They must hold tight: Junction proteins, microbiota and immunity in intestinal mucosa

Current Protein and Peptide Science

Volumn 16, Issue 7, 2015, Pages 655-671

  Castoldi, Angela ^a   de Aguiar, Cristhiane Favero ^a   Moraes Vieira, Pedro Manoel ^b   Câmara, Niels Olsen Saraiva ^a,c  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b HARVARD MEDICAL SCHOOL   (United States)

^c FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Gut microbiota; Immune system; Intestinal epithelium; Intestinal permeability; Tight junctions

Indexed keywords

ARTICLE; BACTERIAL FLORA; EPITHELIUM CELL; GASTROINTESTINAL MUCOSA; HUMAN; IMMUNE SYSTEM; INFLAMMATORY BOWEL DISEASE; MACROPHAGE; METABOLIC DISORDER; MICROBIAL IMMUNITY; NONHUMAN; SIGNAL TRANSDUCTION; ADAPTIVE IMMUNITY; ANIMAL; IMMUNOLOGY; INTESTINE FLORA; INTESTINE MUCOSA; METABOLISM; MICROBIOLOGY; PATHOLOGY; PERMEABILITY; T LYMPHOCYTE; TIGHT JUNCTION;

TOLL LIKE RECEPTOR;

ADAPTIVE IMMUNITY; ANIMALS; EPITHELIAL CELLS; GASTROINTESTINAL MICROBIOME; HUMANS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA; PERMEABILITY; T-LYMPHOCYTES; TIGHT JUNCTIONS; TOLL-LIKE RECEPTORS;

EID: 84939811817     PISSN: 13892037     EISSN: 18755550     Source Type: Journal    
DOI: 10.2174/1389203716666150630133141     Document Type: Article

References (241)

1. Turner, J.R. Intestinal mucosal barrier function in health and disease. Nat. Reviews, 2009, 9(11), 799-809.
2. Kaetzel, C.S. Cooperativity among secretory IgA, the polymeric immunoglobulin receptor, and the gut microbiota promotes hostmicrobial mutualism. Immunol. Lett., 2014, 162(2 Pt A), 10-21.
3. Fries, W.; Belvedere, A.; Vetrano, S. Sealing the broken barrier in IBD: intestinal permeability, epithelial cells and junctions. Curr. Drug Targets, 2013, 14(12), 1460-1470.
4. Hossain, Z.; Hirata, T. Molecular mechanism of intestinal permeability: interaction at tight junctions. Mol. Biosyst., 2008, 4(12), 1181-1185
5. Vetrano, S.; Danese, S. The role of JAM-A in inflammatory bowel disease: unrevealing the ties that bind. Ann. N Y Acad. Sci., 2009, 1165, 308-313.
6. Turner, J.R.; Buschmann, M.M.; Romero-Calvo, I.; Sailer, A.; Shen, L. The role of molecular remodeling in differential regulation of tight junction permeability. Semin. Cell Dev. Biol., 2014, 36, 204-212.
7. Bertiaux-Vandaele, N.; Youmba, S.B.; Belmonte, L.; Lecleire, S.; Antonietti, M.; Gourcerol, G.; Leroi, A.M.; Dechelotte, P.; Menard, J.F.; Ducrotte, P.; Coeffier, M. The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype. Am. J. Gastroenterol., 2011, 106(12), 2165-2173;
8. Schmitz, H.; Barmeyer, C.; Fromm, M.; Runkel, N.; Foss, H.D.; Bentzel, C.J.; Riecken, E.O.; Schulzke, J.D. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology, 1999, 116(2), 301-309
9. Al- Sadi, R.; Ye, D.; Dokladny, K.; Ma, T.Y. Mechanism of IL-1betainduced increase in intestinal epithelial tight junction permeability. J. Immunol., 2008, 180(8), 5653-5661.
10. Groschwitz, K.R.; Hogan, S.P. Intestinal barrier function: molecular regulation and disease pathogenesis. J. Allergy Clin. Immunol., 2009, 124(1), 3-20; quiz 21-2.
11. Muza-Moons, M.M.; Schneeberger, E.E.; Hecht, G.A. Enteropathogenic Escherichia coli infection leads to appearance of aberrant tight junctions strands in the lateral membrane of intestinal epithelial cells. Cell. Microbiol., 2004, 6(8), 783-793
12. Ahrne, S.; Hagslatt, M.L. Effect of lactobacilli on paracellular permeability in the gut. Nutrients, 2011, 3(1), 104-117.
13. Madsen, K.; Cornish, A.; Soper, P.; McKaigney, C.; Jijon, H.; Yachimec, C.; Doyle, J.; Jewell, L.; De Simone, C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology, 2001, 121(3), 580-591
14. Ewaschuk, J.B.; Diaz, H.; Meddings, L.; Diederichs, B.; Dmytrash, A.; Backer, J.; Looijer-van Langen, M.; Madsen, K.L. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am. J. Physiol., 2008, 295(5), G1025-G1034.
15. Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; Taniguchi, T.; Takeda, K.; Hori, S.; Ivanov, II; Umesaki, Y.; Itoh, K.; Honda, K. Induction of colonic regulatory T cells by indigenous Clostridium species. Science, 2011, 331(6015), 337- 341
16. Shulzhenko, N.; Morgun, A.; Hsiao, W.; Battle, M.; Yao, M.; Gavrilova, O.; Orandle, M.; Mayer, L.; Macpherson, A.J.; McCoy, K.D.; Fraser-Liggett, C.; Matzinger, P. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med., 2011, 17(12), 1585-1593.
17. Lavelle, E.C.; Murphy, C.; O'Neill, L.A.; Creagh, E.M. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol., 2010, 3(1), 17-28.
18. Cario, E.; Brown, D.; McKee, M.; Lynch-Devaney, K.; Gerken, G.; Podolsky, D.K. Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am. J. Pathol., 2002, 160(1), 165-173.
19. Matzinger, P. Tolerance, danger, and the extended family. Ann. Rev. Immunol., 1994, 12, 991-1045.
20. Otte, J.M.; Cario, E.; Podolsky, D.K. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology, 2004, 126(4), 1054- 1070.
21. Furrie, E.; Macfarlane, S.; Thomson, G.; Macfarlane, G.T. Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology, 2005, 115(4), 565-574.
22. Rhee, S.H.; Keates, A.C.; Moyer, M.P.; Pothoulakis, C. MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. J. Biol. Chem., 2004, 279(24), 25179-25188.
23. Bailey, M.T. The contributing role of the intestinal microbiota in stressor-induced increases in susceptibility to enteric infection and systemic immunomodulation. Horm. Behav., 2012, 62(3), 286- 294
24. Tanoue, T.; Umesaki, Y.; Honda, K. Immune responses to gut microbiota-commensals and pathogens. Gut Microbes, 2010, 1(4), 224-233.
25. Round, J.L.; Lee, S.M.; Li, J.; Tran, G.; Jabri, B.; Chatila, T.A.; Mazmanian, S.K. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science, 2011, 332(6032), 974-977.
26. Lee, J.; Mo, J.H.; Katakura, K.; Alkalay, I.; Rucker, A.N.; Liu, Y.T.; Lee, H.K.; Shen, C.; Cojocaru, G.; Shenouda, S.; Kagnoff, M.; Eckmann, L.; Ben-Neriah, Y.; Raz, E. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat. Cell Biol., 2006, 8(12), 1327-1336.
27. Vijay-Kumar, M.; Aitken, J.D.; Carvalho, F.A.; Cullender, T.C.; Mwangi, S.; Srinivasan, S.; Sitaraman, S.V.; Knight, R.; Ley, R.E.; Gewirtz, A.T. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science, 2010, 328(5975), 228-231
28. Carvalho, F.A.; Koren, O.; Goodrich, J.K.; Johansson, M.E.; Nalbantoglu, I.; Aitken, J.D.; Su, Y.; Chassaing, B.; Walters, W.A.; Gonzalez, A.; Clemente, J.C.; Cullender, T.C.; Barnich, N.; Darfeuille-Michaud, A.; Vijay-Kumar, M.; Knight, R.; Ley, R.E.; Gewirtz, A.T. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe, 2012, 12(2), 139-152
29. Ji, Y.; Sun, S.; Goodrich, J.K.; Kim, H.; Poole, A.C.; Duhamel, G.E.; Ley, R.E.; Qi, L. Dietinduced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4-deficient mice. Cell Rep., 2014, 8(1), 137- 149.
