Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease

P J Basso, M T C Fonseca, G Bonfá, V B F Alves, H Sales-Campos, V Nardini, C R B Cardoso, P J Basso, M T C Fonseca, G Bonfá, V B F Alves, H Sales-Campos, V Nardini, C R B Cardoso

Abstract

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

Figures

Figure 1. Intestinal immune response in the…
Figure 1. Intestinal immune response in the development of inflammatory bowel disease (IBD). The immune surveillance of the intestine is composed of several cell types, including dendritic cells (DCs), macrophages (MΦ), natural killer (NK) cells, natural killer T (NKT) cells, innate lymphoid cells (ILCs) and intraepithelial lymphocytes (IEL). All these components are altered in some way during IBD. The breakdown of immunological tolerance causes recognition of the intestinal microbiota by the local immune system, activating the inflammatory cascade. The physical/chemical barriers composed by IEL, Paneth cells (PC), microfold cells (M cells) or their products are impaired during the disease and fail to restrain bacterial invasion. In lamina propria (LP), DCs capture and recognize bacterial antigens by projecting their dendrites into the intestinal lumen between intestinal epithelial cells (IEC), while in the Peyer's patches (PP) the antigens become available to DCs through M cells. Afterwards, the LP and PP DCs migrate to the mesenteric lymph nodes (MLN) and present the antigens to naive T cells (Th0). Meanwhile, the PP DCs may also present antigens to Th0 cells located in the follicles. The antigen presentation in the presence of the cytokines interleukin (IL)-12 or IL-23/IL-6/transforming growth factor-beta (TGF-β) leads to polarization of Th0 cells into a pro-inflammatory Th1 or Th17 profile, respectively, which are increased due to low number or function of regulatory T cells (Treg). Th1 and Th17 cells secrete cytokines such as tumor necrosis factor (TNF), interferon γ (IFN-γ), IL17A, IL-17F and IL-21, which in turn contribute to tissue injury and excessive inflammatory response, especially in Crohn's disease. In addition, cytokines such as IL-4, IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) directly or indirectly contribute to the differentiation of Th0 cells into Th2 profile in ulcerative colitis, which may also be under low control of Tregs. The red arrows indicate components that are altered in IBD. The red crosses indicate the absence or reduced function in IBD. It is noteworthy that cytokines and immune mechanisms depicted in the figure are shown according to the scope and information presented in this review. Thus, the mediators described here can also be synthesized from other cell sources as well as other immune pathways may contribute to IBD pathogenesis.

