Gastroenterology
Volume 123, Issue 3 , Pages 689-699 , September 2002

Selected loss of tolerance evidenced by Crohn's disease–associated immune responses to auto- and microbial antigens

  • Carol J. Landers

      Affiliations

    • Cedars–Sinai Medical Center Inflammatory Bowel Disease Center, Los Angeles, California
    • ,
  • Offer Cohavy

      Affiliations

    • Cedars–Sinai Medical Center Inflammatory Bowel Disease Center, Los Angeles, California
    • ,
  • Rajeev Misra

      Affiliations

    • Department of Microbiology, Arizona State University, Tempe, Arizona
    • ,
  • Huiying Yang

      Affiliations

    • Cedars–Sinai Medical Center Division of Medical Genetics, Los Angeles, California
    • ,
  • Ying–Chao Lin

      Affiliations

    • Cedars–Sinai Medical Center Division of Medical Genetics, Los Angeles, California
    • ,
  • Jonathan Braun

      Affiliations

    • University of California–Los Angeles School of Medicine, Department of Pathology, Los Angeles, California
    • ,
  • Stephan R. Targan

      Affiliations

    • Cedars–Sinai Medical Center Inflammatory Bowel Disease Center, Los Angeles, California

Received 22 January 2001 ,Accepted 16 May 2002.