30. Vamadevan, A.S.; Fukata, M.; Arnold, E.T.; Thomas, L.S.; Hsu, D.; Abreu, M.T. Regulation of Toll-like receptor 4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis. Innate Immun., 2010, 16(2), 93-103
31. Abreu, M.T.; Arnold, E.T.; Thomas, L.S.; Gonsky, R.; Zhou, Y.; Hu, B.; Arditi, M. TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J. Biol. Chem., 2002, 277(23), 20431-20437.
32. Pedersen, G.; Andresen, L.; Matthiessen, M.W.; Rask-Madsen, J.; Brynskov, J. Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Clin. Exp. Immunol., 2005, 141(2), 298-306
33. Mueller, T.; Terada, T.; Rosenberg, I.M.; Shibolet, O.; Podolsky, D.K. Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells. J. Immunol., 2006, 176(10), 5805- 5814
34. Dalpke, A.; Heeg, K. Signal integration following Tolllike receptor triggering. Crit. Rev. Immunol., 2002, 22(3), 217-250;
35. Lotz, M.; Konig, T.; Menard, S.; Gutle, D.; Bogdan, C.; Hornef, M.W. Cytokine-mediated control of lipopolysaccharide-induced activation of small intestinal epithelial cells. Immunology, 2007, 122(3), 306-315.
36. Brown, S.L.; Riehl, T.E.; Walker, M.R.; Geske, M.J.; Doherty, J.M.; Stenson, W.F.; Stappenbeck, T.S. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest., 2007, 117(1), 258-269
37. Fukata, M.; Hernandez, Y.; Conduah, D.; Cohen, J.; Chen, A.; Breglio, K.; Goo, T.; Hsu, D.; Xu, R.; Abreu, M.T. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm. Bowel Dis., 2009, 15(7), 997-1006.
38. Fukata, M.; Michelsen, K.S.; Eri, R.; Thomas, L.S.; Hu, B.; Lukasek, K.; Nast, C.C.; Lechago, J.; Xu, R.; Naiki, Y.; Soliman, A.; Arditi, M.; Abreu, M.T. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am. J. Physiol., 2005, 288(5), G1055-G1065
39. Araki, A.; Kanai, T.; Ishikura, T.; Makita, S.; Uraushihara, K.; Iiyama, R.; Totsuka, T.; Takeda, K.; Akira, S.; Watanabe, M. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J. Gastroenterol., 2005, 40(1), 16-23.
40. Fukata, M.; Chen, A.; Vamadevan, A.S.; Cohen, J.; Breglio, K.; Krishnareddy, S.; Hsu, D.; Xu, R.; Harpaz, N.; Dannenberg, A.J.; Subbaramaiah, K.; Cooper, H.S.; Itzkowitz, S.H.; Abreu, M.T. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology, 2007, 133(6), 1869-1881.
41. Cario, E.; Gerken, G.; Podolsky, D.K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology, 2007, 132(4), 1359-1374
42. Le Mandat Schultz, A.; Bonnard, A.; Barreau, F.; Aigrain, Y.; Pierre- Louis, C.; Berrebi, D.; Peuchmaur, M. Expression of TLR-2, TLR- 4, NOD2 and pNF-kappaB in a neonatal rat model of necrotizing enterocolitis. PloS one, 2007, 2(10), e1102.
43. Vijay-Kumar, M.; Sanders, C.J.; Taylor, R.T.; Kumar, A.; Aitken, J.D.; Sitaraman, S.V.; Neish, A.S.; Uematsu, S.; Akira, S.; Williams, I.R.; Gewirtz, A.T. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest., 2007, 117(12), 3909- 3921.
44. Maeda, S.; Hsu, L.C.; Liu, H.; Bankston, L.A.; Iimura, M.; Kagnoff, M.F.; Eckmann, L.; Karin, M. Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science, 2005, 307(5710), 734-738.
45. Wehkamp, J.; Salzman, N.H.; Porter, E.; Nuding, S.; Weichenthal, M.; Petras, R.E.; Shen, B.; Schaeffeler, E.; Schwab, M.; Linzmeier, R.; Feathers, R.W.; Chu, H.; Lima, H., Jr.; Fellermann, K.; Ganz, T.; Stange, E.F.; Bevins, C.L. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc. Natl. Acad. Sci. U. S. A., 2005, 102(50), 18129-18134.
46. Ey, B.; Eyking, A.; Gerken, G.; Podolsky, D.K.; Cario, E. TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury. J. Biol. Chem., 2009, 284(33), 22332-22343.
47. Leaphart, C.L.; Cavallo, J.; Gribar, S.C.; Cetin, S.; Li, J.; Branca, M.F.; Dubowski, T.D.; Sodhi, C.P.; Hackam, D.J. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J. Immunol., 2007, 179(7), 4808-4820.
48. Suzuki, T.; Seth, A.; Rao, R. Role of phospholipase Cgammainduced activation of protein kinase Cepsilon (PKCepsilon) and PKCbetaI in epidermal growth factor-mediated protection of tight junctions from acetaldehyde in Caco-2 cell monolayers. J. Biol. Chem., 2008, 283(6), 3574-3583.
49. Li, X.; Wang, C.; Nie, J.; Lv, D.; Wang, T.; Xu, Y. Toll-like receptor 4 increases intestinal permeability through up-regulation of membrane PKC activity in alcoholic steatohepatitis. Alcohol, 2013, 47(6), 459-465.
50. Moreira, L.O.; Zamboni, D.S. NOD1 and NOD2 Signaling in Infection and Inflammation. Front. Immunol., 2012, 3, 328.
51. Palazzo, M.; Balsari, A.; Rossini, A.; Selleri, S.; Calcaterra, C.; Gariboldi, S.; Zanobbio, L.; Arnaboldi, F.; Shirai, Y.F.; Serrao, G.; Rumio, C. Activation of enteroendocrine cells via TLRs induces hormone, chemokine, and defensin secretion. J. Immunol., 2007, 178(7), 4296-4303
52. Chabot, S.; Wagner, J.S.; Farrant, S.; Neutra, M.R. TLRs regulate the gatekeeping functions of the intestinal follicle-associated epithelium. J. Immunol., 2006, 176(7), 4275-4283.
53. Fusunyan, R.D.; Nanthakumar, N.N.; Baldeon, M.E.; Walker, W.A. Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr. Res., 2001, 49(4), 589-593
54. Gewirtz, A.T.; Navas, T.A.; Lyons, S.; Godowski, P.J.; Madara, J.L. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol., 2001, 167(4), 1882-1885.
55. Ivanov, II; Atarashi, K.; Manel, N.; Brodie, E.L.; Shima, T.; Karaoz, U.; Wei, D.; Goldfarb, K.C.; Santee, C.A.; Lynch, S.V.; Tanoue, T.; Imaoka, A.; Itoh, K.; Takeda, K.; Umesaki, Y.; Honda, K.; Littman, D.R. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell, 2009, 139(3), 485-498
56. Ogura, Y.; Bonen, D.K.; Inohara, N.; Nicolae, D.L.; Chen, F.F.; Ramos, R.; Britton, H.; Moran, T.; Karaliuskas, R.; Duerr, R.H.; Achkar, J.P.; Brant, S.R.; Bayless, T.M.; Kirschner, B.S.; Hanauer, S.B.; Nunez, G.; Cho, J.H. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature, 2001, 411(6837), 603- 606
57. Strober, W.; Watanabe, T. NOD2, an intracellular innate immune sensor involved in host defense and Crohn's disease. Mucosal Immunol., 2011, 4(5), 484-495.
58. Biswas, A.; Liu, Y.J.; Hao, L.; Mizoguchi, A.; Salzman, N.H.; Bevins, C.L.; Kobayashi, K.S. Induction and rescue of Nod2- dependent Th1-driven granulomatous inflammation of the ileum. Proc. Natl. Acad. Sci. U. S. A., 2010, 107(33), 14739-14744.
