Seminars in Immunopathology

, Volume 34, Issue 4, pp 581–600 | Cite as

The immunopathogenesis of celiac disease reveals possible therapies beyond the gluten-free diet

Review Article


Celiac disease is a T cell-mediated autoimmune inflammatory disease of the small intestine that is activated by gluten. The diagnosis of celiac disease is challenging as patients display a wide range of symptoms and some are asymptomatic. A lifelong gluten-free diet is the only currently approved treatment of celiac disease. Although the diet is safe and effective, the compliance rates and patient acceptance vary. Furthermore, many patients treated with a gluten-free diet continue to be mildly to severely symptomatic with persistent histological abnormalities, and a small number of patients develop refractory celiac disease. New therapeutic adjuncts and potential alternatives to the gluten-free diet could improve the treatment options for these patients. Advances in understanding the immunopathogenesis of celiac disease have suggested several types of therapeutic strategies that may augment or supplant the gluten-free diet. Some of these strategies attempt to decrease the immunogenicity of gluten-containing grains by manipulating the grain itself or by using oral enzymes to break down immunogenic peptides that normally remain intact during digestion. Other strategies focus on preventing the absorption of these peptides, preventing tissue transglutaminase from rendering gluten peptides more immunogenic, or inhibiting their binding to celiac disease-specific antigen-presenting molecules. Strategies that limit T cell migration to the small intestine or that reestablish mucosal homeostasis and tolerance to gluten antigens are also being explored. Additionally, it is vital to develop new therapeutic options for refractory celiac disease patients. This review highlights therapeutic strategies that may ultimately improve the health and well-being of individuals with celiac disease.


  1. 1.
    Kagnoff MF (2007) Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest 117(1):41–49PubMedCrossRefGoogle Scholar
  2. 2.
    Marsh MN (1992) Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology 102(1):330–354PubMedGoogle Scholar
  3. 3.
    Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F (2009) Small-intestinal histopathology and mortality risk in celiac disease. JAMA 302(11):1171–1178PubMedCrossRefGoogle Scholar
  4. 4.
    Rubio-Tapia A, Rahim MW, See JA, Lahr BD, Wu TT, Murray JA (2010) Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. Am J Gastroenterol 105(6):1412–1420PubMedCrossRefGoogle Scholar
  5. 5.
    Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, Elitsur Y, Green PH, Guandalini S, Hill ID, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaroli F, Wasserman SS, Murray JA, Horvath K (2003) Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 163(3):286–292PubMedCrossRefGoogle Scholar
  6. 6.
    Abadie V, Sollid LM, Barreiro LB, Jabri B (2011) Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 29:493–525PubMedCrossRefGoogle Scholar
  7. 7.
    Stern M, Ciclitira PJ, van Eckert R, Feighery C, Janssen FW, Mendez E, Mothes T, Troncone R, Wieser H (2001) Analysis and clinical effects of gluten in coeliac disease. Eur J Gastroenterol Hepatol 13(6):741–747PubMedCrossRefGoogle Scholar
  8. 8.
    Shan L, Ãy M, Parrot I, Hausch F, Filiz F, Gray GM, Sollid LM, Khosla C (2002) Structural basis for gluten intolerance in celiac sprue. Science 297(5590):2275–2279PubMedCrossRefGoogle Scholar
  9. 9.
    Sollid LM, Thorsby E (1993) HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 105(3):910–922PubMedGoogle Scholar
  10. 10.
    Henderson KN, Tye-Din JA, Reid HH, Chen Z, Borg NA, Beissbarth T, Tatham A, Mannering SI, Purcell AW, Dudek NL, van Heel DA, McCluskey J, Rossjohn J, Anderson RP (2007) A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity 27(1):23–34PubMedCrossRefGoogle Scholar
  11. 11.
    Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Sollid LM, Jahnsen J, Scott H, Brandtzaeg P (1998) Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 115(3):551–563PubMedCrossRefGoogle Scholar
  12. 12.
