Gastroenterology
Volume 132, Issue 2 , Pages 576-586 , February 2007

NOD2 Variants and Antibody Response to Microbial Antigens in Crohn’s Disease Patients and Their Unaffected Relatives

  • Shane M. Devlin

      Affiliations

    • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Huiying Yang

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Andrew Ippoliti

      Affiliations

    • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Kent D. Taylor

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Carol J. Landers

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Xiaowen Su

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Maria T. Abreu

      Affiliations

    • Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
    • ,
  • Konstantinos A. Papadakis

      Affiliations

    • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Eric A. Vasiliauskas

      Affiliations

    • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Gil Y. Melmed

      Affiliations

    • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Phillip R. Fleshner

      Affiliations

    • Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Ling Mei

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Jerome I. Rotter

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Stephan R. Targan

      Affiliations

    • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
    • Corresponding Author InformationAddress requests for reprints to: Stephan R. Targan, MD, Division of Gastroenterology, Inflammatory Bowel Disease Center, and Immunobiology Institute, Cedars-Sinai Medical Center, 110 George Burns Road, Davis Building, Room 4063, Los Angeles, California 90048. fax: (310) 423-0224.

Received 4 May 2006 ,Accepted 26 October 2006.

References 

  1. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–429
  2. Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn’s disease. Immunol Rev. 2005;206:277–295
  3. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 2002;20:495–549
  4. 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
  5. Cong Y, Weaver CT, Lazenby A, Elson CO. Colitis induced by enteric bacterial antigen-specific CD4+ T cells requires CD40-CD40 ligand interactions for a sustained increase in mucosal IL-12. J Immunol. 2000;165:2173–2182
  6. 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
  7. Cong Y, Weaver CT, Lazenby A, Elson CO. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol. 2002;169:6112–6119
  8. Brandwein SL, McCabe RP, Cong Y, Waites KB, Ridwan BU, Dean PA, et al. Spontaneously colitic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora. J Immunol. 1997;159:44–52
  9. Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891–906
  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. 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
  12. Prantera C, Kohn A, Mangiarotti R, Andreoli A, Luzi C. Antimycobacterial therapy in Crohn’s disease: results of a controlled, double-blind trial with a multiple antibiotic regimen. Am J Gastroenterol. 1994;89:513–518
  13. Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology. 1995;108:1617–1621
  14. Steinhart AH, Feagan BG, Wong CJ, Vandervoort M, Mikolainis S, Croitoru K, et al. Combined budesonide and antibiotic therapy for active Crohn’s disease: a randomized controlled trial. Gastroenterology. 2002;123:33–40
  15. 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
  16. D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology. 1998;114:262–267
  17. Mow WS, Landers CJ, Steinhart AH, Feagan BG, Croitoru K, Seidman E, et al. High-level serum antibodies to bacterial antigens are associated with antibiotic-induced clinical remission in Crohn’s disease: a pilot study. Dig Dis Sci. 2004;49:1280–1286
  18. 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
  19. 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
  20. 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
  21. 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
  22. Landers CJ, Cohavy O, Misra R, Yang H, Lin YC, Braun J, et al. Selected loss of tolerance evidenced by Crohn’s disease-associated immune responses to auto- and microbial antigens. Gastroenterology. 2002;123:689–699
  23. Targan SR, Landers CJ, Yang H, Lodes MJ, Cong Y, Papadakis KA, et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology. 2005;128:2020–2028
  24. Seibold F, Stich O, Hufnagl R, Kamil S, Scheurlen M. Anti-Saccharomyces cerevisiae antibodies in inflammatory bowel disease: a family study. Scand J Gastroenterol. 2001;36:196–201
  25. Glas J, Torok HP, Vilsmaier F, Herbinger KH, Hoelscher M, Folwaczny C. Anti-saccharomyces cerevisiae antibodies in patients with inflammatory bowel disease and their first-degree relatives: potential clinical value. Digestion. 2002;66:173–177
  26. Annese V, Andreoli A, Andriulli A, Dinca R, Gionchetti P, Latiano A, et al. Familial expression of anti-Saccharomyces cerevisiae Mannan antibodies in Crohn’s disease and ulcerative colitis: a GISC study. Am J Gastroenterol. 2001;96:2407–2412
  27. Vermeire S, Peeters M, Vlietinck R, Joossens S, Den Hond E, Bulteel V, et al. Anti-Saccharomyces cerevisiae antibodies (ASCA), phenotypes of IBD, and intestinal permeability: a study in IBD families. Inflamm Bowel Dis. 2001;7:8–15
  28. Sutton CL, Yang H, Li Z, Rotter JI, Targan SR, Braun J. Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn’s disease. Gut. 2000;46:58–63
  29. 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
  30. Mei L, Targan SR, Landers CJ, Dutridge D, Ippoliti A, Vasiliauskas EA, et al. Familial expression of anti-Escherichia coli outer membrane porin C in relatives of patients with Crohn’s disease. Gastroenterology. 2006;130:1078–1085
  31. Beckwith J, Cong Y, Sundberg JP, Elson CO, Leiter EH. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology. 2005;129:1473–1484
  32. Russell RK, Nimmo ER, Satsangi J. Molecular genetics of Crohn’s disease. Curr Opin Genet Dev. 2004;14:264–270