59. Amendola, A.; Butera, A.; Sanchez, M.; Strober, W.; Boirivant, M. Nod2 deficiency is associated with an increased mucosal immunoregulatory response to commensal microorganisms. Mucosal Immunol., 2014, 7(2), 391-404.
60. Schroder, K.; Tschopp, J. The inflammasomes. Cell, 2010, 140(6), 821-832.
61. Lech, M.; Avila-Ferrufino, A.; Skuginna, V.; Susanti, H.E.; Anders, H.J. Quantitative expression of RIG-like helicase, NODlike receptor and inflammasome-related mRNAs in humans and mice. Int. Immunol., 2010, 22(9), 717-728.
62. Gross, O.; Poeck, H.; Bscheider, M.; Dostert, C.; Hannesschlager, N.; Endres, S.; Hartmann, G.; Tardivel, A.; Schweighoffer, E.; Tybulewicz, V.; Mocsai, A.; Tschopp, J.; Ruland, J. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature, 2009, 459(7245), 433-436
63. Kanneganti, T.D.; Body-Malapel, M.; Amer, A.; Park, J.H.; Whitfield, J.; Franchi, L.; Taraporewala, Z.F.; Miller, D.; Patton, J.T.; Inohara, N.; Nunez, G. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem., 2006, 281(48), 36560-36568
64. Mariathasan, S.; Weiss, D.S.; Newton, K.; McBride, J.; O'Rourke, K.; Roose-Girma, M.; Lee, W.P.; Weinrauch, Y.; Monack, D.M.; Dixit, V.M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature, 2006, 440(7081), 228-232.
65. Zaki, M.H.; Boyd, K.L.; Vogel, P.; Kastan, M.B.; Lamkanfi, M.; Kanneganti, T.D. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity, 2010, 32(3), 379-391.
66. Hirota, S.A.; Ng, J.; Lueng, A.; Khajah, M.; Parhar, K.; Li, Y.; Lam, V.; Potentier, M.S.; Ng, K.; Bawa, M.; McCafferty, D.M.; Rioux, K.P.; Ghosh, S.; Xavier, R.J.; Colgan, S.P.; Tschopp, J.; Muruve, D.; MacDonald, J.A.; Beck, P.L. NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm. Bowel Dis., 2011, 17(6), 1359-1372.
67. Allen, I.C.; TeKippe, E.M.; Woodford, R.M.; Uronis, J.M.; Holl, E.K.; Rogers, A.B.; Herfarth, H.H.; Jobin, C.; Ting, J.P. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med., 2010, 207(5), 1045-1056.
68. Takagi, H.; Kanai, T.; Okazawa, A.; Kishi, Y.; Sato, T.; Takaishi, H.; Inoue, N.; Ogata, H.; Iwao, Y.; Hoshino, K.; Takeda, K.; Akira, S.; Watanabe, M.; Ishii, H.; Hibi, T. Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice. Scand. J. Gastroenterol., 2003, 38(8), 837-844
69. Lebeis, S.L.; Powell, K.R.; Merlin, D.; Sherman, M.A.; Kalman, D. Interleukin-1 receptor signaling protects mice from lethal intestinal damage caused by the attaching and effacing pathogen Citrobacter rodentium. Infect. Immun., 2009, 77(2), 604-614.
70. Demon, D.; Kuchmiy, A.; Fossoul, A.; Zhu, Q.; Kanneganti, T.D.; Lamkanfi, M. Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis. Mucosal Immunol., 2014, 7(6), 1504.
71. Carvalho, F.A.; Nalbantoglu, I.; Aitken, J.D.; Uchiyama, R.; Su, Y.; Doho, G.H.; Vijay-Kumar, M.; Gewirtz, A.T. Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges. Mucosal Immunol., 2012, 5(3), 288-298.
72. Bischoff, S.C.; Wedemeyer, J.; Herrmann, A.; Meier, P.N.; Trautwein, C.; Cetin, Y.; Maschek, H.; Stolte, M.; Gebel, M.; Manns, M.P. Quantitative assessment of intestinal eosinophils and mast cells in inflammatory bowel disease. Histopathology, 1996, 28(1), 1-13
73. Jacob, C.; Yang, P.C.; Darmoul, D.; Amadesi, S.; Saito, T.; Cottrell, G.S.; Coelho, A.M.; Singh, P.; Grady, E.F.; Perdue, M.; Bunnett, N.W. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J. Biol. Chem., 2005, 280(36), 31936-31948.
74. Cenac, N.; Andrews, C.N.; Holzhausen, M.; Chapman, K.; Cottrell, G.; Andrade-Gordon, P.; Steinhoff, M.; Barbara, G.; Beck, P.; Bunnett, N.W.; Sharkey, K.A.; Ferraz, J.G.; Shaffer, E.; Vergnolle, N. Role for protease activity in visceral pain in irritable bowel syndrome. J. Clin. Invest., 2007, 117(3), 636-647
75. Santos, J.; Guilarte, M.; Alonso, C.; Malagelada, J.R. Pathogenesis of irritable bowel syndrome: the mast cell connection. Scand. J. Gastroenterol., 2005, 40(2), 129-140.
76. De Winter, B.Y.; van den Wijngaard, R.M.; de Jonge, W.J. Intestinal mast cells in gut inflammation and motility disturbances. Biochim. Biophys. Acta, 2012, 1822(1), 66-73
77. Stoyanova, II; Gulubova, M.V. Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem., 2002, 104(2), 185-192.
78. Hamilton, M.J.; Sinnamon, M.J.; Lyng, G.D.; Glickman, J.N.; Wang, X.; Xing, W.; Krilis, S.A.; Blumberg, R.S.; Adachi, R.; Lee, D.M.; Stevens, R.L. Essential role for mast cell tryptase in acute experimental colitis. Proc. Natl. Acad. Sci. U. S. A., 2011, 108(1), 290-295.
79. Groschwitz, K.R.; Ahrens, R.; Osterfeld, H.; Gurish, M.F.; Han, X.; Abrink, M.; Finkelman, F.D.; Pejler, G.; Hogan, S.P. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proc. Natl. Acad. Sci. U. S. A., 2009, 106(52), 22381-22386
80. Martinez, C.; Vicario, M.; Ramos, L.; Lobo, B.; Mosquera, J.L.; Alonso, C.; Sanchez, A.; Guilarte, M.; Antolin, M.; de Torres, I.; Gonzalez- Castro, A.M.; Pigrau, M.; Saperas, E.; Azpiroz, F.; Santos, J. The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am. J. Gastroenterol., 2012, 107(5), 736-746.
81. Wilcz-Villega, E.M.; McClean, S.; O'Sullivan, M.A. Mast cell tryptase reduces junctional adhesion molecule-A (JAM-A) expression in intestinal epithelial cells: implications for the mechanisms of barrier dysfunction in irritable bowel syndrome. Am. J. Gastroenterol., 2013, 108(7), 1140-1151.
82. Zhang, H.; Xue, Y.; Wang, H.; Huang, Y.; Du, M.; Yang, Q.; Zhu, M.J. Mast cell deficiency exacerbates inflammatory bowel symptoms in interleukin-10-deficient mice. World J. Gastroenterol., 2014, 20(27), 9106-9115.
83. Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev., 2008, 8(6), 411-420
84. Varol, C.; Vallon-Eberhard, A.; Elinav, E.; Aychek, T.; Shapira, Y.; Luche, H.; Fehling, H.J.; Hardt, W.D.; Shakhar, G.; Jung, S. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity, 2009, 31(3), 502-512.
85. Coombes, J.L.; Powrie, F. Dendritic cells in intestinal immune regulation. Nat. Rev., 2008, 8(6), 435-446.
86. Guilliams, M.; Crozat, K.; Henri, S.; Tamoutounour, S.; Grenot, P.; Devilard, E.; de Bovis, B.; Alexopoulou, L.; Dalod, M.; Malissen, B. Skin-draining lymph nodes contain dermis-derived CD103(-) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells. Blood, 2010, 115(10), 1958-1968
87. Pino-Lagos, K.; Guo, Y.; Brown, C.; Alexander, M.P.; Elgueta, R.; Bennett, K.A.; De Vries, V.; Nowak, E.; Blomhoff, R.; Sockanathan, S.; Chandraratna, R.A.; Dmitrovsky, E.; Noelle, R.J. A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J. Exp. Med., 2011, 208(9), 1767-1775.
