–5661 (2008).

  46. 46.

    et al. Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology 136, 236–246 (2009).

  47. 47.

    , , , & Intestinal infection with Giardia spp. reduces epithelial barrier function in a myosin light chain kinase-dependent fashion. Gastroenterology 123, 1179–1190 (2002).

  48. 48.

    et al. Myosin light chain kinase is involved in lipopolysaccharide-induced disruption of colonic epithelial barrier and bacterial translocation in rats. Am. J. Pathol. 167, 1071–1079 (2005).

  49. 49.

    et al. LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK. Eur. Respir. J. 25, 789–796 (2005).

  50. 50.

    et al. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am. J. Pathol. 168, 1148–1154 (2006).

  51. 51.

    , , & ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol. Biol. Cell 20, 3930–3940 (2009).

  52. 52.

    , , & Adenosine monophosphate activated protein kinase mediates the interferon-γ-induced decrease in intestinal epithelial barrier function. J. Biol. Chem. 284, 27952–27563 (2009).

  53. 53.

    et al. Mechanism of IFN-γ-induced endocytosis of tight junction proteins: Myosin II-dependent vacuolarization of the apical plasma membrane. Mol. Biol. Cell 16, 5040–5052 (2005).

  54. 54.

    & Actin depolymerization disrupts tight junctions via caveolae-mediated endocytosis. Mol. Biol. Cell 16, 3919–3936 (2005).

  55. 55.

    , , , & Caveolae-mediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cells. J. Biol. Chem. 284, 19053–19066 (2009).

  56. 56.

    et al. Interferon-γ induces internalization of epithelial tight junction proteins via a macropinocytosis-like process. FASEB J. 19, 923–933 (2005).

  57. 57.

    & TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration. Cell Host Microbe 5, 47–58 (2009).

  58. 58.

    et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000).

  59. 59.

    et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).

  60. 60.

    , & Effect of phosphorylation of myosin light chain by myosin light chain kinase and protein kinase C on conformational change and ATPase activities of human platelet myosin. Blood 78, 3224–3231 (1991).

  61. 61.

    , & Structural and functional regulation of tight junctions by rhoA and rac1 small GTPases. J. Cell Biol. 142, 101–115 (1998).

  62. 62.

    et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273, 245–248 (1996).

  63. 63.

    et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020 (2007).

  64. 64.

    et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005). Here, claudin-2 upregulation in inflammatory bowel disease is shown for the first time.

  65. 65.

    , & Downregulation of claudin-2 expression in renal epithelial cells by metabolic acidosis. Am. J. Physiol. Renal Physiol. 297, F604–F611 (2009).

  66. 66.

    et al. Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L219–L227 (2009).

  67. 67.

    , , , & Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab. Invest. 88, 1110–1120 (2008).

  68. 68.

    et al. Claudin-1 regulates cellular transformation and metastatic behaviour in colon cancer. J. Clin. Invest. 115, 1765–1776 (2005).

  69. 69.

    et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

  70. 70.

    , , & Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118, 1001–1011 (2000).

  71. 71.

    et al. Molecular basis for cation selectivity in claudin-2-based paracellular pores: identification of an electrostatic interaction site. J. Gen. Physiol. 133, 111–127 (2009).

  72. 72.

    & Structure-function studies of claudin extracellular domains by cysteine-scanning mutagenesis. J. Biol. Chem. 284, 29205–29217 (2009).

  73. 73.

    et al. Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. Ann. Intern. Med. 105, 883–885 (1986). This is the first demonstration of increased intestinal permeability in healthy relatives of patients with Crohn's disease.

  74. 74.

    et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 55, 342–347 (2006).

  75. 75.

    , , , & A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nature Immunol. 10, 471–479 (2009).

  76. 76.

    et al. Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm. Bowel Dis. 5, 262–270 (1999).

  77. 77.

    et al. The primary defect in experimental ileitis originates from a nonhematopoietic source. J. Exp. Med. 203, 541–552 (2006).

  78. 78.

    , , , & Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet 341, 1437–1439 (1993).

  79. 79.

    & Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270, 1203–1207 (1995). The first demonstration that genetic insults in epithelial cells can cause experimental inflammatory bowel disease.