References 

  1. De Winter H, Cheroutre H, Kronenberg M. Mucosal immunity and inflammation. II. The yin and yang of T cells in intestinal inflammation: pathogenic and protective roles in a mouse colitis model. Am J Physiol. 1999;276:G1317–G1321
  2. Strober W, Ludviksson BR, Fuss IJ. The pathogenesis of mucosal inflammation in murine models of inflammatory bowel disease and Crohn disease. Ann Intern Med. 1998;128:848–856
  3. Bhan AK, Mizoguchi E, Smith RN, Mizoguchi A. Colitis in transgenic and knockout animals as models of human inflammatory bowel disease. Immunol Rev. 1999;169:195–207
  4. Rath HC, Herfarth HH, Ikeda JS, Grenther WB, Hamm TE, Balish E, et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest. 1996;98:945–953
  5. Sellon RK, Tonkonogy S, Schultz M, Dieleman LA, Grenther W, Balish E, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10–deficient mice. Infect Immun. 1998;66:5224–5231
  6. Kim SC, Tonkonogy SL, Baylish E, Warner T, Sartor RB. IL-10 deficient mice monoassociated with non-pathogenic Enterococcus faecalis develop chronic colitis (abstr). Gastroenterology. 2001;120:A82
  7. Fox JG, Gorelick PL, Kullberg MC, Ge Z, Dewhirst FE, Ward JM. A novel urease-negative Helicobacter species associated with colitis and typhlitis in IL-10–deficient mice. Infect Immun. 1999;67:1757–1762
  8. Cong Y, Brandwein SL, McCabe RP, Lazenby A, Birkenmeier EH, Sundberg JP, et al. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med. 1998;187:855–864
  9. Prantera C, Kohn A, Zannoni F, Spimpolo N, Bonfa M. Metronidazole plus ciprofloxacin in the treatment of active, refractory Crohn's disease: results of an open study. J Clin Gastroenterol. 1994;19:79–80
  10. Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, et al. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol. 1996;91:328–332
  11. Rutgeerts P, Goboes K, Peeters M, Hiele M, Penninckx F, Aerts R, et al. Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum. Lancet. 1991;338:771–774
  12. Wayne LG, Hollander D, Anderson B, Sramek HA, Vadheim CM, Rotter JI. Immunoglobulin A (IgA) and IgG serum antibodies to mycobacterial antigens in Crohn's disease patients and their relatives. J Clin Microbiol. 1992;30:2013–2018
  13. Sanderson JD, Moss MT, Tizard ML, Hermon-Taylor J. Mycobacterium paratuberculosis DNA in Crohn's disease tissue. Gut. 1992;33:890–896
  14. Moss MT, Sanderson JD, Tizard ML, Hermon-Taylor J, el-Zaatari FA, Markesich DC, et al. Polymerase chain reaction detection of Mycobacterium paratuberculosis and Mycobacterium avium subsp silvaticum in long term cultures from Crohn's disease and control tissues. Gut. 1992;33:1209–1213
  15. Fidler HM, Thurrell W, Johnson NM, Rook GA, McFadden JJ. Specific detection of Mycobacterium paratuberculosis DNA associated with granulomatous tissue in Crohn's disease. Gut. 1994;35:506–510
  16. El-Zaatari FA, Naser SA, Graham DY. Characterization of a specific Mycobacterium paratuberculosis recombinant clone expressing 35,000-molecular-weight antigen and reactivity with sera from animals with clinical and subclinical Johne's disease. J Clin Microbiol. 1997;35:1794–1799
  17. Clarkston WK, Presti ME, Petersen PF, Zachary PE, Fan WX, Leonardi CL, et al. Role of Mycobacterium paratuberculosis in Crohn's disease: a prospective, controlled study using polymerase chain reaction. Dis Colon Rectum. 1998;41:195–199
  18. Cohavy O, Bruckner D, Gordon LK, Misra R, Wei B, Eggena ME, et al. Colonic bacteria express an ulcerative colitis pANCA-related protein epitope. Infect Immun. 2000;68:1542–1548
  19. Duchmann R, May E, Heike M, Knolle P, Neurath M, Meyer zum Buschenfelde KH. T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut. 1999;44:812–818
  20. Liu Y, van Kruiningen HJ, West AB, Cartun RW, Cortot A, Colombel JF. Immunocytochemical evidence of Listeria, Escherichia coli, and Streptococcus antigens in Crohn's disease. Gastroenterology. 1995;108:1396–1404
  21. Weiner HL, Friedman A, Miller A, Khoury SJ, al-Sabbagh A, Santos L, et al. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol. 1994;12:809–837
  22. MacDonald TT. Breakdown of tolerance to the intestinal bacterial flora in inflammatory bowel disease (IBD). Clin Exp Immunol. 1995;102:445–447
  23. Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol. 1995;102:448–455
  24. Sutton CL, Kim J, Yamane A, Dalwadi H, Wei B, Landers C, et al. Identification of a novel bacterial sequence associated with Crohn's disease. Gastroenterology. 2000;119:23–31
  25. Vasiliauskas EA, Plevy SE, Landers CJ, Binder SW, Ferguson DM, Yang H, et al. Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup. Gastroenterology. 1996;110:1810–1819
  26. Main J, McKenzie H, Yeaman GR, Kerr MA, Robson D, Pennington CR, et al. Antibody to Saccharomyces cerevisiae (bakers' yeast) in Crohn's disease. BMJ. 1988;297:1105–1106
  27. Cohavy O, Harth G, Horwitz M, Eggena M, Landers C, Sutton C, et al. Identification of a novel mycobacterial histone H1 homologue (HupB) as an antigenic target of pANCA monoclonal antibody and serum immunoglobulin A from patients with Crohn's disease. Infect Immun. 1999;67:6510–6517
  28. Eggena M, Targan SR, Iwanczyk L, Vidrich A, Gordon LK, Braun J. Phage display cloning and characterization of an immunogenetic marker (perinuclear anti-neutrophil cytoplasmic antibody) in ulcerative colitis. J Immunol. 1996;156:4005–4011
  29. Gordon LK, Eggena M, Targan SR, Braun J. Definition of ocular antigens in ciliary body and retinal ganglion cells by the marker antibody pANCA. Invest Ophthalmol Vis Sci. 1999;40:1250–1255
  30. Gordon LK, Eggena M, Targan SR, Braun J. Mast cell and neuroendocrine cytoplasmic autoantigen(s) detected by monoclonal pANCA antibodies. Clin Immunol. 2000;94:42–50