    Mohamed BM, Feighery C, Kelly J, Coates C, O'Shea U, Barnes L, Abuzakouk M (2006) Increased protein expression of matrix metalloproteinases -1, -3, and -9 and TIMP-1 in patients with gluten-sensitive enteropathy. Dig Dis Sci 51(10):1862–1868PubMedCrossRefGoogle Scholar
  13. 13.
    Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4(6):713–717PubMedCrossRefGoogle Scholar
  14. 14.
    Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B (2004) Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21(3):357–366PubMedCrossRefGoogle Scholar
  15. 15.
    Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, Verkarre V, Fodil N, Bahram S, Cerf-Bensussan N, Caillat-Zucman S (2004) A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21(3):367–377PubMedCrossRefGoogle Scholar
  16. 16.
    Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3(7):797–801PubMedCrossRefGoogle Scholar
  17. 17.
    Rostom A, Murray JA, Kagnoff MF (2006) American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 131(6):1981–2002PubMedCrossRefGoogle Scholar
  18. 18.
    Valdimarsson T, Franzen L, Grodzinsky E, Skogh T, Strom M (1996) Is small bowel biopsy necessary in adults with suspected celiac disease and IgA anti-endomysium antibodies? 100% positive predictive value for celiac disease in adults. Dig Dis Sci 41(1):83–87PubMedCrossRefGoogle Scholar
  19. 19.
    Volta U, Granito A, Parisi C, Fabbri A, Fiorini E, Piscaglia M, Tovoli F, Grasso V, Muratori P, Pappas G, De Giorgio R (2010) Deamidated gliadin peptide antibodies as a routine test for celiac disease: a prospective analysis. J Clin Gastroenterol 44(3):186–190PubMedCrossRefGoogle Scholar
  20. 20.
    Oberhuber G, Granditsch G, Vogelsang H (1999) The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 11(10):1185–1194PubMedCrossRefGoogle Scholar
  21. 21.
    Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, Spaenij L, Koning F (2003) The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc National Acad Sci 100(21):12390–12395CrossRefGoogle Scholar
  22. 22.
    Quarsten H, Molberg O, Fugger L, McAdam SN, Sollid LM (1999) HLA binding and T cell recognition of a tissue transglutaminase-modified gliadin epitope. Eur J Immunol 29(8):2506–2514PubMedCrossRefGoogle Scholar
  23. 23.
    Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E (1989) Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med 169(1):345–350PubMedCrossRefGoogle Scholar
  24. 24.
    Pietzak MM, Schofield TC, McGinniss MJ, Nakamura RM (2009) Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles. Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association 7(9):966–971Google Scholar
  25. 25.
    van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, Koning F (1998) Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 161(4):1585–1588PubMedGoogle Scholar
  26. 26.
    Tsuji NM, Kosaka A (2008) Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells. Trends Immunol 29(11):532–540PubMedCrossRefGoogle Scholar
  27. 27.
    Jabri B, Sollid LM (2009) Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 9(12):858–870PubMedCrossRefGoogle Scholar
  28. 28.
    Mention JJ, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, Colombel JF, Cugnenc PH, Ruemmele FM, McIntyre E, Brousse N, Cellier C, Cerf-Bensussan N (2003) Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125(3):730–745PubMedCrossRefGoogle Scholar
  29. 29.
    DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B (2011) Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471(7337):220–224PubMedCrossRefGoogle Scholar
  30. 30.
    Hmida NB, Ahmed MB, Moussa A, Rejeb MB, Said Y, Kourda N, Meresse B, Abdeladhim M, Louzir H, Cerf-Bensussan N (2012) Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease? Am J Gastroenterol 107:604–611PubMedCrossRefGoogle Scholar
  31. 31.