References

    1. Ng SC, Bernstein CN, Vatn MH, Lakatos PL, Loftus EV, Jr, Tysk C, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut. 2013;62:630–649. doi: 10.1136/gutjnl-2012-303661.
    1. Victoria CR, Sassak LY, Nunes HR. Incidence and prevalence rates of inflammatory bowel diseases, in midwestern of São Paulo State, Brazil. Arq Gastroenterol. 2009;46:20–25. doi: 10.1590/S0004-28032009000100009.
    1. De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, et al. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun. 2007;8:387–397. doi: 10.1038/sj.gene.6364398.
    1. Pierik M, Joossens S, Van Steen K, Van Schuerbeek N, Vlietinck R, Rutgeerts P, et al. Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis. 2006;12:1–8. doi: 10.1097/01.MIB.0000195389.11645.ab.
    1. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599–603. doi: 10.1038/35079107.
    1. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246–252. doi: 10.1038/ng.764.
    1. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010;42:1118–1125. doi: 10.1038/ng.717.
    1. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut. 2004;53:1658–1664. doi: 10.1136/gut.2003.032805.
    1. Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, et al. Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nat Genet. 2009;41:71–76. doi: 10.1038/ng.285.
    1. Palomino-Morales RJ, Oliver J, Gomez-Garcia M, Lopez-Nevot MA, Rodrigo L, Nieto A, et al. Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach. Genes Immun. 2009;10:356–364. doi: 10.1038/gene.2009.25.
    1. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955–962. doi: 10.1038/ng.175.
    1. Glas J, Wagner J, Seiderer J, Olszak T, Wetzke M, Beigel F, et al. PTPN2 gene variants are associated with susceptibility to both Crohn's disease and ulcerative colitis supporting a common genetic disease background. PLoS One. 2012;7:e33682. doi: 10.1371/journal.pone.0033682.
    1. Rausch P, Rehman A, Kunzel S, Hasler R, Ott SJ, Schreiber S, et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc Natl Acad Sci U S A. 2011;108:19030–19035. doi: 10.1073/pnas.1106408108.
    1. Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, Folsch UR, et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut. 2004;53:685–693. doi: 10.1136/gut.2003.025403.
    1. Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011;11:7. doi: 10.1186/1471-2180-11-7.
    1. Willing B, Halfvarson J, Dicksved J, Rosenquist M, Jarnerot G, Engstrand L, et al. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease. Inflamm Bowel Dis. 2009;15:653–660. doi: 10.1002/ibd.20783.
    1. Frank DN, Robertson CE, Hamm CM, Kpadeh Z, Zhang T, Chen H, et al. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17:179–184. doi: 10.1002/ibd.21339.
    1. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, et al. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005;102:18129–18134. doi: 10.1073/pnas.0505256102.
    1. Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut. 2004;53:1–4. doi: 10.1136/gut.53.1.1.
    1. Rooks MG, Veiga P, Wardwell-Scott LH, Tickle T, Segata N, Michaud M, et al. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J. 2014
    1. Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol. 2005;43:3380–3389. doi: 10.1128/JCM.43.7.3380-3389.2005.
    1. Gerding DN. Clindamycin, cephalosporins, fluoroquinolones, and Clostridium difficile-associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis. 2004;38:646–648. doi: 10.1086/382084.
    1. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–450. doi: 10.1038/nature12721.
    1. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–455. doi: 10.1038/nature12726.
    1. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139:485–498. doi: 10.1016/j.cell.2009.09.033.
    1. Salzman NH, Hung K, Haribhai D, Chu H, Karlsson-Sjoberg J, Amir E, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. 2010;11:76–83. doi: 10.1038/ni.1825.
    1. Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF, Artis D, et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity. 2013;39:386–399. doi: 10.1016/j.immuni.2013.08.002.
    1. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474:298–306. doi: 10.1038/nature10208.
    1. Gerova VA, Stoynov SG, Katsarov DS, Svinarov DA. Increased intestinal permeability in inflammatory bowel diseases assessed by iohexol test. World J Gastroenterol. 2011;17:2211–2215. doi: 10.3748/wjg.v17.i17..
    1. Kiesslich R, Duckworth CA, Moussata D, Gloeckner A, Lim LG, Goetz M, et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut. 2012;61:1146–1153. doi: 10.1136/gutjnl-2011-300695.
