Gastroenterology
Volume 137, Issue 6 , Pages 1912-1933 , December 2009

Celiac Disease: From Pathogenesis to Novel Therapies

  • Detlef Schuppan

      Affiliations

    • Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    • Corresponding Author InformationReprint requests Address requests for reprints to: Detlef Schuppan, MD, PhD, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215. fax: (617) 667-2767
    • ,
  • Yvonne Junker

      Affiliations

    • Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    • ,
  • Donatella Barisani

      Affiliations

    • Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    • Department of Experimental Medicine, University of Milano Bicocca, Monza, Milan, Italy

Received 20 July 2009 ,Accepted 11 September 2009.

References 

  1. Abdulkarim AS, Murray JA. Celiac disease. Curr Treat Options Gastroenterol. 2002;5:27–38
  2. Ciclitira PJ, King AL, Fraser JS. AGA technical review on Celiac Sprue (American Gastroenterological Association). Gastroenterology. 2001;120:1526–1540
  3. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med. 2002;346:180–188
  4. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–1743
  5. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362:383–391
  6. Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology. 2000;119:234–242
  7. Trier JS. Celiac sprue. N Engl J Med. 1991;325:1709–1719
  8. Sollid LM, Lundin KE. Diagnosis and treatment of celiac disease. Mucosal Immunol. 2009;2:3–7
  9. Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009;373:1480–1493
  10. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286–292
  11. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland. N Engl J Med. 2003;348:2517–2524
  12. Vilppula A, Kaukinen K, Luostarinen L, et al. Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study. BMC Gastroenterol. 2009;9:49
  13. Green PH. The many faces of celiac disease: clinical presentation of celiac disease in the adult population. Gastroenterology. 2005;128:S74–S78
  14. Uibo O, Uibo R, Kleimola V, et al. Serum IgA anti-gliadin antibodies in an adult population sample (High prevalence without celiac disease). Dig Dis Sci. 1993;38:2034–2037
  15. Cascella NG, Kryszak D, Bhatti B, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull. 2009 Jun 3;[Epub ahead of print]
  16. Catassi C, Ratsch IM, Fabiani E, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet. 1994;343:200–203
  17. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology. 2001;120:636–651
  18. Genuis SJ, Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2009 Jun 29;[Epub ahead of print]
  19. Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses. 2009;73:438–440
  20. Grossman G. Neurological complications of coeliac disease: what is the evidence?. Pract Neurol. 2008;8:77–89
  21. Verdu EF, Armstrong D, Murray JA. Between celiac disease and irritable bowel syndrome: the “no man's land” of gluten sensitivity. Am J Gastroenterol. 2009;104:1587–1594
  22. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease (SIGEP Study Group for Autoimmune Disorders in Celiac Disease). Gastroenterology. 1999;117:297–303
  23. Smedby KE, Akerman M, Hildebrand H, et al. Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma. Gut. 2005;54:54–59
  24. Viljamaa M, Kaukinen K, Pukkala E, et al. Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: 30-year population-based study. Dig Liver Dis. 2006;38:374–380
  25. Gao Y, Kristinsson SY, Goldin LR, et al. Increased risk for non-Hodgkin lymphoma in individuals with celiac disease and a potential familial association. Gastroenterology. 2009;136:91–98
  26. Goldacre MJ, Wotton CJ, Yeates D, et al. Cancer in patients with ulcerative colitis, Crohn's disease and coeliac disease: record linkage study. Eur J Gastroenterol Hepatol. 2008;20:297–304
  27. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol. 2002;2:647–655
  28. Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. 2008;103:190–195
  29. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005;307:1920–1925
  30. Dubois PC, van Heel DA. Translational mini-review series on the immunogenetics of gut disease: immunogenetics of coeliac disease. Clin Exp Immunol. 2008;153:162–173
  31. Hunt KA, Zhernakova A, Turner G, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40:395–402
  32. Romanos J, van Diemen CC, Nolte IM, et al. Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease. Gastroenterology. 2009;137:834–840
  33. van Heel DA, Franke L, Hunt KA, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet. 2007;39:827–829
  34. Petronzelli F, Bonamico M, Ferrante P, et al. Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet. 1997;61:307–317
  35. Adamovic S, Amundsen SS, Lie BA, et al. Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families. Genes Immun. 2008;9:364–367
  36. Babron MC, Nilsson S, Adamovic S, et al. Meta and pooled analysis of European coeliac disease data. Eur J Hum Genet. 2003;11:828–834
  37. Dema B, Martinez A, Fernandez-Arquero M, et al. Association of IL18RAP and CCR3 with celiac disease in the Spanish population. J Med Genet. 2009;46:617–619
  38. Djilali-Saiah I, Schmitz J, Harfouch-Hammoud E, et al. CTLA-4 gene polymorphism is associated with predisposition to coeliac disease. Gut. 1998;43:187–189
  39. Garner CP, Murray JA, Ding YC, et al. Replication of celiac disease UK genome-wide association study results in a US population. Hum Mol Genet. 2009;18:4219–4225