88. Rivollier, A.; He, J.; Kole, A.; Valatas, V.; Kelsall, B.L. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J. Exp. Med., 2012, 209(1), 139-155.
89. Watson, A.J.; Duckworth, C.A.; Guan, Y.; Montrose, M.H. Mechanisms of epithelial cell shedding in the Mammalian intestine and maintenance of barrier function. Ann. N. Y. Acad. Sci., 2009, 1165, 135-142.
90. Al-Sadi, R.; Guo, S.; Ye, D.; Ma, T.Y. TNF-alpha modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1. Am. J. Pathol., 2013, 183(6), 1871-1884.
91. Bain, C.C.; Mowat, A.M. Intestinal macrophages - specialised adaptation to a unique environment. Eur. J. Immunol., 2011, 41(9), 2494-2498.
92. Medina-Contreras, O.; Geem, D.; Laur, O.; Williams, I.R.; Lira, S.A.; Nusrat, A.; Parkos, C.A.; Denning, T.L. CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J. Clin. Invest., 2011, 121(12), 4787-4795.
93. Manta, C.; Heupel, E.; Radulovic, K.; Rossini, V.; Garbi, N.; Riedel, C.U.; Niess, J.H. CX(3)CR1(+) macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium. Mucosal Immunol., 2013, 6(1), 177-188.
94. Ghosh, S.S.; Bie, J.; Wang, J.; Ghosh, S. Oral Supplementation with Non-Absorbable Antibiotics or Curcumin Attenuates Western Diet-Induced Atherosclerosis and Glucose Intolerance in LDLR-/- Mice - Role of Intestinal Permeability and Macrophage Activation. PloS One, 2014, 9(9), e108577.
95. Tanriver, Y.; Diefenbach, A. Transcription factors controlling development and function of innate lymphoid cells. Int. Immunol., 2014, 26(3), 119-128.
96. Walker, J.A.; Barlow, J.L.; McKenzie, A.N. Innate lymphoid cells-how did we miss them? Nat. Rev., Immunol., 2013, 13(2), 75-87.
97. Spits, H.; Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Ann. Rev. Immunol., 2012, 30, 647-675.
98. Spits, H.; Artis, D.; Colonna, M.; Diefenbach, A.; Di Santo, J.P.; Eberl, G.; Koyasu, S.; Locksley, R.M.; McKenzie, A.N.; Mebius, R.E.; Powrie, F.; Vivier, E. Innate lymphoid cells--a proposal for uniform nomenclature. Nat. Rev. Immunol., 2013, 13(2), 145-149.
99. Sanos, S.L.; Diefenbach, A. Isolation of NK cells and NK-like cells from the intestinal lamina propria. Methods Mol. Biol., 2010, 612, 505-517
100. Leon, F.; Roldan, E.; Sanchez, L.; Camarero, C.; Bootello, A.; Roy, G. Human small-intestinal epithelium contains functional natural killer lymphocytes. Gastroenterology, 2003, 125(2), 345-356.
101. Steel, A.W.; Mela, C.M.; Lindsay, J.O.; Gazzard, B.G.; Goodier, M.R. Increased proportion of CD16(+) NK cells in the colonic lamina propria of inflammatory bowel disease patients, but not after azathioprine treatment. Aliment. Pharmacol. Ther., 2011, 33(1), 115-126.
102. Takayama, T.; Kamada, N.; Chinen, H.; Okamoto, S.; Kitazume, M.T.; Chang, J.; Matuzaki, Y.; Suzuki, S.; Sugita, A.; Koganei, K.; Hisamatsu, T.; Kanai, T.; Hibi, T. Imbalance of NKp44(+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology, 2010, 139(3), 882-892, 892 e1-3.
103. Vonarbourg, C.; Mortha, A.; Bui, V.L.; Hernandez, P.P.; Kiss, E.A.; Hoyler, T.; Flach, M.; Bengsch, B.; Thimme, R.; Holscher, C.; Honig, M.; Pannicke, U.; Schwarz, K.; Ware, C.F.; Finke, D.; Diefenbach, A. Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptorexpressing RORgammat(+) innate lymphocytes. Immunity, 2010, 33(5), 736-751
104. Bernink, J.H.; Peters, C.P.; Munneke, M.; te Velde, A.A.; Meijer, S.L.; Weijer, K.; Hreggvidsdottir, H.S.; Heinsbroek, S.E.; Legrand, N.; Buskens, C.J.; Bemelman, W.A.; Mjosberg, J.M.; Spits, H. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol., 2013, 14(3), 221-229.
105. Moro, K.; Yamada, T.; Tanabe, M.; Takeuchi, T.; Ikawa, T.; Kawamoto, H.; Furusawa, J.; Ohtani, M.; Fujii, H.; Koyasu, S. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature, 2010, 463(7280), 540- 544
106. Fort, M.M.; Cheung, J.; Yen, D.; Li, J.; Zurawski, S.M.; Lo, S.; Menon, S.; Clifford, T.; Hunte, B.; Lesley, R.; Muchamuel, T.; Hurst, S. D.; Zurawski, G.; Leach, M.W.; Gorman, D.M.; Rennick, D.M. IL-25 induces IL-4, IL-5, and IL-13 and Th2- associated pathologies in vivo. Immunity, 2001, 15(6), 985-995
107. Hurst, S.D.; Muchamuel, T.; Gorman, D.M.; Gilbert, J.M.; Clifford, T.; Kwan, S.; Menon, S.; Seymour, B.; Jackson, C.; Kung, T.T.; Brieland, J.K.; Zurawski, S.M.; Chapman, R.W.; Zurawski, G.; Coffman, R.L. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol., 2002, 169(1), 443-453
108. Halim, T.Y.; Krauss, R.H.; Sun, A.C.; Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity, 2012, 36(3), 451-463.
109. Wilhelm, C.; Hirota, K.; Stieglitz, B.; Van Snick, J.; Tolaini, M.; Lahl, K.; Sparwasser, T.; Helmby, H.; Stockinger, B. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol., 2011, 12(11), 1071-1077
110. Fallon, P.G.; Ballantyne, S.J.; Mangan, N.E.; Barlow, J.L.; Dasvarma, A.; Hewett, D.R.; McIlgorm, A.; Jolin, H.E.; McKenzie, A.N. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med., 2006, 203(4), 1105-1116
111. Monticelli, L.A.; Sonnenberg, G.F.; Abt, M.C.; Alenghat, T.; Ziegler, C.G.; Doering, T.A.; Angelosanto, J.M.; Laidlaw, B.J.; Yang, C.Y.; Sathaliyawala, T.; Kubota, M.; Turner, D.; Diamond, J.M.; Goldrath, A.W.; Farber, D.L.; Collman, R.G.; Wherry, E.J.; Artis, D. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol., 2011, 12(11), 1045-1054.
112. Hoyler, T.; Klose, C.S.; Souabni, A.; Turqueti-Neves, A.; Pfeifer, D.; Rawlins, E.L.; Voehringer, D.; Busslinger, M.; Diefenbach, A. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity, 2012, 37(4), 634-648
113. Liang, H.E.; Reinhardt, R.L.; Bando, J.K.; Sullivan, B.M.; Ho, I.C.; Locksley, R.M. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol., 2012, 13(1), 58-66.
114. Neill, D.R.; Wong, S.H.; Bellosi, A.; Flynn, R.J.; Daly, M.; Langford, T.K.; Bucks, C.; Kane, C.M.; Fallon, P.G.; Pannell, R.; Jolin, H.E.; McKenzie, A.N. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature, 2010, 464(7293), 1367-1370.
115. Price, A.E.; Liang, H.E.; Sullivan, B.M.; Reinhardt, R.L.; Eisley, C.J.; Erle, D.J.; Locksley, R.M. Systemically dispersed innate IL- 13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. U. S. A., 2010, 107(25), 11489-11494.