    Zanzi D, Stefanile R, Santagata S, Iaffaldano L, Iaquinto G, Giardullo N, Lania G, Vigliano I, Vera AR, Ferrara K, Auricchio S, Troncone R, Mazzarella G (2011) IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in celiac disease. Am J Gastroenterol 106(7):1308–1317PubMedCrossRefGoogle Scholar
  32. 32.
    Klitz W, Maiers M, Spellman S, Baxter-Lowe LA, Schmeckpeper B, Williams TM, Fernandez-Viña M (2003) New HLA haplotype frequency reference standards: high-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans. Tissue Antigens 62(4):296–307PubMedCrossRefGoogle Scholar
  33. 33.
    Nistico L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG, Paparo F, D'Alfonso S, Giordano M, Sferlazzas C, Magazzu G, Momigliano-Richiardi P, Greco L, Stazi MA (2006) Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 55(6):803–808PubMedCrossRefGoogle Scholar
  34. 34.
    van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MC, Bethel G, Holmes GK, Feighery C, Jewell D, Kelleher D, Kumar P, Travis S, Walters JR, Sanders DS, Howdle P, Swift J, Playford RJ, McLaren WM, Mearin ML, Mulder CJ, McManus R, McGinnis R, Cardon LR, Deloukas P, Wijmenga C (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39(7):827–829PubMedCrossRefGoogle Scholar
  35. 35.
    Hunt KA, Zhernakova A, Turner G, Heap GAR, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D, Gwilliam R, Takeuchi F, McLaren WM, Holmes GKT, Howdle PD, Walters JRF, Sanders DS, Playford RJ, Trynka G, Mulder CJJ, Mearin ML, Verbeek WHM, Trimble V, Stevens FM, O'Morain C, Kennedy NP, Kelleher D, Pennington DJ, Strachan DP, McArdle WL, Mein CA, Wapenaar MC, Deloukas P, McGinnis R, McManus R, Wijmenga C, van Heel DA (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40(4):395–402PubMedCrossRefGoogle Scholar
  36. 36.
    Bevan S, Popat S, Braegger CP, Busch A, O'Donoghue D, Falth-Magnusson K, Ferguson A, Godkin A, Hogberg L, Holmes G, Hosie KB, Howdle PD, Jenkins H, Jewell D, Johnston S, Kennedy NP, Kerr G, Kumar P, Logan RF, Love AH, Marsh M, Mulder CJ, Sjoberg K, Stenhammer L, Walker-Smith J, Marossy AM, Houlston RS (1999) Contribution of the MHC region to the familial risk of coeliac disease. J Med Genet 36(9):687–690PubMedGoogle Scholar
  37. 37.
    Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adany R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernandez-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Maki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Nunez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42(4):295–302PubMedCrossRefGoogle Scholar
  38. 38.
    Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, Bakker SF, Bardella MT, Bhaw-Rosun L, Castillejo G, de la Concha EG, de Almeida RC, Dias KR, van Diemen CC, Dubois PC, Duerr RH, Edkins S, Franke L, Fransen K, Gutierrez J, Heap GA, Hrdlickova B, Hunt S, Izurieta LP, Izzo V, Joosten LA, Langford C, Mazzilli MC, Mein CA, Midah V, Mitrovic M, Mora B, Morelli M, Nutland S, Nunez C, Onengut-Gumuscu S, Pearce K, Platteel M, Polanco I, Potter S, Ribes-Koninckx C, Ricano-Ponce I, Rich SS, Rybak A, Santiago JL, Senapati S, Sood A, Szajewska H, Troncone R, Varade J, Wallace C, Wolters VM, Zhernakova A, Thelma BK, Cukrowska B, Urcelay E, Bilbao JR, Mearin ML, Barisani D, Barrett JC, Plagnol V, Deloukas P, Wijmenga C, van Heel DA (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43(12):1193–1201PubMedCrossRefGoogle Scholar
  39. 39.