  40. Greco L, Corazza G, Babron MC, et al. Genome search in celiac disease. Am J Hum Genet. 1998;62:669–675
  41. Haimila K, Einarsdottir E, de Kauwe A, et al. The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. Genes Immun. 2009;10:151–161
  42. Koskinen LL, Einarsdottir E, Dukes E, et al. Association study of the IL18RAP locus in three European populations with coeliac disease. Hum Mol Genet. 2009;18:1148–1155
  43. Liu J, Juo SH, Holopainen P, et al. Genomewide linkage analysis of celiac disease in Finnish families. Am J Hum Genet. 2002;70:51–59
  44. Monsuur AJ, de Bakker PI, Alizadeh BZ, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet. 2005;37:1341–1344
  45. Naluai AT, Nilsson S, Gudjonsdottir AH, et al. Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11. Eur J Hum Genet. 2001;9:938–944
  46. Naluai AT, Nilsson S, Samuelsson L, et al. The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders. Tissue Antigens. 2000;56:350–355
  47. Romanos J, Barisani D, Trynka G, et al. Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease. J Med Genet. 2009;46:60–63
  48. van Belzen MJ, Mulder CJ, Zhernakova A, et al. CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients. Eur J Hum Genet. 2004;12:782–785
  49. Woolley N, Holopainen P, Ollikainen V, et al. A new locus for coeliac disease mapped to chromosome 15 in a population isolate. Hum Genet. 2002;111:40–45
  50. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293:2343–2351
  51. Collado MC, Calabuig M, Sanz Y. Differences between the fecal microbiota of coeliac infants and healthy controls. Curr Issues Intest Microbiol. 2007;8:9–14
  52. Collado MC, Donat E, Ribes-Koninckx C, et al. Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol. 2008;8:232
  53. Collado MC, Donat E, Ribes-Koninckx C, et al. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol. 2009;62:264–269
  54. Pavone P, Nicolini E, Taibi R, et al. Rotavirus and celiac disease. Am J Gastroenterol. 2007;102:1831
  55. Stene LC, Honeyman MC, Hoffenberg EJ, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol. 2006;101:2333–2340
  56. Zanoni G, Navone R, Lunardi C, et al. In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes. PLoS Med. 2006;3:e358
  57. Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997;3:797–801
  58. Elli L, Bergamini CM, Bardella MT, et al. Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver Dis. 2009;41:541–550
  59. Piacentini M, Rodolfo C, Farrace MG, et al. “Tissue” transglutaminase in animal development. Int J Dev Biol. 2000;44:655–662
  60. Aeschlimann D, Thomazy V. Protein crosslinking in assembly and remodelling of extracellular matrices: the role of transglutaminases. Connect Tissue Res. 2000;41:1–27
  61. Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003;4:140–156
  62. Schuppan D, Dieterich W, Ehnis T, et al. Identification of the autoantigen of celiac disease. Ann N Y Acad Sci. 1998;859:121–126
  63. Anderson RP, Degano P, Godkin AJ, et al. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med. 2000;6:337–342
  64. Arentz-Hansen H, McAdam SN, Molberg O, et al. Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology. 2002;123:803–909
  65. Fleckenstein B, Molberg O, Qiao SW, et al. Gliadin T cell epitope selection by tissue transglutaminase in celiac disease (Role of enzyme specificity and pH influence on the transamidation versus deamidation process). J Biol Chem. 2002;277:34109–34116
  66. Molberg O, McAdam SN, Korner R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998;4:713–717
  67. Qiao SW BE, Molberg O, Xia J, et al. Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion. J Immunol. 2004;173:1757–1762
  68. Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297:2275–2279
  69. Vader LW, de Ru A, van der Wal Y, et al. Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med. 2002;195:643–649
  70. Vader LW, Stepniak DT, Bunnik EM, et al. Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology. 2003;125:1105–1113
  71. Vader W, Kooy Y, Van Veelen P, et al. The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology. 2002;122:1729–1737
  72. van de Wal Y, Kooy Y, van Veelen P, et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol. 1998;161:1585–1588
  73. Clemente MG, De Virgiliis S, Kang JS, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003;52:218–223
  74. Schumann M, Richter JF, Wedell I, et al. Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue. Gut. 2008;57:747–754
  75. Zimmer KP, Poremba C, Weber P, et al. Translocation of gliadin into HLA-DR antigen containing lysosomes in coeliac disease enterocytes. Gut. 1995;36:703–709
  76. Matysiak-Budnik T, Candalh C, Dugave C, et al. Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology. 2003;125:696–707
  77. Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. 2008;205:143–154
  78. Niess JH, Brand S, Gu X, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005;307:254–258
  79. Man AL, Prieto-Garcia ME, Nicoletti C. Improving M cell mediated transport across mucosal barriers: do certain bacteria hold the keys?. Immunology. 2004;113:15–22
  80. Cinova J, Palova-Jelinkova L, Smythies LE, et al. Gliadin peptides activate blood monocytes from patients with celiac disease. J Clin Immunol. 2007;27:201–209
  81. Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. 2003;362:30–37
  82. Palova-Jelinkova L, Rozkova D, Pecharova B, et al. Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol. 2005;175:7038–7045