  80. 80.

    et al. Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis. PLoS One 4, e6073 (2009).

  81. 81.

    et al. Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology 120, 925–937 (2001).

  82. 82.

    et al. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest. 117, 258–269 (2007).

  83. 83.

    et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signalling: Role in proliferation and apoptosis in the intestine. Gastroenterology 131, 862–877 (2006).

  84. 84.

    Crohn's disease — a permeability disorder of the tight junction? Gut 29, 1621–1624 (1988).

  85. 85.

    & Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterology 119, 1740–1744 (2000).

  86. 86.

    , , , & Genetic ablation of myosin light chain kinase limits epithelial barrier dysfunction and attenuates experimental inflammatory bowel disease. Gastroenterology Abstr. 136, A81 (2009).

  87. 87.

    et al. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins. Nature Immunol. 9, 880–886 (2008).

  88. 88.

    , , & Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut 58, 41–48 (2009).

  89. 89.

    et al. Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology 135, 173–184 (2008).

  90. 90.

    et al. JAM-A regulates permeability and inflammation in the intestine in vivo. J. Exp. Med. 204, 3067–3076 (2007).

  91. 91.

    et al. Deletion of JAM-A causes morphological defects in the corneal epithelium. Int. J. Biochem. Cell Biol. 39, 576–585 (2007).

  92. 92.

    et al. A transient breach in the epithelial barrier leads to regulatory T-cell generation and resistance to experimental colitis. Gastroenterology 135, 1612–1623 (2008). This is the first detailed analysis of the effects of transient epithelial cell damage on immunoregulation in the gut.

  93. 93.

    , , , & Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. (2009). This study shows that epithelial cells can direct DCs to facilitate regulatory T cell differentiation.

  94. 94.

    Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577–594 (2008).

  95. 95.

    , , , & The role of antibiotic and probiotic therapies in current and future management of inflammatory bowel disease. Curr. Gastroenterol. Rep. 8, 486–498 (2006).

  96. 96.

    et al. Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. J. Immunol. 158, 3464–3473 (1997).

  97. 97.

    et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998).

  98. 98.

    Barrier-protective function of intestinal epithelial Toll-like receptor 2. Mucosal Immunol. 1, S62–S66 (2008).

  99. 99.

    et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

  100. 100.

    et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

  101. 101.

    et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).

  102. 102.

    et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nature Genet. 40, 710–712 (2008).

  103. 103.

    et al. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J. Clin. Invest. 118, 545–559 (2008).

  104. 104.

    et al. NOD2 transgenic mice exhibit enhanced MDP-mediated downregulation of TLR2 responses and resistance to colitis induction. Gastroenterology 133, 1510–1521 (2007).

  105. 105.

    , , & Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc. Natl Acad. Sci. USA 104, 19440–19445 (2007).

  106. 106.

    , , , & Evidence for a genetic defect in oral tolerance induction in inflammatory bowel disease. Inflamm. Bowel Dis. 12, 82–88 (2006).

  107. 107.

    , , , & Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation. J. Biol. Chem. 280, 1688–1695 (2005).

  108. 108.

    et al. Decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions. N. Engl. J. Med. 279, 176–181 (1968).

  109. 109.

    et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut 56, 61–72 (2007).

  110. 110.

    , & Intestinal permeability in long-term follow-up of patients with celiac disease on a gluten-free diet. Dig. Dis. Sci. 50, 785–790 (2005).

  111. 111.

    , , , & Intestinal permeability in children with Crohn's disease and coeliac disease. Br. Med. J. (Clin. Res. Ed) 285, 20–21 (1982).

  112. 112.

    et al. IFN-γ-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology 131, 1153–1163 (2006).

  113. 113.

    et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).

  114. 114.

    et al. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm. Bowel Dis. 13, 1202–1211 (2007).

  115. 115.

    et al. Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a−/− mice. Inflamm. Bowel Dis. 14, 620–631 (2008).

  116. 116.

    , & Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a −/− mice. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G153–G162 (2005).

  117. 117.

    et al. Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect. Immun. 69, 1329–1336 (2001).

  118. 118.

    et al. Translocated EspF protein from enteropathogenic Escherichia coli disrupts host intestinal barrier function. J. Clin. Invest. 107, 621–629 (2001).