116. Takatori, H.; Kanno, Y.; Watford, W.T.; Tato, C.M.; Weiss, G.; Ivanov, II; Littman, D.R.; O'Shea, J.J. Lymphoid tissue inducerlike cells are an innate source of IL-17 and IL-22. J. Exp. Med., 2009, 206(1), 35-41.
117. Honda, K.; Nakano, H.; Yoshida, H.; Nishikawa, S.; Rennert, P.; Ikuta, K.; Tamechika, M.; Yamaguchi, K.; Fukumoto, T.; Chiba, T.; Nishikawa, S.I. Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis. J. Exp. Med., 2001, 193(5), 621-630
118. Kanamori, Y.; Ishimaru, K.; Nanno, M.; Maki, K.; Ikuta, K.; Nariuchi, H.; Ishikawa, H. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med., 1996, 184(4), 1449-1459.
119. Cella, M.; Fuchs, A.; Vermi, W.; Facchetti, F.; Otero, K.; Lennerz, J.K.; Doherty, J.M.; Mills, J.C.; Colonna, M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature, 2009, 457(7230), 722-725
120. Luci, C.; Reynders, A.; Ivanov, II; Cognet, C.; Chiche, L.; Chasson, L.; Hardwigsen, J.; Anguiano, E.; Banchereau, J.; Chaussabel, D.; Dalod, M.; Littman, D.R.; Vivier, E.; Tomasello, E. Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat. Immunol., 2009, 10(1), 75-82
121. Sanos, S.L.; Vonarbourg, C.; Mortha, A.; Diefenbach, A. Control of epithelial cell function by interleukin- 22-producing RORgammat+ innate lymphoid cells. Immunology, 2011, 132(4), 453-465
122. Satoh-Takayama, N.; Vosshenrich, C.A.; Lesjean-Pottier, S.; Sawa, S.; Lochner, M.; Rattis, F.; Mention, J.J.; Thiam, K.; Cerf-Bensussan, N.; Mandelboim, O.; Eberl, G.; Di Santo, J.P. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity, 2008, 29(6), 958-970.
123. Sonnenberg, G.F.; Monticelli, L.A.; Elloso, M.M.; Fouser, L.A.; Artis, D. CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity, 2011, 34(1), 122-134.
124. Sawa, S.; Lochner, M.; Satoh-Takayama, N.; Dulauroy, S.; Berard, M.; Kleinschek, M.; Cua, D.; Di Santo, J.P.; Eberl, G. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol., 2011, 12(4), 320-326.
125. Hanash, A.M.; Dudakov, J.A.; Hua, G.; O'Connor, M.H.; Young, L.F.; Singer, N.V.; West, M.L.; Jenq, R.R.; Holland, A.M.; Kappel, L.W.; Ghosh, A.; Tsai, J.J.; Rao, U.K.; Yim, N.L.; Smith, O.M.; Velardi, E.; Hawryluk, E.B.; Murphy, G.F.; Liu, C.; Fouser, L.A.; Kolesnick, R.; Blazar, B.R.; van den Brink, M.R. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity, 2012, 37(2), 339-350.
126. Reynders, A.; Yessaad, N.; Vu Manh, T.P.; Dalod, M.; Fenis, A.; Aubry, C.; Nikitas, G.; Escaliere, B.; Renauld, J.C.; Dussurget, O.; Cossart, P.; Lecuit, M.; Vivier, E.; Tomasello, E. Identity, regulation and in vivo function of gut NKp46+RORgammat+ and NKp46+RORgammat- lymphoid cells. EMBO J., 2011, 30(14), 2934-2947
127. Sawa, S.; Cherrier, M.; Lochner, M.; Satoh- Takayama, N.; Fehling, H.J.; Langa, F.; Di Santo, J.P.; Eberl, G. Lineage relationship analysis of RORgammat+ innate lymphoid cells. Science, 2010, 330(6004), 665-669.
128. Kiss, E.A.; Vonarbourg, C.; Kopfmann, S.; Hobeika, E.; Finke, D.; Esser, C.; Diefenbach, A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science, 2011, 334(6062), 1561-1565
129. Lee, J.S.; Cella, M.; McDonald, K.G.; Garlanda, C.; Kennedy, G.D.; Nukaya, M.; Mantovani, A.; Kopan, R.; Bradfield, C.A.; Newberry, R.D.; Colonna, M. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol., 2012, 13(2), 144-151
130. Qiu, J.; Heller, J.J.; Guo, X.; Chen, Z.M.; Fish, K.; Fu, Y. X.; Zhou, L. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity, 2012, 36(1), 92-104
131. Perdew, G.H.; Babbs, C.F. Production of Ah receptor ligands in rat fecal suspensions containing tryptophan or indole-3-carbinol. Nutr. Cancer, 1991, 16(3-4), 209-218
132. Stockinger, B.; Hirota, K.; Duarte, J.; Veldhoen, M. External influences on the immune system via activation of the aryl hydrocarbon receptor. Semin. Immunol., 2011, 23(2), 99-105.
133. Shaw, M.H.; Kamada, N.; Kim, Y.G.; Nunez, G. Microbiotainduced IL-1beta, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J. Exp. Med., 2012, 209(2), 251-258
134. Hughes, T.; Becknell, B.; Freud, A.G.; McClory, S.; Briercheck, E.; Yu, J.; Mao, C.; Giovenzana, C.; Nuovo, G.; Wei, L.; Zhang, X.; Gavrilin, M.A.; Wewers, M.D.; Caligiuri, M.A. Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity, 2010, 32(6), 803-814
135. Manta, C.; Heupel, E.; Radulovic, K.; Rossini, V.; Garbi, N.; Riedel, C.U.; Niess, J.H. CX(3)CR1(+) macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium. Mucosal Immunol., 2013, 6(1), 177-188
136. Niess, J.H.; Adler, G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J. Immunol., 2010, 184(4), 2026-2037.
137. Fink, L.N.; Zeuthen, L.H.; Christensen, H.R.; Morandi, B.; Frokiaer, H.; Ferlazzo, G. Distinct gut-derived lactic acid bacteria elicit divergent dendritic cell-mediated NK cell responses. Int. Immunol., 2007, 19(12), 1319-1327
138. Koizumi, S.; Wakita, D.; Sato, T.; Mitamura, R.; Izumo, T.; Shibata, H.; Kiso, Y.; Chamoto, K.; Togashi, Y.; Kitamura, H.; Nishimura, T. Essential role of Tolllike receptors for dendritic cell and NK1.1(+) cell-dependent activation of type 1 immunity by Lactobacillus pentosus strain SPT84. Immunol. Lett., 2008, 120(1-2), 14-19.
139. Qiu, J.; Guo, X.; Chen, Z.M.; He, L.; Sonnenberg, G.F.; Artis, D.; Fu, Y.X.; Zhou, L. Group 3 innate lymphoid cells inhibit T-cellmediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity, 2013, 39(2), 386-399.
140. Goto, Y.; Obata, T.; Kunisawa, J.; Sato, S.; Ivanov, II; Lamichhane, A.; Takeyama, N.; Kamioka, M.; Sakamoto, M.; Matsuki, T.; Setoyama, H.; Imaoka, A.; Uematsu, S.; Akira, S.; Domino, S.E.; Kulig, P.; Becher, B.; Renauld, J.C.; Sasakawa, C.; Umesaki, Y.; Benno, Y.; Kiyono, H. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science, 2014, 345(6202), 1254009.
141. Terahara, K.; Nochi, T.; Yoshida, M.; Takahashi, Y.; Goto, Y.; Hatai, H.; Kurokawa, S.; Jang, M.H.; Kweon, M.N.; Domino, S.E.; Hiroi, T.; Yuki, Y.; Tsunetsugu-Yokota, Y.; Kobayashi, K.; Kiyono, H. Distinct fucosylation of M cells and epithelial cells by Fut1 and Fut2, respectively, in response to intestinal environmental stress. Biochem. Biophys. Res. Commun., 2011, 404(3), 822-828.