  83. Tuckova L, Novotna J, Novak P, et al. Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol. 2002;71:625–631
  84. Thomas KE, Sapone A, Fasano A, et al. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol. 2006;176:2512–2521
  85. Meresse B, Cerf-Bensussan N. Innate T cell responses in human gut. Semin Immunol. 2009;21:121–129
  86. Palmer E. The generation of T cell tolerance. Swiss Med Wkly. 2007;137(Suppl 155):99S–100S
  87. Londei M, Ciacci C, Ricciardelli I, et al. Gliadin as a stimulator of innate responses in celiac disease. Mol Immunol. 2005;42:913–918
  88. Junker Y, Leffler DA, Wieser H, et al. Gastroenterology. 2009;36(Suppl 1):M2022
  89. Ciccocioppo R, Di Sabatino A, Parroni R, et al. Cytolytic mechanisms of intraepithelial lymphocytes in coeliac disease (CoD). Clin Exp Immunol. 2000;120:235–240
  90. Di Sabatino A, Ciccocioppo R, Cupelli F, et al. Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut. 2006;55:469–477
  91. Salvati VM, Mazzarella G, Gianfrani C, et al. Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa. Gut. 2005;54:46–53
  92. Burgess SJ, Maasho K, Masilamani M, et al. The NKG2D receptor: immunobiology and clinical implications. Immunol Res. 2008;40:18–34
  93. Hue S, Mention JJ, Monteiro RC, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity. 2004;21:367–377
  94. Meresse B, Chen Z, Ciszewski C, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 2004;21:357–366
  95. Terrazzano G, Sica M, Gianfrani C, et al. Gliadin regulates the NK-dendritic cell cross-talk by HLA-E surface stabilization. J Immunol. 2007;179:372–381
  96. Jabri B, de Serre NP, Cellier C, et al. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology. 2000;118:867–879
  97. Meresse B, Curran SA, Ciszewski C, et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med. 2006;203:1343–1355
  98. Bhagat G, Naiyer AJ, Shah JG, et al. Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J Clin Invest. 2008;118:281–293
  99. Benahmed M, Meresse B, Arnulf B, et al. Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease. Gastroenterology. 2007;132:994–1008
  100. Bernardo D, Garrote JA, Allegretti Y, et al. Higher constitutive IL15R alpha expression and lower IL-15 response threshold in coeliac disease patients. Clin Exp Immunol. 2008;154:64–73
  101. Maiuri L, Ciacci C, Auricchio S, et al. Interleukin 15 mediates epithelial changes in celiac disease. Gastroenterology. 2000;119:996–1006
  102. Mention JJ, Ben Ahmed M, Begue B, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology. 2003;125:730–745
  103. Maiuri L, Ciacci C, Vacca L, et al. IL-15 drives the specific migration of CD94+ and TCR-gammadelta+ intraepithelial lymphocytes in organ cultures of treated celiac patients. Am J Gastroenterol. 2001;96:150–156
  104. Meresse B, Verdier J, Cerf-Bensussan N. The cytokine interleukin 21: a new player in coeliac disease?. Gut. 2008;57:879–881
  105. Izcue A, Coombes JL, Powrie F. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol. 2009;27:313–338
  106. Frisullo G, Nociti V, Iorio R, et al. Increased CD4+CD25+Foxp3+ T cells in peripheral blood of celiac disease patients: correlation with dietary treatment. Hum Immunol. 2009;70:430–435
  107. Gianfrani C, Levings MK, Sartirana C, et al. Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol. 2006;177:4178–4186
  108. Mucida D, Park Y, Cheroutre H. From the diet to the nucleus: vitamin A and TGF-beta join efforts at the mucosal interface of the intestine. Semin Immunol. 2009;21:14–21
  109. Iwata M, Eshima Y, Kagechika H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int Immunol. 2003;15:1017–1025
  110. Mora JR, Iwata M, Eksteen B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. 2006;314:1157–1160
  111. Papadakis KA, Prehn J, Nelson V, et al. The role of thymus expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol. 2000;165:5069–5076
  112. Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–260
  113. Smith TR, Kumar V. Revival of CD8+ Treg-mediated suppression. Trends Immunol. 2008;29:337–342
  114. van Wijk F, Cheroutre H. Intestinal T cells: facing the mucosal immune dilemma with synergy and diversity. Semin Immunol. 2009;21:130–138
  115. Cheroutre H. In IBD eight can come before four. Gastroenterology. 2006;131:667–670
  116. Nancey S, Holvoet S, Graber I, et al. CD8+ cytotoxic T cells induce relapsing colitis in normal mice. Gastroenterology. 2006;131:485–496
  117. Westendorf AM, Fleissner D, Deppenmeier S, et al. Autoimmune-mediated intestinal inflammation—impact and regulation of antigen-specific CD8+ T cells. Gastroenterology. 2006;131:510–524
  118. Przemioslo RT, Lundin KE, Sollid LM, et al. Histological changes in small bowel mucosa induced by gliadin sensitive T lymphocytes can be blocked by anti-interferon gamma antibody. Gut. 1995;36:874–879
  119. Forsberg G, Hernell O, Melgar S, et al. Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology. 2002;123:667–678
  120. Pender SL, Tickle SP, Docherty AJ, et al. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol. 1997;158:1582–1590
  121. Daum S, Bauer U, Foss HD, et al. Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease. Gut. 1999;44:17–25
  122. Ciccocioppo R, Di Sabatino A, Bauer M, et al. Matrix metalloproteinase pattern in celiac duodenal mucosa. Lab Invest. 2005;85:397–407
  123. Schuppan D, Freitag T. Fistulising Crohn's disease: MMPs gone awry. Gut. 2004;53:622–624
  124. Abdulkarim AS, Burgart LJ, See J, et al. Etiology of nonresponsive celiac disease: results of a systematic approach. Am J Gastroenterol. 2002;97:2016–2021