    Sperandeo MP, Tosco A, Izzo V, Tucci F, Troncone R, Auricchio R, Romanos J, Trynka G, Auricchio S, Jabri B, Greco L (2011) Potential celiac patients: a model of celiac disease pathogenesis. PLoS One 6(7):e21281PubMedCrossRefGoogle Scholar
  40. 40.
    Ventura A, Magazzu G, Greco L (1999) 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 117(2):297–303PubMedCrossRefGoogle Scholar
  41. 41.
    Megiorni F, Mora B, Bonamico M, Barbato M, Montuori M, Viola F, Trabace S, Mazzilli MC (2008) HLA-DQ and susceptibility to celiac disease: evidence for gender differences and parent-of-origin effects. Am J Gastroenterol 103(4):997–1003PubMedCrossRefGoogle Scholar
  42. 42.
    Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JHM, Howson JMM, Stevens H, McManus R, Wijmenga C, Heap GA, Dubois PC, Clayton DG, Hunt KA, van Heel DA, Todd JA (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359(26):2767–2777PubMedCrossRefGoogle Scholar
  43. 43.
    Dube C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, Sampson M, Zhang L, Yazdi F, Mamaladze V, Pan I, Macneil J, Mack D, Patel D, Moher D (2005) The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 128(4 Suppl 1):S57–67PubMedCrossRefGoogle Scholar
  44. 44.
    Akobeng AK, Ramanan AV, Buchan I, Heller RF (2006) Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch Dis Child 91(1):39–43PubMedCrossRefGoogle Scholar
  45. 45.
    Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, Welling GW (2000) Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr 30(1):61–67PubMedCrossRefGoogle Scholar
  46. 46.
    Sanchez E, De Palma G, Capilla A, Nova E, Pozo T, Castillejo G, Varea V, Marcos A, Garrote JA, Polanco I, Lopez A, Ribes-Koninckx C, Garcia-Novo MD, Calvo C, Ortigosa L, Palau F, Sanz Y (2011) Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by Bacteroides species. Appl Environ Microbiol 77(15):5316–5323PubMedCrossRefGoogle Scholar
  47. 47.
    Howie PW, Forsyth JS, Ogston SA, Clark A, Florey CD (1990) Protective effect of breast feeding against infection. BMJ 300(6716):11–16PubMedCrossRefGoogle Scholar
  48. 48.
    Plot L, Amital H (2009) Infectious associations of celiac disease. Autoimmun Rev 8(4):316–319PubMedCrossRefGoogle Scholar
  49. 49.
    Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, Taki I, Norris JM, Erlich HA, Eisenbarth GS, Rewers M (2006) Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 101(10):2333–2340PubMedCrossRefGoogle Scholar
  50. 50.
    Pavone P, Nicolini E, Taibi R, Ruggieri M (2007) Rotavirus and celiac disease. Am J Gastroenterol 102(8):1831–1831PubMedCrossRefGoogle Scholar
  51. 51.
    Ivarsson A, Hernell O, Nystrom L, Persson LA (2003) Children born in the summer have increased risk for coeliac disease. J Epidemiol Community Health 57(1):36–39PubMedCrossRefGoogle Scholar
  52. 52.
    Lewy H, Meirson H, Laron Z (2009) Seasonality of birth month of children with celiac disease differs from that in the general population and between sexes and is linked to family history and environmental factors. J Pediatr Gastroenterol Nutr 48(2):181–185PubMedCrossRefGoogle Scholar
  53. 53.
    Camilleri M, Nullens S, Nelsen T (2012) Enteroendocrine and neuronal mechanisms in pathophysiology of acute infectious diarrhea. Dig Dis Sci 57(1):19–27PubMedCrossRefGoogle Scholar
  54. 54.
    Monteleone G, Pender SL, Wathen NC, MacDonald TT (2001) Interferon-alpha drives T cell-mediated immunopathology in the intestine. Eur J Immunol 31(8):2247–2255PubMedCrossRefGoogle Scholar
  55. 55.