142. Zhu, J.; Paul, W.E. CD4 T cells: fates, functions, and faults. Blood, 2008, 112(5), 1557-1569.
143. Zhou, L.; Chong, M.M.; Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity, 2009, 30(5), 646-655.
144. Singh, B.; Read, S.; Asseman, C.; Malmstrom, V.; Mottet, C.; Stephens, L.A.; Stepankova, R.; Tlaskalova, H.; Powrie, F. Control of intestinal inflammation by regulatory T cells. Immunol. Rev., 2001, 182, 190-200
145. Annacker, O.; Asseman, C.; Read, S.; Powrie, F. Interleukin-10 in the regulation of T cell-induced colitis. J. Autoimmun., 2003, 20(4), 277-279.
146. Neurath, M.F.; Weigmann, B.; Finotto, S.; Glickman, J.; Nieuwenhuis, E.; Iijima, H.; Mizoguchi, A.; Mizoguchi, E.; Mudter, J.; Galle, P.R.; Bhan, A.; Autschbach, F.; Sullivan, B.M.; Szabo, S.J.; Glimcher, L.H.; Blumberg, R.S. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J. Exp. Med., 2002, 195(9), 1129-1143;
147. Simpson, S.J.; Shah, S.; Comiskey, M.; de Jong, Y.P.; Wang, B.; Mizoguchi, E.; Bhan, A.K.; Terhorst, C. T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells. J. Exp. Med., 1998, 187(8), 1225-1234.
148. Powrie, F.; Leach, M.W.; Mauze, S.; Menon, S.; Caddle, L.B.; Coffman, R.L. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity, 1994, 1(7), 553-562.
149. Breese, E.; Braegger, C.P.; Corrigan, C.J.; Walker-Smith, J.A.; MacDonald, T.T. Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology, 1993, 78(1), 127-131.
150. Honda, K.; Nakamura, K.; Matsui, N.; Takahashi, M.; Kitamura, Y.; Mizutani, T.; Harada, N.; Nawata, H.; Hamano, S.; Yoshida, H. T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis. Inflamm. Bowel Dis., 2005, 11(12), 1044-1052.
151. Dann, S.M.; Le, C.; Choudhury, B.K.; Liu, H.; Saldarriaga, O.; Hanson, E.M.; Cong, Y.; Eckmann, L. Attenuation of intestinal inflammation in interleukin-10-deficient mice infected with Citrobacter rodentium. Infect. Immun., 2014, 82(5), 1949-1958.
152. Rovedatti, L.; Kudo, T.; Biancheri, P.; Sarra, M.; Knowles, C.H.; Rampton, D.S.; Corazza, G.R.; Monteleone, G.; Di Sabatino, A.; Macdonald, T.T. Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut, 2009, 58(12), 1629-1636
153. Vainer, B.; Nielsen, O.H.; Hendel, J.; Horn, T.; Kirman, I. Colonic expression and synthesis of interleukin 13 and interleukin 15 in inflammatory bowel disease. Cytokine, 2000, 12(10), 1531-1536.
154. Basu, R.; Hatton, R.D.; Weaver, C.T. The Th17 family: flexibility follows function. Immunol. Rev., 2013, 252(1), 89-103.
155. Yen, D.; Cheung, J.; Scheerens, H.; Poulet, F.; McClanahan, T.; McKenzie, B.; Kleinschek, M.A.; Owyang, A.; Mattson, J.; Blumenschein, W.; Murphy, E.; Sathe, M.; Cua, D.J.; Kastelein, R.A.; Rennick, D. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest., 2006, 116(5), 1310-1316.
156. Neurath, M.F. IL-12 family members in experimental colitis. Mucosal Immunol., 2008, 1(Suppl 1), S28-S30.
157. Schmidt, C.; Giese, T.; Ludwig, B.; Mueller-Molaian, I.; Marth, T.; Zeuzem, S.; Meuer, S.C.; Stallmach, A. Expression of interleukin- 12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm. Bowel Dis., 2005, 11(1), 16-23.
158. Weaver, C.T.; Elson, C.O.; Fouser, L.A.; Kolls, J.K. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu. Rev. Pathol., 2013, 8, 477-512.
159. Reynolds, J.M.; Martinez, G.J.; Nallaparaju, K.C.; Chang, S.H.; Wang, Y.H.; Dong, C. Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J. Immunol., 2012, 189(9), 4226-4230.
160. Zakostelska, Z.; Kverka, M.; Klimesova, K.; Rossmann, P.; Mrazek, J.; Kopecny, J.; Hornova, M.; Srutkova, D.; Hudcovic, T.; Ridl, J.; Tlaskalova-Hogenova, H. Lysate of probiotic Lactobacillus casei DN-114 001 ameliorates colitis by strengthening the gut barrier function and changing the gut microenvironment. PLoS One, 2011, 6(11), e27961.
161. Liu, W.; Chen, Y.; Golan, M.A.; Annunziata, M.L.; Du, J.; Dougherty, U.; Kong, J.; Musch, M.; Huang, Y.; Pekow, J.; Zheng, C.; Bissonnette, M.; Hanauer, S.B.; Li, Y.C. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J. Clin. Invest., 2013, 123(9), 3983-3996.
162. Cheroutre, H. IELs: enforcing law and order in the court of the intestinal epithelium. Immunol. Rev., 2005, 206, 114-131.
163. Beagley, K.W.; Fujihashi, K.; Lagoo, A.S.; Lagoo- Deenadaylan, S.; Black, C.A.; Murray, A.M.; Sharmanov, A.T.; Yamamoto, M.; McGhee, J.R.; Elson, C.O.; et al. Differences in intraepithelial lymphocyte T cell subsets isolated from murine small versus large intestine. J. Immunol., 1995, 154(11), 5611- 5619
164. Mysorekar, I.U.; Lorenz, R.G.; Gordon, J.I. A gnotobiotic transgenic mouse model for studying interactions between small intestinal enterocytes and intraepithelial lymphocytes. J. Biol. Chem., 2002, 277(40), 37811-37819.
165. Arcaro, A.; Gregoire, C.; Bakker, T.R.; Baldi, L.; Jordan, M.; Goffin, L.; Boucheron, N.; Wurm, F.; van der Merwe, P.A.; Malissen, B.; Luescher, I.F. CD8beta endows CD8 with efficient coreceptor function by coupling T cell receptor/CD3 to raftassociated CD8/p56(lck) complexes. J. Exp. Med., 2001, 194(10), 1485-1495
166. Thome, M.; Duplay, P.; Guttinger, M.; Acuto, O. Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex. J. Exp. Med., 1995, 181(6), 1997-2006.
167. Gao, G.F.; Tormo, J.; Gerth, U.C.; Wyer, J.R.; McMichael, A.J.; Stuart, D.I.; Bell, J.I.; Jones, E.Y.; Jakobsen, B.K. Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature, 1997, 387(6633), 630-634.
168. Cole, D.K.; Gao, G.F. CD8: adhesion molecule, co-receptor and immuno-modulator. Cell. Mol. Immunol., 2004, 1(2), 81-88.
169. Renard, V.; Romero, P.; Vivier, E.; Malissen, B.; Luescher, I.F. CD8 beta increases CD8 coreceptor function and participation in TCR-ligand binding. J. Exp. Med., 1996, 184(6), 2439-2444.
170. Wheeler, C.J.; von Hoegen, P.; Parnes, J.R. An immunological role for the CD8 beta-chain. Nature, 1992, 357(6375), 247-249
171. Doucey, M.A.; Legler, D.F.; Faroudi, M.; Boucheron, N.; Baumgaertner, P.; Naeher, D.; Cebecauer, M.; Hudrisier, D.; Ruegg, C.; Palmer, E.; Valitutti, S.; Bron, C.; Luescher, I.F. The beta1 and beta3 integrins promote T cell receptor-mediated cytotoxic T lymphocyte activation. J. Biol. Chem., 2003, 278(29), 26983-26991.
172. Cheroutre, H.; Lambolez, F. Doubting the TCR coreceptor function of CD8alphaalpha. Immunity, 2008, 28(2), 149-159
173. Cawthon, A.G.; Lu, H.; Alexander-Miller, M.A. Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8alphabeta versus CD8alphaalpha expression. J. Immunol., 2001, 167(5), 2577-2584.
174. Cheroutre, H.; Lambolez, F.; Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol., 2011, 11(7), 445-456
175. Guy-Grand, D.; Cerf-Bensussan, N.; Malissen, B.; Malassis-Seris, M.; Briottet, C.; Vassalli, P. Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J. Exp. Med., 1991, 173(2), 471-481.