  125. Leffler DA, Dennis M, Hyett B, et al. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol. 2007;5:445–450
  126. Al-Toma A, Verbeek WH, Hadithi M, et al. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut. 2007;56:1373–1378
  127. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma (French Coeliac Disease Study Group). Lancet. 2000;356:203–208
  128. Malamut G, Afchain P, Verkarre V, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136:81–90
  129. Rubio-Tapia A, Kyle RA, Kaplan EL, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009;137:88–93
  130. Jabri B, Sollid LM. Mechanisms of disease: immunopathogenesis of celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2006;3:516–525
  131. Verbeek WH, Goerres MS, von Blomberg BM, et al. Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in refractory celiac disease. Clin Immunol. 2008;126:48–56
  132. Al-toma A, Visser OJ, van Roessel HM, et al. Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells. Blood. 2007;109:2243–2249
  133. Catassi C, Bearzi I, Holmes GK. Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology. 2005;128:S79–S86
  134. Holmes GK, Prior P, Lane MR, et al. Malignancy in coeliac disease—effect of a gluten free diet. Gut. 1989;30:333–338
  135. Marietta E, Schuppan D, Murray JA. In vitro and in vivo models of celiac disease. Exp Opin Drug Discov (in press).
  136. de Ritis G, Auricchio S, Jones HW, et al. In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in celiac disease. Gastroenterology. 1988;94:41–49
  137. Falchuk ZM, Gebhard RL, Sessoms C, et al. An in vitro model of gluten-sensitive enteropathy (Effect of gliadin on intestinal epithelial cells of patients with gluten-sensitive enteropathy in organ culture). J Clin Invest. 1974;53:487–500
  138. Picarelli A, Maiuri L, Frate A, et al. Production of antiendomysial antibodies after in-vitro gliadin challenge of small intestine biopsy samples from patients with coeliac disease. Lancet. 1996;348:1065–1067
  139. Batt RM, McLean L, Carter MW. Sequential morphologic and biochemical studies of naturally occurring wheat-sensitive enteropathy in Irish setter dogs. Dig Dis Sci. 1987;32:184–194
  140. Hall EJ, Batt RM. Dietary modulation of gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs. Gut. 1992;33:198–205
  141. Polvi A, Garden OA, Houlston RS, et al. Genetic susceptibility to gluten sensitive enteropathy in Irish setter dogs is not linked to the major histocompatibility complex. Tissue Antigens. 1998;52:543–549
  142. Black KE, Murray JA, David CS. HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J Immunol. 2002;169:5595–5600
  143. Cheng S, Smart M, Hanson J, et al. Characterization of HLA DR2 and DQ8 transgenic mouse with a new engineered mouse class II deletion, which lacks all endogenous class II genes. J Autoimmun. 2003;21:195–199
  144. D'Arienzo R, Maurano F, Luongo D, et al. Adjuvant effect of Lactobacillus casei in a mouse model of gluten sensitivity. Immunol Lett. 2008;119:78–83
  145. Senger S, Maurano F, Mazzeo MF, et al. Identification of immunodominant epitopes of alpha-gliadin in HLA-DQ8 transgenic mice following oral immunization. J Immunol. 2005;175:8087–8095
  146. Marietta E, Black K, Camilleri M, et al. A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J Clin Invest. 2004;114:1090–1097
  147. Karell K, Louka AS, Moodie SJ, et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol. 2003;64:469–477
  148. Chen D, Ueda R, Harding F, et al. Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal model for autoimmune disease studies. Eur J Immunol. 2003;33:172–182
  149. de Kauwe AL, Chen Z, Anderson RP, et al. Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol. 2009;182:7440–7450
  150. Sestak K, Merritt CK, Borda J, et al. Infectious agent and immune response characteristics of chronic enterocolitis in captive rhesus macaques. Infect Immun. 2003;71:4079–4086
  151. Bethune MT, Borda JT, Ribka E, et al. A non-human primate model for gluten sensitivity. PLoS ONE. 2008;3:e1614
  152. Freitag T, Rietdijk S, Junker Y, et al. Gliadin-primed CD4+CD45RBlowCD25- effector/memory T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice. Gut. 2009 Aug 10;[Epub ahead of print]
  153. Kontakou M, Przemioslo RT, Sturgess RP, et al. Expression of tumour necrosis factor-alpha, interleukin-6, and interleukin-2 mRNA in the jejunum of patients with coeliac disease. Scand J Gastroenterol. 1995;30:456–463
  154. Nilsen EM, Jahnsen FL, Lundin KE, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998;115:551–563
  155. Westerholm-Ormio M, Garioch J, Ketola I, et al. Inflammatory cytokines in small intestinal mucosa of patients with potential coeliac disease. Clin Exp Immunol. 2002;128:94–101
  156. Castellanos-Rubio A, Santin I, Irastorza I, et al. TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity. 2009;42:69–73
  157. Salvati VM, MacDonald TT, Bajaj-Elliott M, et al. Interleukin 18 and associated markers of T helper cell type 1 activity in coeliac disease. Gut. 2002;50:186–190
  158. Barker CC, Mitton C, Jevon G, et al. Can tissue transglutaminase antibody titers replace small-bowel biopsy to diagnose celiac disease in select pediatric populations?. Pediatrics. 2005;115:1341–1346
  159. Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? (A prospective, biopsy-confirmed study with economic analysis). Clin Gastroenterol Hepatol. 2008;6:314–320