    1. Mankertz J, Tavalali S, Schmitz H, Mankertz A, Riecken EO, Fromm M, et al. Expression from the human occludin promoter is affected by tumor necrosis factor alpha and interferon gamma. J Cell Sci. 2000;113((Part 11)):2085–2090.
    1. Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem. 2011;286:31263–31271. doi: 10.1074/jbc.M111.238147.
    1. Buisine MP, Desreumaux P, Leteurtre E, Copin MC, Colombel JF, Porchet N, et al. Mucin gene expression in intestinal epithelial cells in Crohn's disease. Gut. 2001;49:544–551. doi: 10.1136/gut.49.4.544.
    1. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000;68:7010–7017. doi: 10.1128/IAI.68.12.7010-7017.2000.
    1. Pedersen G, Andresen L, Matthiessen MW, 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;141:298–306. doi: 10.1111/j.1365-2249.2005.02848.x.
    1. Hausmann M, Kiessling S, Mestermann S, Webb G, Spottl T, Andus T, et al. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology. 2002;122:1987–2000. doi: 10.1053/gast.2002.33662.
    1. Fort MM, Mozaffarian A, Stover AG, Correia JS, Johnson DA, Crane RT, et al. A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J Immunol. 2005;174:6416–6423. doi: 10.4049/jimmunol.174.10.6416.
    1. Torok HP, Glas J, Endres I, Tonenchi L, Teshome MY, Wetzke M, et al. Epistasis between Toll-like receptor-9 polymorphisms and variants in NOD2 and IL23R modulates susceptibility to Crohn's disease. Am J Gastroenterol. 2009;104:1723–1733. doi: 10.1038/ajg.2009.184.
    1. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–97. doi: 10.1038/nm.2069.
    1. Jiang W, Wang X, Zeng B, Liu L, Tardivel A, Wei H, et al. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J Exp Med. 2013;210:2465–2476. doi: 10.1084/jem.20122490.
    1. Couturier-Maillard A, Secher T, Rehman A, Normand S, De AA, Haesler R, et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest. 2013;123:700–711.
    1. 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;7:391–404. doi: 10.1038/mi.2013.58.
    1. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005;307:254–258. doi: 10.1126/science.1102901.
    1. Varol C, Zigmond E, Jung S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nat Rev Immunol. 2010;10:415–426. doi: 10.1038/nri2778.
    1. Annacker O, Coombes JL, Malmstrom V, Uhlig HH, Bourne T, Johansson-Lindbom B, et al. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med. 2005;202:1051–1061. doi: 10.1084/jem.20040662.
    1. Siddiqui KR, Laffont S, Powrie F. E-cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity. 2010;32:557–567. doi: 10.1016/j.immuni.2010.03.017.
    1. Baumgart DC, Thomas S, Przesdzing I, Metzke D, Bielecki C, Lehmann SM, et al. Exaggerated inflammatory response of primary human myeloid dendritic cells to lipopolysaccharide in patients with inflammatory bowel disease. Clin Exp Immunol. 2009;157:423–436. doi: 10.1111/j.1365-2249.2009.03981.x.
    1. Cai Z, Zhang W, Li M, Yue Y, Yang F, Yu L, et al. TGF-beta1 gene-modified, immature dendritic cells delay the development of inflammatory bowel disease by inducing CD4(+)Foxp3(+) regulatory T cells. Cell Mol Immunol. 2010;7:35–43. doi: 10.1038/cmi.2009.107.
    1. Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2013;6:498–510. doi: 10.1038/mi.2012.89.
    1. Schenk M, Bouchon A, Seibold F, Mueller C. TREM-1 - expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest. 2007;117:3097–3106. doi: 10.1172/JCI30602.
    1. Liu Z, Yang L, Cui Y, Wang X, Guo C, Huang Z, et al. Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:1133–1144. doi: 10.1002/ibd.20923.
    1. Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J, et al. Imbalance of NKp44(+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology. 2010;139:882–92, 892. doi: 10.1053/j.gastro.2010.05.040.
    1. Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol. 2009;10:66–74. doi: 10.1038/ni.1668.
    1. Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010;464:1371–1375. doi: 10.1038/nature08949.
    1. Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol. 2012;13:144–151. doi: 10.1038/ni.2187.
    1. Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Berard M, Kleinschek M, et al. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol. 2011;12:320–326. doi: 10.1038/ni.2002.
    1. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29:947–957. doi: 10.1016/j.immuni.2008.11.003.
    1. Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157:1261–1270.
    1. Verdier J, Begue B, Cerf-Bensussan N, Ruemmele FM. Compartmentalized expression of Th1 and Th17 cytokines in pediatric inflammatory bowel diseases. Inflamm Bowel Dis. 2012;18:1260–1266. doi: 10.1002/ibd.21905.