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Acknowledgements

I am indebted to current and past members of my laboratory for discussions and investigations that contributed to this article. Thanks also to A. M. Marchiando and C. R. Weber for the images used in figures 1 and 2. Work in my laboratory is currently supported by the US National Institutes of Health (DK061931, DK068271, DK67887 and HL091889), the University of Chicago Cancer Center (CA14599), the University of Chicago Digestive Disease Research Core Center (DK042086), the US Department of Defense (W81XWH-09-1-0341), the Broad Medical Research Program (IBD-0272) and the Chicago Biomedical Consortium. I apologize to colleagues whose work and publications could not be referenced owing to space constraints.

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  1. Department of Pathology, The University of Chicago, 5841 South Maryland, MC 1089, Chicago, Illinois 60637, USA.  jturner@bsd.uchicago.edu

    • Jerrold R. Turner

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Glossary

Mucosa-associated lymphoid tissue

(MALT). The collections of B cells, T cells, plasma cells, macrophages and other antigen-presenting cells found in the mucosal linings of organs including the gastrointestinal tract, lungs, salivary glands and conjuctiva.

Tight junction

Also known as the zonula occludens, this is a site of close apposition of adjacent epithelial cell membranes — kiss points — that create a barrier against the free diffusion of water and solutes.

Mucins

A family of heavily glycosylated proteins that are secreted as large aggregates by mucous epithelial cells.

Unstirred layer

A thin layer of fluid at epithelial cell surfaces that is separated from the mixing forces created by luminal flow and, in the intestine, peristalsis.

Coeliac disease

A chronic inflammatory condition of the upper small intestine in humans that is caused by immunological hypersensitivity to the α-gliadin component of wheat gluten. It can cause severe villous atrophy, which can lead to malabsorption and malnutrition if gluten-containing foods are not removed from the diet.

Paracellular pathway

The route of transepithelial transport that involves passive movement through the space between adjacent cells.

Adherens junction

Also known as the zonula adherens, this junction is immediately subjacent to the tight junction and requires the activity of lineage-specific Ca2+-dependent adhesion proteins, termed cadherins.

Desmosome

An adhesive junction that connects adjacent epithelial cells. These junctions are composed of multiple protein subunits and are the points where keratin filaments attach to the plasma membrane.

Claudin

From the Latin claudere, meaning 'to close', members of this family of transmembrane proteins are variably expressed by specific epithelial cell types and thereby contribute to the unique barrier properties of different tissues.

Occludin

The first transmembrane tight junction protein identified. The function of occludin remains controversial but it is likely to have roles in barrier regulation and tumour suppression. It also serves as a cofactor in hepatitis C virus entry.

Zonula occludens 1

A peripheral membrane, or plaque, protein containing multiple protein interaction domains that, along with the related protein zonula occludens 2, is required for tight junction assembly.

Transcellular pathway

The route of transepithelial transport that involves active or passive movement across cell membranes, usually as a result of the action of specific transport channels.

Transepithelial transport

The sum of transport through the transcellular and paracellular pathways.

Thick ascending limb of Henle

The portion of the nephron just proximal to the distal tubule. This is a site of active Na+, K+ and Cl reabsorption, which generates an electrochemical gradient that drives paracellular reabsorption of Mg2+ and Ca2+.

Myosin light chain kinase

The Ca2+ – calmodulin-dependent kinase that phosphorylates myosin II regulatory light chain at serine 19 and threonine 18 to activate myosin ATPase.

Caveolae

Specialized flask-shaped invaginations of the plasma membrane that contain the protein caveolin-1 and cholesterol. These proteins mediate uptake of some extracellular materials and are involved in cell signalling.

SAMP1/yit mice

An outbred mouse strain that spontaneously develops a chronic intestinal inflammation similar to human Crohn's disease.

CD4+CD45RBhi T cell adoptive transfer colitis model

A well-characterized model of chronic colitis induced by transfer of CD4+CD45RBhi (naive) T cells from healthy wild-type mice into immunodeficient syngeneic recipients.

Latency-associated peptide

A small peptide derived from the N-terminal region of the TGFβ precursor protein; it can modulate TGFβ signalling.

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https://doi.org/10.1038/nri2653

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