  160. Kotze LM, Utiyama SR, Nisihara RM, et al. IgA class anti-endomysial and anti-tissue transglutaminase antibodies in relation to duodenal mucosa changes in coeliac disease. Pathology. 2003;35:56–60
  161. Tursi A, Brandimarte G, Giorgetti GM. Prevalence of antitissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol. 2003;36:219–221
  162. Schilling J, Spiekerkoetter U, Wohlrab U, et al. Immunoglobulin isotype profile of tissue transglutaminase autoantibodies is correlated with the clinical presentation of coeliac disease. Scand J Immunol. 2005;61:207–212
  163. Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006;26:813–827
  164. Tursi A, Brandimarte G, Giorgetti GM. Lack of usefulness of anti-transglutaminase antibodies in assessing histologic recovery after gluten-free diet in celiac disease. J Clin Gastroenterol. 2003;37:387–391
  165. Korponay-Szabo IR, Dahlbom I, Laurila K, et al. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut. 2003;52:1567–1571
  166. Farrell RJ, Kelly CP. Diagnosis of celiac sprue. Am J Gastroenterol. 2001;96:3237–3246
  167. Pyle GG, Paaso B, Anderson BE, et al. Low-dose gluten challenge in celiac sprue: malabsorptive and antibody responses. Clin Gastroenterol Hepatol. 2005;3:679–686
  168. Juby LD, Rothwell J, Axon AT. Lactulose/mannitol test: an ideal screen for celiac disease. Gastroenterology. 1989;96:79–85
  169. Vogelsang H, Wyatt J, Penner E, et al. Screening for celiac disease in first-degree relatives of patients with celiac disease by lactulose/mannitol test. Am J Gastroenterol. 1995;90:1838–1842
  170. Paterson BM, Lammers KM, Arrieta MC, et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther. 2007;26:757–766
  171. Kelly CP, Green PH, Murray JA, et al. Intestinal permeability of larazotide acetate in celiac disease: results of a phase IIB 6-week gluten-challenge clinical trial (abstr). Gastroenterology. 2009;136(Suppl 1):M2048
  172. Johnston SD, Watson RG, Middleton D, et al. Genetic, morphometric and immunohistochemical markers of latent coeliac disease. Eur J Gastroenterol Hepatol. 1999;11:1283–1288
  173. Mustalahti K, Lohiniemi S, Collin P, et al. Gluten-free diet and quality of life in patients with screen-detected celiac disease. Eff Clin Pract. 2002;5:105–113
  174. Leffler DA, Dennis M, Edwards George J, et al. A validated disease specific symptom index for adults with celiac disease. Clin Gastroenterol Hepatol. 2009 Aug 7;[Epub ahead of print]
  175. Arentz-Hansen H, Korner R, Molberg O, et al. The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med. 2000;191:603–612
  176. Sjostrom H, Lundin KE, Molberg O, et al. Identification of a gliadin T-cell epitope in coeliac disease: general importance of gliadin deamidation for intestinal T-cell recognition. Scand J Immunol. 1998;48:111–115
  177. Stepniak D, Wiesner M, de Ru AH, et al. Large-scale characterization of natural ligands explains the unique gluten-binding properties of HLA-DQ2. J Immunol. 2008;180:3268–3278
  178. van de Wal Y, Kooy YM, van Veelen P, et al. Glutenin is involved in the gluten-driven mucosal T cell response. Eur J Immunol. 1999;29:3133–3139
  179. van de Wal Y, Kooy YM, van Veelen PA, et al. Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc Natl Acad Sci U S A. 1998;95:10050–10054
  180. Quarsten H, McAdam SN, Jensen T, et al. Staining of celiac disease-relevant T cells by peptide-DQ2 multimers. J Immunol. 2001;167:4861–4868
  181. Raki M, Fallang LE, Brottveit M, et al. Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc Natl Acad Sci U S A. 2007;104:2831–2836
  182. Anderson RP, van Heel DA, Tye-Din JA, et al. Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease. Gut. 2006;55:485–491
  183. Andersson EC, Hansen BE, Jacobsen H, et al. Definition of MHC and T cell receptor contacts in the HLA-DR4restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice. Proc Natl Acad Sci U S A. 1998;95:7574–7579
  184. Hansson T, Dannaeus A, Klareskog L. Cytokine-producing cells in peripheral blood of children with coeliac disease secrete cytokines with a type 1 profile. Clin Exp Immunol. 1999;116:246–250
  185. Hoffman SA, Joo WA, Echan LA, et al. Higher dimensional (Hi-D) separation strategies dramatically improve the potential for cancer biomarker detection in serum and plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;849:43–52
  186. Issaq HJ, Veenstra TD. The role of electrophoresis in disease biomarker discovery. Electrophoresis. 2007;28:1980–1988
  187. Patterson SD, Aebersold RH. Proteomics: the first decade and beyond. Nat Genet. 2003;33(Suppl):311–323
  188. Sollid LM, Khosla C. Future therapeutic options for celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2005;2:140–147
  189. Feldman M. The origin of cultivated wheat. In:  Bonjean AP,  Angus WJ editor. The world wheat book. London: Intercept; 2001;p. 1–56
  190. Auricchio S, De Ritis G, De Vincenzi M, et al. Effects of gliadin-derived peptides from bread and durum wheats on small intestinal cultures from rat fetus and celiac children. Pediatr Res. 1982;16:1004–1010
  191. Frisoni M, Corazza GR, Lafiandra D, et al. Wheat deficient in gliadins: promising tool for treatment of coeliac disease. Gut. 1995;36:375–378
  192. Molberg O, Kett K, Scott H, et al. Gliadin specific, HLA DQ2-restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand J Immunol. 1997;46:103–108
  193. Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, et al. Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology. 2005;129:797–806