  31. Eggena M, Cohavy O, Parseghian MH, Hamkalo BA, Clemens D, Targan SR, et al. Identification of histone H1 as a cognate antigen of the ulcerative colitis-associated marker antibody pANCA. J Autoimmun. 2000;14:83–97
  32. Landers CJ, Cohavy O, Yang H, Lin S, Braun J, Targan SRGA. Selected, not global, loss of tolerance using Crohn's disease (CD)-associated immune responses to auto-and specific bacterial antigens (abstr). Gastroenterology. 2001;120:A519
  33. Barnes RM, Allan S, Taylor-Robinson CH, Finn R, Johnson PM. Serum antibodies reactive with Saccharomyces cerevisiae in inflammatory bowel disease: is IgA antibody a marker for Crohn's disease?. Int Arch Allergy Appl Immunol. 1990;92:9–15
  34. McKenzie H, Main J, Pennington CR, Parratt D. Antibody to selected strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and Candida albicans in Crohn's disease. Gut. 1990;31:536–538
  35. Sendid B, Colombel JF, Jacquinot PM, Faille C, Fruit J, Cortot A, et al. Specific antibody response to oligomannosidic epitopes in Crohn's disease. Clin Diagn Lab Immunol. 1996;3:219–226
  36. Sendid B, Quinton JF, Charrier G, Goulet O, Cortot A, Grandbastien B, et al. Anti-Saccharomyces cerevisiae mannan antibodies in familial Crohn's disease. Am J Gastroenterol. 1998;93:1306–1310
  37. Quinton JF, Sendid B, Reumaux D, Duthilleul P, Cortot A, Grandbastien B, et al. Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut. 1998;42:788–791
  38. Landers CJ, Yang H, Lin Y, Vasiliauskas EA, Braun J, Targan SR. IgA serum antibody reactivity with I2, a novel Crohn's disease marker: anti-I2 level is independent from ASCA and ANCA levels even though IgA ASCA positivity is correlated with anti-I2 positivity (abstr). Gastroenterology. 2000;118:A348
  39. Wei B, Huang T, Dalwadi H, Braun J. The Crohn's disease lesion derived gene I2 encodes the core peptide of a transcriptional regulator of Pseudomonas fluorescens in the functional domain of a novel T cell superantigen (abstr). Gastroenterology. 2001;120:A53
  40. Duerr RH, Targan SR, Landers CJ, LaRusso NF, Lindsay KL, Wiesner RH, et al. Neutrophil cytoplasmic antibodies: a link between primary sclerosing cholangitis and ulcerative colitis. Gastroenterology. 1991;100:1385–1391
  41. Targan SR, Landers C, Vidrich A, Czaja AJ. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology. 1995;108:1159–1166
  42. Saxon A, Shanahan F, Landers C, Ganz T, Targan S. A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol. 1990;86:202–210
  43. Vidrich A, Lee J, James E, Cobb L, Targan S. Segregation of pANCA antigenic recognition by DNase treatment of neutrophils: ulcerative colitis, type 1 autoimmune hepatitis, and primary sclerosing cholangitis. J Clin Immunol. 1995;15:293–299
  44. Guan KL, Dixon JE. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal Biochem. 1991;192:262–267
  45. Sokal RR, Rohlf FJ. Biometry. 3rd ed. New York: WH Freeman & Co; 1997;
  46. Dillon W, Goldstein M. Multivariate analysis. New York: John Wiley and Sons; 1984;
  47. Vasiliauskas EA, Kam LY, Karp LC, Gaiennie J, Yang H, Targan SR. Marker antibody expression stratifies Crohn's disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut. 2000;47:487–496
  48. Fleshner PF, Vasiliauskas EA, Kam LY, Karp LC, Gaiennie J, Yang H, et al. High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut. 2001;49:671–677
  49. Blaser MJ, Miller RA, Lacher J, Singleton JW. Patients with active Crohn's disease have elevated serum antibodies to antigens of seven enteric bacterial pathogens. Gastroenterology. 1984;87:888–894
  50. Duchmann R, Marker-Hermann E, Meyer zum Buschenfelde KH. Bacteria-specific T-cell clones are selective in their reactivity towards different enterobacteria or H. pylori and increased in inflammatory bowel disease. Scand J Immunol. 1996;44:71–79
  51. Naser SA, Hulten K, Shafran I, Graham DY, El-Zaatari FA. Specific seroreactivity of Crohn's disease patients against p35 and p36 antigens of M. avium subsp. paratuberculosis. Vet Microbiol. 2000;77:497–504
  52. Metcalf J. Is measles infection associated with Crohn's disease?. BMJ. 1998;316:166
  53. Macpherson A, Khoo UY, Forgacs I, Philpott-Howard J, Bjarnason I. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut. 1996;38:365–375
  54. Lindberg E, Magnusson KE, Tysk C, Jarnerot G. Antibody (IgG, IgA, and IgM) to baker's yeast (Saccharomyces cerevisiae), yeast mannan, gliadin, ovalbumin and betalactoglobulin in monozygotic twins with inflammatory bowel disease. Gut. 1992;33:909–913
  55. Duchmann R, Neurath MF, Meyer zum Buschenfelde KH. Responses to self and non-self intestinal microflora in health and inflammatory bowel disease. Res Immunol. 1997;148:589–594
  56. Duchmann R, Schmitt E, Knolle P, Meyer zum Buschenfelde KH, Neurath M. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol. 1996;26:934–938
  57. Saparov A, Kraus LA, Cong Y, Marwill J, Xu XY, Elson CO, et al. Memory/effector T cells in TCR transgenic mice develop via recognition of enteric antigens by a second, endogenous TCR. Int Immunol. 1999;11:1253–1264

☆ Address requests for reprints to: Stephan R. Targan, M.D., Director, Division of Gastroenterology, and Inflammatory Bowel Disease Center, 8700 Beverly Boulevard, Suite D4063, Los Angeles, California 90048. e-mail: targans@cshs.org; fax: (310) 423-0224.

☆☆ Supported by United States Public Health Service/National Institutes of Health grant PO 1 DK46763.

PII: S0016-5085(02)00159-2

Gastroenterology
Volume 123, Issue 3 , Pages 689-699 , September 2002

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