176. Mayrhofer, G. Thymus-dependent and thymus-independent subpopulations of intestinal intraepithelial lymphocytes: a granular subpopulation of probable bone marrow origin and relationship to mucosal mast cells. Blood, 1980, 55(3), 532-535.
177. Komano, H.; Fujiura, Y.; Kawaguchi, M.; Matsumoto, S.; Hashimoto, Y.; Obana, S.; Mombaerts, P.; Tonegawa, S.; Yamamoto, H.; Itohara, S.; et al. Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc. Natl. Acad. Sci. U. S. A., 1995, 92(13), 6147-6151.
178. Chen, Y.; Chou, K.; Fuchs, E.; Havran, W.L.; Boismenu, R. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc. Natl. Acad. Sci. U. S. A., 2002, 99(22), 14338-14343.
179. Lepage, A.C.; Buzoni-Gatel, D.; Bout, D.T.; Kasper, L.H. Gutderived intraepithelial lymphocytes induce long term immunity against Toxoplasma gondii. J. Immunol., 1998, 161(9), 4902-4908.
180. Ismail, A.S.; Severson, K.M.; Vaishnava, S.; Behrendt, C.L.; Yu, X.; Benjamin, J.L.; Ruhn, K.A.; Hou, B.; DeFranco, A.L.; Yarovinsky, F.; Hooper, L.V. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl. Acad. Sci. U. S. A., 2011, 108(21), 8743-8748.
181. Kuhl, A.A.; Pawlowski, N.N.; Grollich, K.; Loddenkemper, C.; Zeitz, M.; Hoffmann, J.C. Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models. J. Leukoc. Biol. 2007, 81(1), 168-175
182. Tsuchiya, T.; Fukuda, S.; Hamada, H.; Nakamura, A.; Kohama, Y.; Ishikawa, H.; Tsujikawa, K.; Yamamoto, H. Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J. Immunol., 2003, 171(10), 5507-5513
183. Simpson, S.J.; Hollander, G.A.; Mizoguchi, E.; Allen, D.; Bhan, A.K.; Wang, B.; Terhorst, C. Expression of pro-inflammatory cytokines by TCR alpha beta+ and TCR gamma delta+ T cells in an experimental model of colitis. Eur. J. Immunol., 1997, 27(1), 17-25
184. Kawaguchi-Miyashita, M.; Shimada, S.; Kurosu, H.; Kato-Nagaoka, N.; Matsuoka, Y.; Ohwaki, M.; Ishikawa, H.; Nanno, M. An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Eur. J. Immunol., 2001, 31(4), 980-988
185. Mizoguchi, A.; Mizoguchi, E.; de Jong, Y.P.; Takedatsu, H.; Preffer, F.I.; Terhorst, C.; Bhan, A.K. Role of the CD5 molecule on TCR gammadelta T cell-mediated immune functions: development of germinal centers and chronic intestinal inflammation. Int. Immunol., 2003, 15(1), 97-108.
186. Park, S.G.; Mathur, R.; Long, M.; Hosh, N.; Hao, L.; Hayden, M.S.; Ghosh, S. T regulatory cells maintain intestinal homeostasis by suppressing gammadelta T cells. Immunity, 2010, 33(5), 791- 803.
187. Campbell, D.J.; Butcher, E.C. Rapid acquisition of tissuespecific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues. The J. Exp. Med., 2002, 195(1), 135-141
188. Agace, W.W. T-cell recruitment to the intestinal mucosa. Trends Immunol., 2008, 29(11), 514-522.
189. Dharakul, T.; Labbe, M.; Cohen, J.; Bellamy, A.R.; Street, J.E.; Mackow, E.R.; Fiore, L.; Rott, L.; Greenberg, H.B. Immunization with baculovirus-expressed recombinant rotavirus proteins VP1, VP4, VP6, and VP7 induces CD8+ T lymphocytes that mediate clearance of chronic rotavirus infection in SCID mice. J. Virol., 1991, 65(11), 5928-5932
190. Kanwar, S.S.; Ganguly, N.K.; Walia, B.N.; Mahajan, R.C. Direct and antibody dependent cell mediated cytotoxicity against Giardia lamblia by splenic and intestinal lymphoid cells in mice. Gut, 1986, 27(1), 73-77
191. Muller, S.; Buhler-Jungo, M.; Mueller, C. Intestinal intraepithelial lymphocytes exert potent protective cytotoxic activity during an acute virus infection. J. Immunol., 2000, 164(4), 1986-1994.
192. Cheroutre, H. In IBD eight can come before four. Gastroenterology, 2006, 131(2), 667-670
193. Nancey, S.; Holvoet, S.; Graber, I.; Joubert, G.; Philippe, D.; Martin, S.; Nicolas, J.F.; Desreumaux, P.; Flourie, B.; Kaiserlian, D. CD8+ cytotoxic T cells induce relapsing colitis in normal mice. Gastroenterology, 2006, 131(2), 485-496
194. Tajima, M.; Wakita, D.; Noguchi, D.; Chamoto, K.; Yue, Z.; Fugo, K.; Ishigame, H.; Iwakura, Y.; Kitamura, H.; Nishimura, T. IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17- producing CD8+ T cells. J. Exp. Med., 2008, 205(5), 1019-1027.
195. Godkin, A.; Jewell, D. The pathogenesis of celiac disease. Gastroenterology, 1998, 115(1), 206-210
196. Sollid, L.M.; Markussen, G.; Ek, J.; Gjerde, H.; Vartdal, F.; Thorsby, E. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J. Exp. Med., 1989, 169(1), 345- 350.
197. Hue, S.; Mention, J.J.; Monteiro, R.C.; Zhang, S.; Cellier, C.; Schmitz, J.; Verkarre, V.; Fodil, N.; Bahram, S.; Cerf-Bensussan, N.; Caillat-Zucman, S. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity, 2004, 21(3), 367-377
198. Kutlu, T.; Brousse, N.; Rambaud, C.; Le Deist, F.; Schmitz, J.; Cerf-Bensussan, N. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut, 1993, 34(2), 208-214
199. Meresse, B.; Chen, Z.; Ciszewski, C.; Tretiakova, M.; Bhagat, G.; Krausz, T.N.; Raulet, D.H.; Lanier, L.L.; Groh, V.; Spies, T.; Ebert, E.C.; Green, P.H.; Jabri, B. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity, 2004, 21(3), 357-366.
200. Inagaki-Ohara, K.; Sawaguchi, A.; Suganuma, T.; Matsuzaki, G.; Nawa, Y. Intraepithelial lymphocytes express junctional molecules in murine small intestine. Biochem. Biophys. Res. Commun., 2005, 331(4), 977-983.
201. Edelblum, K.L.; Shen, L.; Weber, C.R.; Marchiando, A.M.; Clay, B.S.; Wang, Y.; Prinz, I.; Malissen, B.; Sperling, A.I.; Turner, J.R. Dynamic migration of gammadelta intraepithelial lymphocytes requires occludin. Proc. Natl. Acad. Sci. U. S. A., 2012, 109(18), 7097-7102.
202. Cepek, K.L.; Shaw, S.K.; Parker, C.M.; Russell, G.J.; Morrow, J.S.; Rimm, D.L.; Brenner, M.B. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature, 1994, 372(6502), 190-193.
203. Schluns, K.S.; Nowak, E.C.; Cabrera-Hernandez, A.; Puddington, L.; Lefrancois, L.; Aguila, H.L. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proc. Natl. Acad. Sci. U. S. A., 2004, 101(15), 5616-5621
204. Yu, Q.; Tang, C.; Xun, S.; Yajima, T.; Takeda, K.; Yoshikai, Y. MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8 alpha alpha TCR alpha beta and TCR gamma delta intestinal intraepithelial lymphocytes. J. Immunol., 2006, 176(10), 6180- 6185.
205. Bauer, S.; Groh, V.; Wu, J.; Steinle, A.; Phillips, J.H.; Lanier, L.L.; Spies, T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science, 1999, 285(5428), 727- 729
206. Girardi, M.; Oppenheim, D.E.; Steele, C.R.; Lewis, J.M.; Glusac, E.; Filler, R.; Hobby, P.; Sutton, B.; Tigelaar, R.E.; Hayday, A.C. Regulation of cutaneous malignancy by gammadelta T cells. Science, 2001, 294(5542), 605-609.