  194. Molberg O, Uhlen AK, Jensen T, et al. Mapping of gluten T-cell epitopes in the bread wheat ancestors: implications for celiac disease. Gastroenterology. 2005;128:393–401
  195. van Herpen TW, Goryunova SV, van der Schoot J, et al. Alpha-gliadin genes from the A, B, and D genomes of wheat contain different sets of celiac disease epitopes. BMC Genomics. 2006;7:1
  196. Vincentini O, Maialetti F, Gazza L, et al. Environmental factors of celiac disease: cytotoxicity of hulled wheat species Triticum monococcum, T. turgidum ssp. dicoccum and T. aestivum ssp. spelta. J Gastroenterol Hepatol. 2007;22:1816–1822
  197. Pizzuti D, Buda A, D'Odorico A, et al. Lack of intestinal mucosal toxicity of Triticum monococcum in celiac disease patients. Scand J Gastroenterol. 2006;41:1305–1311
  198. van den Broeck HC, van Herpen TW, Schuit C, et al. Removing celiac disease-related gluten proteins from bread wheat while retaining technological properties: a study with Chinese Spring deletion lines. BMC Plant Biol. 2009;9:41
  199. Comai L, Young K, Till BJ, et al. Efficient discovery of DNA polymorphisms in natural populations by Ecotilling. Plant J. 2004;37:778–786
  200. Greene EA, Codomo CA, Taylor NE, et al. Spectrum of chemically induced mutations from a large-scale reverse-genetic screen in Arabidopsis. Genetics. 2003;164:731–740
  201. McCallum CM, Comai L, Greene EA, et al. Targeting induced local lesions IN genomes (TILLING) for plant functional genomics. Plant Physiol. 2000;123:439–442
  202. Till BJ, Reynolds SH, Greene EA, et al. Large-scale discovery of induced point mutations with high-throughput TILLING. Genome Res. 2003;13:524–530
  203. Barkley NA, Wang ML. Application of TILLING and EcoTILLING as reverse genetic approaches to elucidate the function of genes in plants and animals. Curr Genomics. 2008;9:212–226
  204. Di Cagno R, De Angelis M, Lavermicocca P, et al. Proteolysis by sourdough lactic acid bacteria: effects on wheat flour protein fractions and gliadin peptides involved in human cereal intolerance. Appl Environ Microbiol. 2002;68:623–633
  205. Rizzello CG, De Angelis M, Di Cagno R, et al. Highly efficient gluten degradation by lactobacilli and fungal proteases during food processing: new perspectives for celiac disease. Appl Environ Microbiol. 2007;73:4499–4507
  206. De Angelis M, Rizzello CG, Fasano A, et al. VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for Celiac Sprue. Biochim Biophys Acta. 2006;1762:80–93
  207. Di Cagno R, De Angelis M, Auricchio S, et al. Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appl Environ Microbiol. 2004;70:1088–1096
  208. Kiyosaki T, Matsumoto I, Asakura T, et al. Gliadain, a gibberellin-inducible cysteine proteinase occurring in germinating seeds of wheat, Triticum aestivum L., specifically digests gliadin and is regulated by intrinsic cystatins. FEBS J. 2007;274:1908–1917
  209. Gianfrani C, Siciliano RA, Facchiano AM, et al. Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology. 2007;133:780–789
  210. Yokoyama K, Nio N, Kikuchi Y. Properties and applications of microbial transglutaminase. Appl Microbiol Biotechnol. 2004;64:447–454
  211. Pasternack R, Dorsch S, Otterbach JT, et al. Bacterial pro-transglutaminase from Streptoverticillium mobaraense—purification, characterisation and sequence of the zymogen. Eur J Biochem. 1998;257:570–576
  212. Cabrera-Chavez F, Rouzaud-Sandez O, Sotelo-Cruz N, et al. Transglutaminase treatment of wheat and maize prolamins of bread increases the serum IgA reactivity of celiac disease patients. J Agric Food Chem. 2008;56:1387–1391
  213. Cabrera-Chavez F, Rouzaud-Sandez O, Sotelo-Cruz N, et al. Bovine milk caseins and transglutaminase-treated cereal prolamins are differentially recognized by IgA of celiac disease patients according to their age. J Agric Food Chem. 2009;57:3754–3759
  214. Wieser H. Relation between gliadin structure and coeliac toxicity. Acta Paediatr Suppl. 1996;412:3–9
  215. Hausch F, Shan L, Santiago NA, et al. Intestinal digestive resistance of immunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol. 2002;283:G996–G1003
  216. Mamone G, Ferranti P, Rossi M, et al. Identification of a peptide from alpha-gliadin resistant to digestive enzymes: implications for celiac disease. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;855:236–241
  217. Marti T, Molberg O, Li Q, et al. Prolyl endopeptidase-mediated destruction of T cell epitopes in whole gluten: chemical and immunological characterization. J Pharmacol Exp Ther. 2005;312:19–26
  218. Cornell HJ, Macrae FA, Melny J, et al. Enzyme therapy for management of coeliac disease. Scand J Gastroenterol. 2005;40:1304–1312
  219. Stepniak D, Spaenij-Dekking L, Mitea C, et al. Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease. Am J Physiol Gastrointest Liver Physiol. 2006;291:G621–G629
  220. Mitea C, Havenaar R, Drijfhout JW, et al. Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for coeliac disease. Gut. 2008;57:25–32
  221. Pyle GG, Paaso B, Anderson BE, et al. Effect of pretreatment of food gluten with prolyl endopeptidase on gluten-induced malabsorption in celiac sprue. Clin Gastroenterol Hepatol. 2005;3:687–694
  222. Fulop V, Szeltner Z, Polgar L. Catalysis of serine oligopeptidases is controlled by a gating filter mechanism. EMBO Rep. 2000;1:277–281
  223. Shan L, Marti T, Sollid LM, et al. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem J. 2004;383:311–318