  33. Mathew CG, Lewis CM. Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet. 2004;13:R161–R168
  34. Watts DA, Satsangi J. The genetic jigsaw of inflammatory bowel disease. Gut. 2002;50(Suppl 3):III31–III36
  35. Noble CL, Nimmo ER, Drummond H, Ho GT, Tenesa A, Smith L, et al. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn’s disease. Gastroenterology. 2005;129:1854–1864
  36. Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, et al. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature. 1996;379:821–823
  37. 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
  38. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–606
  39. Inohara N, Ogura Y, Nunez G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr Opin Microbiol. 2002;5:76–80
  40. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F, et al. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem. 2002;277:41701–41705
  41. Rosenstiel P, Fantini M, Brautigam K, Kuhbacher T, Waetzig GH, Seegert D, et al. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology. 2003;124:1001–1009
  42. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, et al. Crohn’s disease and the NOD2 gene: a role for paneth cells. Gastroenterology. 2003;125:47–57
  43. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem. 2001;276:4812–4818
  44. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–734
  45. Shaw SH, Hampe J, White R, Mathew CG, Curran ME, Schreiber S. Stratification by CARD15 variant genotype in a genome-wide search for inflammatory bowel disease susceptibility loci. Hum Genet. 2003;113:514–521
  46. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002;70:845–857
  47. Sugimura K, Taylor KD, Lin YC, Hang T, Wang D, Tang YM, et al. A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews. Am J Hum Genet. 2003;72:509–518
  48. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2 (Implications for Crohn’s disease). J Biol Chem. 2003;278:5509–5512
  49. Li J, Moran T, Swanson E, Julian C, Harris J, Bonen DK, et al. Regulation of IL-8 and IL-1beta expression in Crohn’s disease associated NOD2/CARD15 mutations. Hum Mol Genet. 2004;13:1715–1725
  50. 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
  51. Oostenbrug LE, Drenth JP, de Jong DJ, Nolte IM, Oosterom E, van Dullemen HM, et al. Association between Toll-like receptor 4 and inflammatory bowel disease. Inflamm Bowel Dis. 2005;11:567–575
  52. Brand S, Staudinger T, Schnitzler F, Pfennig S, Hofbauer K, Dambacher J, et al. The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn’s disease. Inflamm Bowel Dis. 2005;11:645–652
  53. Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, et al. Deficient host-bacteria interactions in inflammatory bowel disease? (The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis). Gut. 2004;53:987–992
  54. Torok HP, Glas J, Tonenchi L, Bruennler G, Folwaczny M, Folwaczny C. Crohn’s disease is associated with a toll-like receptor-9 polymorphism. Gastroenterology. 2004;127:365–366
  55. Mow WS, Vasiliauskas EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology. 2004;126:414–424
  56. Abreu MT, Taylor KD, Lin YC, Hang T, Gaiennie J, Landers CJ, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology. 2002;123:679–688
  57. The International HapMap Project. Nature. 2003;426:789–796
  58. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265
  59. Armitage P, Berry G, Matthews JNS. Statistical methods in medical research. Malden, MA: Blackwell; 2005;
  60. Chamaillard M, Philpott D, Girardin SE, Zouali H, Lesage S, Chareyre F, et al. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci U S A. 2003;100:3455–3460
  61. Walker LJ, Aldhous MC, Drummond HE, Smith BR, Nimmo ER, Arnott ID, et al. Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn’s disease are associated with disease severity but not NOD2/CARD15 mutations. Clin Exp Immunol. 2004;135:490–496
  62. Arnott ID, Landers CJ, Nimmo EJ, Drummond HE, Smith BK, Targan SR, et al. Sero-reactivity to microbial components in Crohn’s disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. Am J Gastroenterol. 2004;99:2376–2384
  63. Annese V, Lombardi G, Perri F, D’Inca R, Ardizzone S, Riegler G, et al. Variants of CARD15 are associated with an aggressive clinical course of Crohn’s disease—an IG-IBD study. Am J Gastroenterol. 2005;100:84–92
  64. Cruyssen BV, Peeters H, Hoffman IE, Laukens D, Coucke P, Marichal D, et al. CARD15 polymorphisms are associated with anti-Saccharomyces cerevisiae antibodies in caucasian Crohn’s disease patients. Clin Exp Immunol. 2005;140:354–359
  65. Goodarzi MO, Taylor KD, Guo X, Quinones MJ, Cui J, Li X, et al. Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait. Diabetes. 2005;54:1222–1227
  66. Motulsky AG, Brunzell JD. Genetics of coronary atherosclerosis. In:  King RA,  Rotter JI,  Motulsky AG editor. The genetic basis of common disease. 2nd ed.. New York, NY: Oxford University Press; 2002;p. 105–126
  67. Cario E. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut. 2005;54:1182–1193
  68. Arnott ID, Nimmo ER, Drummond HE, Fennell J, Smith BR, MacKinlay E, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within Europe?. Genes Immun. 2004;5:417–425
  69. Gazouli M, Mantzaris G, Kotsinas A, Zacharatos P, Papalambros E, Archimandritis A, et al. Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15/NOD2 and inflammatory bowel disease in the Greek population. World J Gastroenterol. 2005;11:681–685
  70. Thjodleifsson B, Sigthorsson G, Cariglia N, Reynisdottir I, Gudbjartsson DF, Kristjansson K, et al. Subclinical intestinal inflammation: an inherited abnormality in Crohn’s disease relatives?. Gastroenterology. 2003;124:1728–1737

 Supported by National Institutes of Health grant PO1 DK46763.

PII: S0016-5085(06)02468-1

doi: 10.1053/j.gastro.2006.11.013

Gastroenterology
Volume 132, Issue 2 , Pages 576-586 , February 2007

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