207. Groh, V.; Bahram, S.; Bauer, S.; Herman, A.; Beauchamp, M.; Spies, T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl. Acad. Sci. U. S. A., 1996, 93(22), 12445-12450.
208. Allez, M.; Tieng, V.; Nakazawa, A.; Treton, X.; Pacault, V.; Dulphy, N.; Caillat-Zucman, S.; Paul, P.; Gornet, J.M.; Douay, C.; Ravet, S.; Tamouza, R.; Charron, D.; Lemann, M.; Mayer, L.; Toubert, A. CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology, 2007, 132(7), 2346-2358
209. Ito, Y.; Kanai, T.; Totsuka, T.; Okamoto, R.; Tsuchiya, K.; Nemoto, Y.; Yoshioka, A.; Tomita, T.; Nagaishi, T.; Sakamoto, N.; Sakanishi, T.; Okumura, K.; Yagita, H.; Watanabe, M. Blockade of NKG2D signaling prevents the development of murine CD4+ T cellmediated colitis. Am. J. Physiol. Gastrointest. Liver Physiol., 2008, 294(1), G199-G207.
210. Hansen, C.H.; Holm, T.L.; Krych, L.; Andresen, L.; Nielsen, D.S.; Rune, I.; Hansen, A.K.; Skov, S. Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells. Eur. J. Immunol., 2013, 43(2), 447-457.
211. Hooper, L.V.; Wong, M.H.; Thelin, A.; Hansson, L.; Falk, P.G.; Gordon, J.I. Molecular analysis of commensal host-microbial relationships in the intestine. Science, 2001, 291(5505), 881-884;
212. Pull, S.L.; Doherty, J.M.; Mills, J.C.; Gordon, J.I.; Stappenbeck, T.S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. U. S. A., 2005, 102(1), 99-104
213. Wick, M.J.; Madara, J.L.; Fields, B.N.; Normark, S.J. Molecular cross talk between epithelial cells and pathogenic microorganisms. Cell, 1991, 67(4), 651-659.
214. Lefrancois, L.; Goodman, T. In vivo modulation of cytolytic activity and Thy-1 expression in TCR-gamma delta+ intraepithelial lymphocytes. Science, 1989, 243(4899), 1716-1718
215. Umesaki, Y.; Setoyama, H.; Matsumoto, S.; Okada, Y. Expansion of alpha beta T-cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology, 1993, 79(1), 32-37.
216. Jiang, W.; Wang, X.; Zeng, B.; Liu, L.; Tardivel, A.; Wei, H.; Han, J.; MacDonald, H.R.; Tschopp, J.; Tian, Z.; Zhou, R. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med., 2013, 210(11), 2465-2476.
217. Alberts B, J.A.; Lewis, J. Molecular Biology of the Cell. 4th ed.; Garland Science: New York, 2002.
218. Chaudhuri, J.; Alt, F.W. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat. Rev. Immunol., 2004, 4(7), 541-552
219. Chaudhuri, J.; Tian, M.; Khuong, C.; Chua, K.; Pinaud, E.; Alt, F.W. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature, 2003, 422(6933), 726-730
220. Muramatsu, M.; Nagaoka, H.; Shinkura, R.; Begum, N.A.; Honjo, T. Discovery of activationinduced cytidine deaminase, the engraver of antibody memory. Adv. Immunol., 2007, 94, 1-36
221. Stavnezer, J.; Guikema, J.E.; Schrader, C.E. Mechanism and regulation of class switch recombination. Ann. Rev. Immunol., 2008, 26, 261-292.
222. Golby, S.J.; Spencer, J. Where do IgA plasma cells in the gut come from? Gut, 2002, 51(2), 150-151.
223. Mostov, K.E. Transepithelial transport of immunoglobulins. Ann. Rev. Immunol., 1994, 12, 63-84.
224. Brandtzaeg, P.; Prydz, H. Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulins. Nature, 1984, 311(5981), 71-73
225. Mestecky, J.; Russell, M.W.; Elson, C.O. Intestinal IgA: novel views on its function in the defence of the largest mucosal surface. Gut, 1999, 44(1), 2-5
226. Mestecky, J.; Zikan, J.; Butler, W.T. Immunoglobulin M and secretory immunoglobulin A: presence of a common polypeptide chain different from light chains. Science, 1971, 171(3976), 1163-1165
227. Phalipon, A.; Cardona, A.; Kraehenbuhl, J.P.; Edelman, L.; Sansonetti, P.J.; Corthesy, B. Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity, 2002, 17(1), 107-115
228. Phalipon, A.; Corthesy, B. Novel functions of the polymeric Ig receptor: well beyond transport of immunoglobulins. Trends Immunol., 2003, 24(2), 55-58.
229. Fernandez, M.I.; Pedron, T.; Tournebize, R.; Olivo-Marin, J.C.; Sansonetti, P.J.; Phalipon, A. Anti-inflammatory role for intracellular dimeric immunoglobulin a by neutralization of lipopolysaccharide in epithelial cells. Immunity, 2003, 18(6), 739- 749
230. Macpherson, A.J.; Hunziker, L.; McCoy, K.; Lamarre, A. IgA responses in the intestinal mucosa against pathogenic and nonpathogenic microorganisms. Microbes Infect., 2001, 3(12), 1021- 1035.
231. Fagarasan, S.; Muramatsu, M.; Suzuki, K.; Nagaoka, H.; Hiai, H.; Honjo, T. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science, 2002, 298(5597), 1424-1427.
232. Brandtzaeg, P.; Carlsen, H.S.; Halstensen, T.S. The B-cell system in inflammatory bowel disease. Adv. Exp. Med. Biol., 2006, 579, 149-167.
233. Cupi, M.L.; Sarra, M.; Marafini, I.; Monteleone, I.; Franze, E.; Ortenzi, A.; Colantoni, A.; Sica, G.; Sileri, P.; Rosado, M.M.; Carsetti, R.; MacDonald, T.T.; Pallone, F.; Monteleone, G. Plasma cells in the mucosa of patients with inflammatory bowel disease produce granzyme B and possess cytotoxic activities. J. Immunol., 2014, 192(12), 6083-6091.
234. Arnason, B.G.; Salomon, J.C.; Grabar, P. Anti-Liver Antibodies and Serum Immunoglobulins in the Standard and Axenic Mice; a Comparative Study after Acute Hepatic Necrosis Induced by Carbon Tetrachlorode (Cc14). C. R. Hebd. Seances. Acad. Sci., 1964, 259, 4882-4885
235. Crabbe, P.A.; Nash, D.R.; Bazin, H.; Eyssen, H.; Heremans, J.F. Immunohistochemical observations on lymphoid tissues from conventional and germ-free mice. Lab. Invest., 1970, 22(5), 448-457
236. Fahey, J.L.; Sell, S. The Immunoglobulins of Mice. V. The Metabolic (Catabolic) Properties of Five Immunoglobulin Classes. J. Exp. Med., 1965, 122, 41-58;
237. Glaister, J.R. Factors affecting the lymphoid cells in the small intestinal epithelium of the mouse. Int. Arch. Allergy Appl. Immunol., 1973, 45(5), 719-730
238. Gordon, H.A. Morphological and physiological characterization of germfree life. Ann. N. Y. Acad. Sci., 1959, 78, 208-220
239. Moreau, M.C.; Ducluzeau, R.; Guy-Grand, D.; Muller, M.C. Increase in the population of duodenal immunoglobulin A plasmocytes in axenic mice associated with different living or dead bacterial strains of intestinal origin. Infect. Immun., 1978, 21(2), 532-539.
240. King, C.; Tangye, S.G.; Mackay, C.R. T follicular helper (TFH) cells in normal and dysregulated immune responses. Ann. Rev. Immunol., 2008, 26, 741-766
241. Suzuki, K.; Meek, B.; Doi, Y.; Muramatsu, M.; Chiba, T.; Honjo, T.; Fagarasan, S. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl. Acad. Sci. U. S. A., 2004, 101(7), 1981-1986.