  224. Cerf-Bensussan N, Matysiak-Budnik T, Cellier C, et al. Oral proteases: a new approach to managing coeliac disease. Gut. 2007;56:157–160
  225. Matysiak-Budnik T, Candalh C, Cellier C, et al. Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Gastroenterology. 2005;129:786–796
  226. Gass J, Vora H, Bethune MT, et al. Effect of barley endoprotease EP-B2 on gluten digestion in the intact rat. J Pharmacol Exp Ther. 2006;318:1178–1186
  227. Gass J, Bethune MT, Siegel M, et al. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology. 2007;133:472–480
  228. Pinier M, Verdu EF, Nasser-Eddine M, et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. 2009;136:288–298
  229. Warny M, Fatimi A, Bostwick EF, et al. Bovine immunoglobulin concentrate-clostridium difficile retains C difficile toxin neutralising activity after passage through the human stomach and small intestine. Gut. 1999;44:212–217
  230. Lu R, Wang W, Uzzau S, et al. Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain. J Neurochem. 2000;74:320–326
  231. Uzzau S, Lu R, Wang W, et al. Purification and preliminary characterization of the zonula occludens toxin receptor from human (CaCo2) and murine (IEC6) intestinal cell lines. FEMS Microbiol Lett. 2001;194:1–5
  232. Choi K, Siegel M, Piper JL, et al. Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. Chem Biol. 2005;12:469–475
  233. Lai TS, Slaughter TF, Peoples KA, et al. Regulation of human tissue transglutaminase function by magnesium-nucleotide complexes (Identification of distinct binding sites for Mg-GTP and Mg-ATP). J Biol Chem. 1998;273:1776–1781
  234. Siegel M, Khosla C. Transglutaminase 2 inhibitors and their therapeutic role in disease states. Pharmacol Ther. 2007;115:232–245
  235. Watts T, Berti I, Sapone A, et al. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci U S A. 2005;102:2916–2921
  236. Jeitner TM, Delikatny EJ, Ahlqvist J, et al. Mechanism for the inhibition of transglutaminase 2 by cystamine. Biochem Pharmacol. 2005;69:961–970
  237. Pardin C, Roy I, Lubell WD, et al. Reversible and competitive cinnamoyl triazole inhibitors of tissue transglutaminase. Chem Biol Drug Des. 2008;72:189–196
  238. de Macedo P, Marrano C, Keillor JW. Synthesis of dipeptide-bound epoxides and alpha,beta-unsaturated amides as potential irreversible transglutaminase inhibitors. Bioorg Med Chem. 2002;10:355–360
  239. Hausch F, Halttunen T, Maki M, et al. Design, synthesis, and evaluation of gluten peptide analogs as selective inhibitors of human tissue transglutaminase. Chem Biol. 2003;10:225–231
  240. Molberg O, McAdam S, Lundin KE, et al. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol. 2001;31:1317–1323
  241. Maiuri L, Ciacci C, Ricciardelli I, et al. Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology. 2005;129:1400–1413
  242. De Vincenzi M, Dessi MR, Giovannini C, et al. Agglutinating activity of wheat gliadin peptide fractions in coeliac disease. Toxicology. 1995;96:29–35
  243. De Vincenzi M, Gasbarrini G, Silano V. A small peptide from durum wheat gliadin prevents cell agglutination induced by prolamin-peptides toxic in coeliac disease. Toxicology. 1997;120:207–213
  244. De Vincenzi M, Luchetti R, Giovannini C, et al. In vitro toxicity testing of alcohol-soluble proteins from diploid wheat Triticum monococcum in celiac disease. Biochem Toxicol. 1996;11:313–318
  245. De Vincenzi M, Stammati A, Luchetti R, et al. Structural specificities and significance for coeliac disease of wheat gliadin peptides able to agglutinate or to prevent agglutination of K562(S) cells. Toxicology. 1998;127:97–106
  246. Giovannini C, Sanchez M, Straface E, et al. Induction of apoptosis in caco-2 cells by wheat gliadin peptides. Toxicology. 2000;145:63–71
  247. Silano M, Di Benedetto R, Trecca A, et al. A decapeptide from durum wheat prevents celiac peripheral blood lymphocytes from activation by gliadin peptides. Pediatr Res. 2007;61:67–71
  248. Silano M, Di Benedetto R, Maialetti F, et al. A 10-residue peptide from durum wheat promotes a shift from a Th1-type response toward a Th2-type response in celiac disease. Am J Clin Nutr. 2008;87:415–423
  249. Silano M, Leonardi F, Trecca A, et al. Prevention by a decapeptide from durum wheat of in vitro gliadin peptide-induced apoptosis in small-bowel mucosa from coeliac patients. Scand J Gastroenterol. 2007;42:786–787
  250. Biagi F, Ellis HJ, Parnell ND, et al. A non-toxic analogue of a coeliac-activating gliadin peptide: a basis for immunomodulation?. Aliment Pharmacol Ther. 1999;13:945–950
  251. Kapoerchan VV, Wiesner M, Overhand M, et al. Design of azidoproline containing gluten peptides to suppress CD4+ T-cell responses associated with celiac disease. Bioorg Med Chem. 2008;16:2053–2062
  252. Xia J, Siegel M, Bergseng E, et al. Inhibition of HLA-DQ2-mediated antigen presentation by analogues of a high affinity 33-residue peptide from alpha2-gliadin. J Am Chem Soc. 2006;128:1859–1867
  253. Bolin DR, Swain AL, Sarabu R, et al. Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules (Design, structure-activity relationships, and X-ray crystal structures). J Med Chem. 2000;43:2135–2148
  254. Falcioni F, Ito K, Vidovic D, et al. Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules. Nat Biotechnol. 1999;17:562–567
  255. Ishioka GY, Adorini L, Guery JC, et al. Failure to demonstrate long-lived MHC saturation both in vitro and in vivo (Implications for therapeutic potential of MHC-blocking peptides). J Immunol. 1994;152:4310–4319
  256. Siegel M, Xia J, Khosla C. Structure-based design of alpha-amido aldehyde containing gluten peptide analogues as modulators of HLA-DQ2 and transglutaminase 2. Bioorg Med Chem. 2007;15:6253–6261
  257. Xia J, Bergseng E, Fleckenstein B, et al. Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorg Med Chem. 2007;15:6565–6573
  258. Matysiak-Budnik T, Malamut G, de Serre NP, et al. Long-term follow-up of 61 coeliac patients diagnosed in childhood: evolution toward latency is possible on a normal diet. Gut. 2007;56:1379–1386
  259. Maurano F, Siciliano RA, De Giulio B, et al. Intranasal administration of one alpha gliadin can downregulate the immune response to whole gliadin in mice. Scand J Immunol. 2001;53:290–295
  260. Rossi M, Maurano F, Caputo N, et al. Intravenous or intranasal administration of gliadin is able to down-regulate the specific immune response in mice. Scand J Immunol. 1999;50:177–182
  261. Senger S, Luongo D, Maurano F, et al. Intranasal administration of a recombinant alpha-gliadin down-regulates the immune response to wheat gliadin in DQ8 transgenic mice. Immunol Lett. 2003;88:127–134
  262. Keech CL, Dromey J, Chen Z, et al. Immune tolerance induced by peptide immunotherapy in an HLA-DQ2-dependent mouse model of gluten immunity. Gastroenterology. 2009;136:A355
  263. Medina M, De Palma G, Ribes-Koninckx C, et al. Bifidobacterium strains suppress in vitro the pro-inflammatory milieu triggered by the large intestinal microbiota of coeliac patients. J Inflamm (Lond). 2008;5:19
  264. Elliott DE, Summers RW, Weinstock JV. Helminths as governors of immune-mediated inflammation. Int J Parasitol. 2007;37:457–464
  265. Summers RW, Elliott DE, Urban JF, et al. Trichuris suis therapy in Crohn's disease. Gut. 2005;54:87–90
  266. Summers RW, Elliott DE, Urban JF, et al. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology. 2005;128:825–832
  267. Huibregtse IL, Marietta EV, Rashtak S, et al. Induction of antigen-specific tolerance by oral administration of lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic abdegrees Dq8 transgenic mice. J Immunol. 2009;183:2390–2396
  268. Berlin C, Berg EL, Briskin MJ, et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74:185–195
  269. Papadakis KA, Prehn J, Moreno ST, et al. CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease. Gastroenterology. 2001;121:246–254
  270. Zabel BA, Agace WW, Campbell JJ, et al. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J Exp Med. 1999;190:1241–1256
  271. Olaussen RW, Karlsson MR, Lundin KEA, et al. Reduced chemokine receptor 9 on intraepithelial lymphocytes in celiac disease suggests persistent epithelial activation. Gastroenterology. 2007;132:2371–2382
  272. Rivera-Nieves J, Bamias G, Knight RF, et al. Blockade of CCL25/CCR9 attenuates early chronic murine ileitis. Gastroenterology. 2006;131:1518–1529
  273. Wei Z, Baumgart T, Rubas W, et al. Cc chemokine receptor 9 (ccr9) antagonist ameliorates experimental ileitis and colitis (abstr). Gastroenterology. 2005;128:A204–A205
  274. Keshav S, Ungashe S, Zheng W, et al. Ccx282-B, An orally active inhibitor of chemokine receptor Ccr9, shows anti-inflammatory & clinical activity in the treatment of Crohn's disease. Gastroenterology. 2007;132:A157
  275. Keshav S, Johnson D, Bekker P, et al. PROTECT-1 study demonstrated efficacy of the intestine-specific chemokine receptor antagonist CCX282-B (Traficet-EN) in treatment of patients with moderate to severe Crohn's disease. Gastroenterology. 2009;136(Suppl 1):A392
  276. Hamilton G, Maki M, Lahdeaho M, et al. Gastroenterology. 2008;134(Suppl 1):T1143
  277. Baslund B, Tvede N, Danneskiold-Samsoe B, et al. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 2005;52:2686–2692
  278. West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs. 2009;10:491–504
  279. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147
  280. Garcia-Castro J, Trigueros C, Madrenas J, et al. Mesenchymal stem cells and their use as cell replacement therapy and disease modelling tool. J Cell Mol Med. 2008;12:2552–2565
  281. Tse WT, Pendleton JD, Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75:389–397
  282. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822
  283. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–3843
  284. Francois S, Bensidhoum M, Mouiseddine M, et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells. 2006;24:1020–1029
  285. Costantino G, della Torre A, Lo Presti MA, et al. Treatment of life-threatening type I refractory coeliac disease with long-term infliximab. Dig Liver Dis. 2008;40:74–77
  286. Gillett HR, Arnott ID, McIntyre M, et al. Successful infliximab treatment for steroid-refractory celiac disease: a case report. Gastroenterology. 2002;122:800–805
  287. Vivas S, Ruiz de Morales JM, Ramos F, et al. Alemtuzumab for refractory celiac disease in a patient at risk for enteropathy-associated T-cell lymphoma. N Engl J Med. 2006;354:2514–2515

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by grant 1R21DK073254-02 from the National Institutes of Health, a grant from the German Ministery for Education and Research (to D.S.), a 1-year fellowship grant from the German Ministry for Education and Research (to Y.J.), and a Fulbright Research Scholar fellowship (to D.B.).

PII: S0016-5085(09)01600-X

doi: 10.1053/j.gastro.2009.09.008

Gastroenterology
Volume 137, Issue 6 , Pages 1912-1933 , December 2009

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