    1. Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995;182:1281–1290. doi: 10.1084/jem.182.5.1281.
    1. Oh SY, Cho KA, Kang JL, Kim KH, Woo SY. Comparison of experimental mouse models of inflammatory bowel disease. Int J Mol Med. 2014;33:333–340.
    1. Dige A, Stoy S, Rasmussen TK, Kelsen J, Hvas CL, Sandahl TD, et al. Increased levels of circulating Th17 cells in quiescent versus active Crohn's disease. J Crohns Colitis. 2013;7:248–255. doi: 10.1016/j.crohns.2012.06.015.
    1. Ito R, Kita M, Shin-Ya M, Kishida T, Urano A, Takada R, et al. Involvement of IL-17A in the pathogenesis of DSS-induced colitis in mice. Biochem Biophys Res Commun. 2008;377:12–16. doi: 10.1016/j.bbrc.2008.09.019.
    1. Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F, et al. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008;134:1038–1048. doi: 10.1053/j.gastro.2008.01.041.
    1. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med. 2006;203:2473–2483. doi: 10.1084/jem.20061099.
    1. Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007;132:2359–2370. doi: 10.1053/j.gastro.2007.03.104.
    1. Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, et al. Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol. 2010;185:679–687. doi: 10.4049/jimmunol.1000366.
    1. Boirivant M, Fuss IJ, Chu A, Strober W. Oxazolone colitis: A murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med. 1998;188:1929–1939. doi: 10.1084/jem.188.10.1929.
    1. Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity. 2002;17:629–638. doi: 10.1016/S1074-7613(02)00453-3.
    1. Liao CM, Zimmer MI, Shanmuganad S, Yu HT, Cardell SL, Wang CR. dysregulation of CD1d-restricted type ii natural killer T cells leads to spontaneous development of colitis in mice. Gastroenterology. 2012;142:326–334. doi: 10.1053/j.gastro.2011.10.030.
    1. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113:1490–1497. doi: 10.1172/JCI19836.
    1. Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013;497:258–262. doi: 10.1038/nature12079.
    1. Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003;170:3939–3943. doi: 10.4049/jimmunol.170.8.3939.
    1. Ishikawa D, Okazawa A, Corridoni D, Jia LG, Wang XM, Guanzon M, et al. Tregs are dysfunctional in vivo in a spontaneous murine model of Crohn's disease. Mucosal Immunol. 2013;6:267–275. doi: 10.1038/mi.2012.67.
    1. Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996;183:2669–2674. doi: 10.1084/jem.183.6.2669.
    1. Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006;177:5852–5860. doi: 10.4049/jimmunol.177.9.5852.
    1. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12:171–181. doi: 10.1016/S1074-7613(00)80170-3.
    1. Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C, et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology. 2009;136:1308–1316. doi: 10.1053/j.gastro.2008.12.053.
    1. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274. doi: 10.1016/0092-8674(93)80068-P.
    1. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–2045. doi: 10.1056/NEJMoa0907206.
    1. Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. 2008;122:1105–1112. doi: 10.1016/j.jaci.2008.09.027.
    1. Eastaff-Leung N, Mabarrack N, Barbour A, Cummins A, Barry S. Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J Clin Immunol. 2010;30:80–89. doi: 10.1007/s10875-009-9345-1.
    1. Ueno A, Jijon H, Chan R, Ford K, Hirota C, Kaplan GG, et al. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm Bowel Dis. 2013;19:2522–2534. doi: 10.1097/MIB.0b013e3182a85709.
    1. Veltkamp C, Anstaett M, Wahl K, Moller S, Gangl S, Bachmann O, et al. Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFalpha treatment. Gut. 2011;60:1345–1353. doi: 10.1136/gut.2010.217117.
    1. Wang J, Ioan-Facsinay A, van d, V, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol. 2007;37:129–138. doi: 10.1002/eji.200636435.
    1. Horwitz DA, Zheng SG, Gray JD. Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol. 2008;29:429–435. doi: 10.1016/j.it.2008.06.005.
    1. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–645. doi: 10.1016/j.immuni.2009.04.010.
    1. Huber S, Gagliani N, Esplugues E, O'Connor W, Jr, Huber FJ, Chaudhry A, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34:554–565. doi: 10.1016/j.immuni.2011.01.020.
    1. Jeon SG, Kayama H, Ueda Y, Takahashi T, Asahara T, Tsuji H, et al. Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog. 2012;8:e1002714. doi: 10.1371/journal.ppat.1002714.
    1. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010;107:12204–12209. doi: 10.1073/pnas.0909122107.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe