Insights into inflammatory bowel disease using Toxoplasma gondii as an infectious trigger

Immunology and Cell Biology

Volumn 90, Issue 7, 2012, Pages 668-675

  Egan, Charlotte E ^a   Cohen, Sara B ^a   Denkers, Eric Y ^a  

^a Department of Obstetrics Gynecology   (United States)

Author keywords

infection; inflammation; mucosal immunity; protozoan

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 23; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA;

BACTERIUM ADHERENCE; C57BL 6 MOUSE; CD4+ T LYMPHOCYTE; CROHN DISEASE; CYTOKINE PRODUCTION; ENTERITIS; ESCHERICHIA COLI; HUMAN; ILEITIS; IMMUNE DEFICIENCY; IMMUNOPATHOLOGY; INTESTINE EPITHELIUM; INTESTINE FLORA; MUCOSAL IMMUNITY; NONHUMAN; OPPORTUNISTIC INFECTION; REVIEW; T CELL DEPLETION; TH1 CELL; TOXOPLASMA GONDII; TOXOPLASMOSIS;

ANIMALS; CYTOKINES; DISEASE MODELS, ANIMAL; HUMANS; ILEITIS; INFLAMMATORY BOWEL DISEASES; MICE; MODELS, IMMUNOLOGICAL; RECEPTORS, CCR2; TOXOPLASMA; TOXOPLASMOSIS, ANIMAL;

MUS; PROTOZOA; TOXOPLASMA; TOXOPLASMA GONDII;

EID: 84864830852     PISSN: 08189641     EISSN: 14401711     Source Type: Journal    
DOI: 10.1038/icb.2011.93     Document Type: Review

References (128)

1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369: 1627-1640. (Pubitemid 46722636)
2. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010; 28: 573-621.
3. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427-434. (Pubitemid 47123518)
4. Brand S. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 2009; 58: 1152-1167.
5. Rhodes JM, Campbell BJ. Inflammation and colorectal cancer: IBD-associated and sporadic cancer compared. Trends Mol Med 2002; 8: 10-16. (Pubitemid 34044673)
6. Kappelman MD, Rifas-Shiman SL, Porter CQ, Ollendorf DA, Sandler RS, Galanko JA et al. Direct health care costs of Crohn's disease and ulcerative colitis in US children and adults. Gastroenterology 2008; 135: 1907-1913.
7. Hansen R, Thomson JM, El-Omar EM, Hold GL. The role of infection in the aetiology of inflammatory bowel disease. J Gastroenterol 2010; 45: 266-276.
8. Blonski W, Buchner AM, Lichtenstein GR. Inflammatory bowel disease therapy: current state-of-the-art. Curr Opin Gastroenterol 2011; 27: 346-357.
9. Korzenik JR, Podolsky DK. Evolving knowledge and therapy of inflammatory bowel disease. Nat Rev Drug Discov 2006; 5: 197-209. (Pubitemid 43336033)
10. Podolsky DK. Beyond tumor necrosis factor: next-generation biologic therapy for inflammatory bowel disease. Dig Dis 2009; 27: 366-369.
11. Reiff C, Kelly D. Inflammatory bowel disease, gut bacteria and probiotic therapy. Int J Med Microbiol 2010; 300: 25-33.
12. Nell S, Suerbaum S, Josenhans C. The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nat Rev Microbiol 2010; 8: 564-577.
13. Strober W. Why study animal models of IBD? Inflamm Bowel Dis 2008; 14(Suppl 2): S129-S131.
14. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol 2002; 20: 495-549. (Pubitemid 34293433)
15. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 1999; 10: 387-398. (Pubitemid 29165293)
16. Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 2003; 170: 3939-3943. (Pubitemid 36428153)
17. Pizarro TT, Arseneau KO, Bamias G, Cominelli F. Mouse models for the study of Crohn's disease. Trends Mol Med 2003; 9: 218-222. (Pubitemid 36713392)
18. Dubey JP. The history and life-cycle of Toxoplasma gondii. In: Weiss LM, Kim K (eds) Toxoplasma Gondii. The Model Apicomplexan: Perspective and Methods. Academic Press: San Diego, 2007 pp 1-17.
19. Latkany P. Ocular disease due to Toxoplasma gondii. In: Weiss LM, Kim K (eds) Toxoplasma Gondii, the Model Apicomplexan: Perspectives and Methods. Academic Press: Amsterdam, 2007 pp 101-131.
20. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004; 363: 1965-1976. (Pubitemid 38759657)
21. Peterson E, Liesenfeld O. Clinical disease and diagnostics. In: Weiss LM, Kim K (eds) Toxoplasma Gondii. The Model Apicomplexan: Perspectives and Methods. Academic Press: Amsterdam, 2007 pp 81-100.
22. Montoya JG, Remington JS. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis 2008; 47: 554-566.
23. Sher A, Oswald IO, Hieny S, Gazzinelli RT. Toxoplasma gondii induces a T-independent IFN-g response in NK cells which requires both adherent accessory cells and TNF-a. J Immunol 1993; 150: 3982-3989. (Pubitemid 23129780)
24. Gazzinelli RT, Hieny S, Wynn T, Wolf S, Sher A. IL-12 is required for the T-cell independent induction of IFN-g by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci USA 1993; 90: 6115-6119. (Pubitemid 23191465)
25. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P et al. Parasiteinduced IL-12 stimulates early IFN-g synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 1994; 153: 2533-2543. (Pubitemid 24278122)
26. Denkers EY, Gazzinelli RT. Regulation and function of T cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev 1998; 11: 569-588. (Pubitemid 28497562)
27. Bliss SK, Marshall AJ, Zhang Y, Denkers EY. Human polymorphonuclear leukocytes produce IL-12, TNF-a, and the chemokines macrophage-inflammatory protein-1a and-1b in response to Toxoplasma gondii antigens. J Immunol 1999; 162: 7369-7375. (Pubitemid 29277713)
28. Liu CH, Fan YT, Dias A, Esper L, Corn RA, Bafica A et al. Cutting edge: dendritic cells are essential for in vivo IL-12 production and development of resistance against Toxoplasma gondii infection in mice. J Immunol 2006; 177: 31-35. (Pubitemid 43939111)
29. Scanga CA, Aliberti J, Jankovic D, Tilloy F, Bennouna S, Denkers EY et al. Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J Immunol 2002; 168: 5997-6001. (Pubitemid 34620012)
30. Sukhumavasi W, Egan CE, Warren AL, Taylor GA, Fox BA, Bzik DJ et al. TLR adaptor MyD88 is essential for pathogen control during oral Toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite. J Immunol 2008; 181: 3464-3473.
31. Hitziger N, Dellacasa I, Albiger B, Barragan A. Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin-1 receptor signalling for host resistance assessed by in vivo bioluminescence imaging. Cell Micro 2005; 6: 837-848. (Pubitemid 40740379)
32. Hou B, Benson A, Kuzmich L, DeFranco AL, Yarovinsky F. Critical coordination of innate immune defense against Toxoplasma gondii by dendritic cells responding via their Toll-like receptors. Proc Natl Acad Sci U S A 2011; 108: 278-283.
33. Debierre-Grockiego F, Campos MA, Azzouz N, Schmidt J, Bieker U, Resende MG et al. Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from Toxoplasma gondii. J Immunol 2007; 179: 1129-1137.
34. Del Rio L, Butcher BA, Bennouna S, Hieny S, Sher A, Denkers EY. Toxoplasma gondii triggers MyD88-dependent and CCL2(MCP-1) responses using distinct parasite molecules and host receptors. J Immunol 2004; 172: 6954-6960.
35. Minns LA, Menard LC, Foureau DM, Darche S, Ronet C, Mielcarz DW et al. TLR9 is required for the gut-associated lymphoid tissue response following oral infection of Toxoplasma gondii. J Immunol 2006; 176: 7589-7597. (Pubitemid 43853053)
36. Mun H-S, Aosai F, Norose K, Chen M, Piao L-X, Takeuchi O et al. TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection. Int Parasitol 2003; 15: 1081-1087. (Pubitemid 37063207)
37. Yarovinsky F, Zhang D, Anderson JF, Bannenberg GL, Serhan CN, Hayden MS et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 2005; 308: 1626-1629. (Pubitemid 40807512)
38. Plattner F, Yarovinsky F, Romero S, Didry D, Carlier MF, Sher A et al. Toxoplasma profilin is essential for host cell invasion and TLR dependent induction of interleukin-12. Cell Host Microbe 2008; 14: 77-87. (Pubitemid 351201784)
39. Pifer R, Benson A, Sturge CR, Yarovinsky F. UNC93B1 is essential for TLR11 activation and IL-12 dependent host resistance to Toxoplasma Gondii. J Biol Chem 2011; 286: 3307-3314.
40. Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol 1992; 149: 175-180.
41. Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-g: the major mediator of resistance against Toxoplasma gondii. Science 1988; 240: 516-518.
42. Suzuki Y, Remington JS. Dual regulation of resistance against Toxoplasma gondii infection by Lyt-2+ and Lyt1+,L3T4+ T cells in mice. J Immunol 1988; 140: 3943-3946.
43. Denkers EY, Yap G, Scharton-Kersten T, Charest H, Butcher B, Caspar P et al. Perforinmediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. J Immunol 1997; 159: 1903-1908. (Pubitemid 127484179)
44. Wang X, Kang H, Kikuchi T, Suzuki Y. Gamma interferon production, but not perforinmediated cytolytic activity, of T cells is required for prevention of toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease. Infect Immun 2004; 72: 4432-4438. (Pubitemid 38989299)
45. Gavrilescu LC, Butcher BA, Del Rio L, Taylor GA, Denkers EY. STAT1 is essential for antimicrobial function but dispensable for gamma interferon production during Toxoplasma gondii infection. Infect Immun 2004; 72: 1257-1264. (Pubitemid 38263743)
46. Lieberman LA, Banica M, Reiner SL, Hunter CA. STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis. J Immunol 2004; 172: 457-463. (Pubitemid 38020501)
47. Scharton-Kersten T, Yap G, Magram J, Sher A. Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J Exp Med 1997; 185: 1-13.
48. Zhao YO, Khaminets A, Hunn JP, Howard JC. Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. PLoS Pathog 2009; 5: e1000288.
49. Howard JC, Hunn JP, Steinfeldt T. The IRG protein-based resistance mechanism in mice and its relation to virulence in Toxoplasma gondii. Curr Opin Microbiol 2011; 14: 414-421.
50. Bekpen C, Hunn JP, Rohde C, Parvanova I, Guethlein L, Dunn DM et al. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol 2005; 6: R92.
51. MacMicking J, Xie Q, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997; 15: 323-350. (Pubitemid 27169284)
52. Andrade RM, Wessendarp M, Gubbels MJ, Striepen B, Subauste CS. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Invest 2006; 116: 2366-2377. (Pubitemid 44330135)
53. Andrade RM, Wessendarp M, Subauste CS. CD154 activates macrophage antimicrobial activity in the absence of IFN-g through a TNF-a-dependent mechanism. J Immunol 2003; 171: 6750-6756. (Pubitemid 37532108)
54. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 2003; 3: 331-341. (Pubitemid 37328685)
55. Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol 2011; 11: 445-456.
56. Bierly AL, Shufesky WJ, Sukhumavasi W, Morelli A, Denkers EY. Dendritic cells expressing plasmacytoid marker PDCA-1 are Trojan horses during Toxoplasma gondii infection. J Immunol 2008; 181: 8445-8491.
57. Courret N, Darche S, Sonigo P, Milon G, Buzoni-Gatel D, Tardieux I. CD11c and CD11b expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain. Blood 2006; 107: 309-316. (Pubitemid 43053557)
58. Lambert H, Hitziger N, Dellacasa I, Svensson M, Barragan A. Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination. Cell Microbiol 2006; 8: 1611-1623. (Pubitemid 44350020)
59. Dunay IR, Damatta RA, Fux B, Presti R, Greco S, Colonna M et al. Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 2008; 29: 306-317.
60. Fentress SJ, Behnke MS, Dunay IR, Mashayekhi M, Rommereim LM, Fox BA et al. Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence. Cell Host Microbe 2010; 8: 484-495.
61. Egan CE, Sukhumavasi W, Butcher BA, Denkers EY. Functional aspects of toll-like receptor/MyD88 signalling during protozoan infection: focus on Toxoplasma gondii. Clin Exp Immunol 2009; 156: 17-24.
62. Benson A, Pifer R, Behrendt CL, Hooper LV, Yarovinsky F. Gut commensal bacteria direct a protective immune response against Toxoplasma gondii. Cell Host Microbe 2009; 6: 187-196.
63. Heimesaat MM, Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J et al. Gramnegative bacteria aggravate murine small intestinal Th1-Type immunopathology following oral infection with Toxoplasma gondii. J Immunol 2006; 177: 8785-8795. (Pubitemid 44893845)
64. Chardes T, Buzoni-Gatel D, Lepage A, Bernard F, Bout D. Toxoplasma gondii oral infection induces specific cytotoxic CD8a/b+ Thy-1+ gut iintraepithelial lymphocytes, lytic for parasite-infected enterocytes. J Immunol 1994; 153: 4596-4603. (Pubitemid 24346855)
65. Buzoni-Gatel D, Debbabi H, Mennechet FJD, Martin V, LePage AC, Schwartzman JD et al. Murine ileitis after intracellular parasite infection is controlled by TGF-bproducing intraepithelial lymphocytes. Gastroenterol 2001; 120: 914-924. (Pubitemid 32193188)
66. Buzoni-Gatel D, Debbabi H, Moretto M, Dimier-Poisson IH, Lepage AC, Bout DT et al. Intraepithelial lymphocytes traffic to the intestine and enhance resistance to Toxoplasma gondii oral infection. J Immunol 1999; 162: 5846-5852. (Pubitemid 29314937)
67. Luangsay S, Kasper LH, Rachinel N, Minns LA, Mennechet FJD, Vandewalle A et al. CCR5 mediates specific migration of Toxoplasma gondii-primed CD8+ lymphocytes to inflammatory intestinal epithelial cells. Gastroenterol 2003; 125: 491-500. (Pubitemid 36929431)
68. Lepage AC, Buzoni-Gatel D, Bout DT, Kasper LH. Gut-derived intraepithelial lymphocytes induce long term immunity against Toxoplasma gondii. J Immunol 1998; 161: 4902-4908. (Pubitemid 28492069)
69. Mennechet FJD, Kasper LH, Rachinel N, Li W, Vandewalle A, Buzoni-Gatel D. Lamina propria CD4+ T lymphocytes synergize with murine intestinal epithelial cells to enhance proinflammatory response against an intracellular pathogen. J Immunol 2002; 168: 2988-2996. (Pubitemid 34211680)
70. Mennechet FJ, Kasper LH, Rachinel N, Minns LA, Luangsay S, Vandewalle A et al. Intestinal intraepithelial lymphocytes prevent pathogen-driven inflammation and regulate the Smad/T-bet pathway of lamina propria CD4+ T cells. Eur J Immunol 2004; 34: 1059-1067. (Pubitemid 39255984)
71. Dalton JE, Cruickshank SM, Egan CE, Mears R, Newton DJ, Andrew EM et al. Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 2006; 131: 818-829. (Pubitemid 44307063)
72. Liesenfeld O, Kosek J, Remington JS, Suzuki Y. Association of CD4+ T cell-dependent, IFN-g-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Exp Med 1996; 184: 597-607. (Pubitemid 26324113)
73. Schreiner M, Liesenfeld O. Small intestinal inflammation following oral infection with Toxoplasma gondii does not occur exclusively in C57BL/6 mice: review of 70 reports from the literature. Mem Inst Oswaldo Cruz 2009; 104: 221-233.
74. Khan IA, Schwartzman JD, Matsuura T, Kasper LH. A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice. Proc Natl Acad Sci USA 1997; 94: 13955-13960. (Pubitemid 28009691)
75. Liesenfeld O, Kang H, Park D, Nguyen TA, Parkhe CV, Watanabe H et al. TNF-a, nitric oxide and IFN-g are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii. Parasite Immunol 1999; 21: 365-376. (Pubitemid 29296741)
76. Khan IA, Thomas SY, Moretto MM, Lee FS, Islam SA, Combe C et al. CCR5 is essential for NK cell trafficking and host survival following Toxoplasma gondii infection. PLoS Pathog 2006; 2: e49.
77. Vossenkamper A, Struck D, Alvarado-Esquivel C, Went T, Takeda K, Akira S et al. Both IL-12 and IL-18 contribute to small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii, but IL-12 is dominant over IL-18 in parasite control. Eur J Immunol 2004; 34: 3197-3207. (Pubitemid 39549398)
78. Munoz M, Heimesaat MM, Danker K, Struck D, Lohmann U, Plickert R et al. Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17. J Exp Med 2009; 206: 3047-3059.
79. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 2006; 116: 1310-1316.
80. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. A genomewide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461-1463. (Pubitemid 44871953)
81. Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S et al. 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: 16-23. (Pubitemid 40340252)
82. Baugh MD, Evans GS, Hollander AP, Davies DR, Perry MJ, Lobo AJ et al. Expression of matrix metalloproteases in inflammatory bowel disease. Ann N Y Acad Sci 1998; 859: 249-253. (Pubitemid 29021034)
83. Castaneda FE, Walia B, Vijay-Kumar M, Patel NR, Roser S, Kolachala VL et al. Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP. Gastroenterology 2005; 129: 1991-2008. (Pubitemid 41772976)
84. 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.
85. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 2008; 14: 282-289. (Pubitemid 351347912)
86. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM et al. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 2006; 290: G827-G838.
87. Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, Paschos E et al. Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis 2008; 14: 204-212. (Pubitemid 351288041)
88. Guiton R, Vasseur V, Charron S, Arias MT, Van Langendonck N, Buzoni-Gatel D et al. Interleukin 17 receptor signaling is deleterious during Toxoplasma gondii infection in susceptible BL6 mice. J Infect Dis 2010; 202: 427-435.
89. Kelly MN, Kolls JK, Happel K, Schwartzman JD, Schwarzenberger P, Combe C et al. Interleukin-17/interleukin-17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infect Immun 2005; 73: 617-621. (Pubitemid 40041158)
90. Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent upon CD4+ T cells and accompanied by overproduction of IL-12, IFN-g, and TNF-a. J Immunol 1996; 157: 798-805. (Pubitemid 26231385)
91. Suzuki Y, Sher A, Yap G, Park D, Ellis Neyer L, Liesenfeld O et al. IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii. J Immunol 2000; 164: 5375-5382. (Pubitemid 30305218)
92. Murai M, Krause P, Cheroutre H, Kronenberg M. Regulatory T-cell stability and plasticity in mucosal and systemic immune systems. Mucosal Immunol 2010; 3: 443-449.
93. Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, Dos Santos L et al. Decrease of Foxp3(+) Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009; 31: 772-786.
94. Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, Wilson M et al. Conventional T-bet+Foxp3-Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med 2007; 204: 273-283. (Pubitemid 46294544)
95. Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, Karp CL et al. Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe 2009; 6: 503-512.
96. Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 2004; 127: 412-421. (Pubitemid 39091889)
97. Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 2004; 113: 1296-1306. (Pubitemid 39069929)
98. 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. (Pubitemid 40981351)
99. Tabaqchali S, O'Donoghue DP, Bettelheim KA. Escherichia coli antibodies in patients with inflammatory bowel disease. Gut 1978; 19: 108-113. (Pubitemid 8316085)
100. Hans W, Scholmerich J, Gross V, Falk W. The role of the resident intestinal flora in acute and chronic dextran sulfate sodium-induced colitis in mice. Eur J Gastroenterol Hepatol 2000; 12: 267-273. (Pubitemid 30168579)
101. Madsen KL, Doyle JS, Tavernini MM, Jewell LD, Rennie RP, Fedorak RN. Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology 2000; 118: 1094-1105. (Pubitemid 30346986)
102. Egan CE, Craven MD, Leng J, Mack M, Simpson KW, Denkers EY. CCR2-dependent intraepithelial lymphocytes mediate inflammatory gut pathology during Toxoplasma gondii infection. Mucosal Immunol 2009; 2: 527-535.
103. Erridge C, Duncan SH, Bereswill S, Heimesaat MM. The induction of colitis and ileitis in mice is associated with marked increases in intestinal concentrations of stimulants of TLRs 2, 4, and 5. PLoS One 2010; 5: e9125.
104. Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R et al. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J Gastroenterol 2005; 40: 16-23. (Pubitemid 40796328)
105. Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K et al. 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 Gastrointest Liver Physiol 2005; 288: G1055-G1065. (Pubitemid 40563149)
106. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118: 229-241. (Pubitemid 38962578)
107. Heimesaat MM, Fischer A, Jahn HK, Niebergall J, Freudenberg M, Blaut M et al. Exacerbation of murine ileitis by toll-like receptor 4 meditated sensing of lipopolysaccharide from commensal escherichia coli. Gut 2007; 56: 941-948. (Pubitemid 46999077)
108. Furuta T, Kikuchi T, Akira S, Watanabe N, Yoshikawa Y. Roles of the small intestine for induction of toll-like receptor 4-mediated innate resistance in naturally acquired murine toxoplasmosis. Int Immunol 2006; 18: 1655-1662. (Pubitemid 44884028)
109. Foureau DM, Mielcarz DW, Menard LC, Schulthess J, Werts C, Vasseur V et al. TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J Immunol 2010; 184: 7022-7029.
110. Benevides L, Milanezi CM, Yamauchi LM, Benjamim CF, Silva JS, Silva NM. CCR2 receptor is essential to activate microbicidal mechanisms to control Toxoplasma gondii infection in the central nervous system. Am J Pathol 2008; 173: 741-751.
111. Connor SJ, Paraskevopoulos N, Newman R, Cuan N, Hampartzoumian T, Lloyd AR et al. CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the ileum in Crohn's disease. Gut 2004; 53: 1287-1294. (Pubitemid 39120114)
112. Zhong W, Kolls JK, Chen H, McAllister F, Oliver PD, Zhang Z. Chemokines orchestrate leukocyte trafficking in inflammatory bowel disease. Front Biosci 2008; 13: 1654-1664. (Pubitemid 351599723)
113. Cheroutre H. In IBD eight can come before four. Gastroenterology 2006; 131: 667-670. (Pubitemid 44142479)
114. Nancey S, Holvoet S, Graber I, Joubert G, Philippe D, Martin S et al. CD8+ cytotoxic T cells induce relapsing colitis in normal mice. Gastroenterology 2006; 131: 485-496. (Pubitemid 44150610)
115. Westendorf AM, Fleissner D, Deppenmeier S, Gruber AD, Bruder D, Hansen W et al. Autoimmune-mediated intestinal inflammation-impact and regulation of antigenspecific CD8+ T cells. Gastroenterology 2006; 131: 510-524. (Pubitemid 44142451)
116. Nussler NC, Stange B, Hoffman RA, Schraut WH, Bauer AJ, Neuhaus P. Enhanced cytolytic activity of intestinal intraepithelial lymphocytes in patients with Crohn's disease. Langenbecks Arch Surg 2000; 385: 218-224. (Pubitemid 30316925)
117. Watanabe M, Hayashi A, Hosoda Y, Ohara M, Iwao Y, Ishii H et al. Preferential activation of CD4+V beta 5.2/5.3+ intestinal intraepithelial lymphocytes in the inflamed lesions of Crohn's disease. Clin Immunol Immunopathol 1996; 78: 130-139. (Pubitemid 26084592)
118. Egan CE, Maurer KJ, Cohen SB, Mack M, Simpson KW, Denkers EY. Synergy between intraepithelial lymphocytes and lamina propria T cells drives intestinal inflammation during infection. Mucosal Immunol 2011; 4: 658-670.
119. Rachinel N, Buzoni-Gatel D, Dutta C, Mennechet FJD, Laungsay S, Minns LA et al. The induction of acute ileitis by a single microbial antigen of Toxoplasma gondii. J Immunol 2004; 173: 2725-2735. (Pubitemid 39063134)
120. Jensen KD, Wang Y, Wojno ED, Shastri AJ, Hu K, Cornel L et al. Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell Host Microbe 2011; 9: 472-483.
121. Leng J, Butcher BA, Denkers EY. Dysregulation of macrophage signal transduction by Toxoplasma gondii: past progress and recent advances. Parasite Immunol 2009; 31: 717-728.
122. Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B et al. Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet 2006; 367: 668-678. (Pubitemid 43289157)
123. Segal AW, Loewi G. Neutrophil dysfunction in Crohn's disease. Lancet 1976; 2: 219-221.
124. Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med 2009; 206: 1883-1897.
125. Lidar M, Langevitz P, Barzilai O, Ram M, Porat-Katz BS, Bizzaro N et al. Infectious serologies and autoantibodies in inflammatory bowel disease: insinuations at a true pathogenic role. Ann N Y Acad Sci 2009; 1173: 640-648.
126. Liesenfeld O. Oral infection of C57BL/6 mice with Toxoplasma gondii: a new model of inflammatory bowel disease? J Infect Dis 2002; 185: S96-S101. (Pubitemid 34142835)
127. Craggs A, Welfare M, Donaldson PT, Mansfield JC. The CC chemokine receptor 5 delta32 mutation is not associated with inflammatory bowel disease (IBD) in NE England. Genes Immun 2001; 2: 114-116. (Pubitemid 33674238)
128. Rector A, Vermeire S, Thoelen I, Keyaerts E, Struyf F, Vlietinck R et al. Analysis of the CC chemokine receptor 5 (CCR5) delta-32 polymorphism in inflammatory bowel disease. Hum Genet 2001; 108: 190-193. (Pubitemid 32293663)