    Cammarota G, Cuoco L, Cianci R, Pandolfi F, Gasbarrini G (2000) Onset of coeliac disease during treatment with interferon for chronic hepatitis C. Lancet 356(9240):1494–1495PubMedCrossRefGoogle Scholar
  56. 56.
    Hernandez L, Johnson TC, Naiyer AJ, Kryszak D, Ciaccio EJ, Min A, Bodenheimer HC Jr, Brown RS Jr, Fasano A, Green PH (2008) Chronic hepatitis C virus and celiac disease, is there an association? Dig Dis Sci 53(1):256–261PubMedCrossRefGoogle Scholar
  57. 57.
    Tjon JM, van Bergen J, Koning F (2010) Celiac disease: how complicated can it get? Immunogenetics 62(10):641–651PubMedCrossRefGoogle Scholar
  58. 58.
    Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N, Brousse N (2000) Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 356(9225):203–208PubMedCrossRefGoogle Scholar
  59. 59.
    Daum S, Cellier C, Mulder CJ (2005) Refractory coeliac disease. Best Pract Res Clin Gastroenterol 19(3):413–424PubMedCrossRefGoogle Scholar
  60. 60.
    Rubio-Tapia A, Murray JA (2010) Classification and management of refractory coeliac disease. Gut 59(4):547–557PubMedCrossRefGoogle Scholar
  61. 61.
    Malamut G, Afchain P, Verkarre V, Lecomte T, Amiot A, Damotte D, Bouhnik Y, Colombel JF, Delchier JC, Allez M, Cosnes J, Lavergne-Slove A, Meresse B, Trinquart L, Macintyre E, Radford-Weiss I, Hermine O, Brousse N, Cerf-Bensussan N, Cellier C (2009) Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 136(1):81–90PubMedCrossRefGoogle Scholar
  62. 62.
    Dicke WK, Weijers HA, Van De Kamer JH (1953) Coeliac disease.II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr 42(1):34–42PubMedCrossRefGoogle Scholar
  63. 63.
    Van De Kamer JH, Weijers HA, Dicke WK (1953) Coeliac disease. IV. An investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease. Acta Paediatr 42(3):223–231CrossRefGoogle Scholar
  64. 64.
    French JM, Hawkins CF, Smith N (1957) The effect of a wheat-gluten-free diet in adult idiopathic steatorrhoea; a study of 22 cases. Q J Med 26(104):481–499PubMedGoogle Scholar
  65. 65.
    van Overbeek FM, Uil-Dieterman IG, Mol IW, Kohler-Brands L, Heymans HS, Mulder CJ (1997) The daily gluten intake in relatives of patients with coeliac disease compared with that of the general Dutch population. Eur J Gastroenterol Hepatol 9(11):1097–1099PubMedCrossRefGoogle Scholar
  66. 66.
    Hischenhuber C, Crevel R, Jarry B, Maki M, Moneret-Vautrin DA, Romano A, Troncone R, Ward R (2006) Safe amounts of gluten for patients with wheat allergy or coeliac disease. Aliment Pharmacol Ther 23(5):559–575PubMedCrossRefGoogle Scholar
  67. 67.
    Catassi C, Fabiani E, Iacono G, D'Agate C, Francavilla R, Biagi F, Volta U, Accomando S, Picarelli A, De Vitis I, Pianelli G, Gesuita R, Carle F, Mandolesi A, Bearzi I, Fasano A (2007) A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr 85(1):160–166PubMedGoogle Scholar
  68. 68.
    Codex Alimentarius Commission (2008) Codex standard for foods for special dietary use for persons intolerant to gluten. Codex Stan 118-1979Google Scholar
  69. 69.
    Gibert A, Espadaler M, Angel Canela M, Sanchez A, Vaque C, Rafecas M (2006) Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20, 100 or 200 p.p.m.? Eur J Gastroenterol Hepatol 18(11):1187–1195PubMedCrossRefGoogle Scholar
  70. 70.
    Food and Drug Administration (2011) A glimpse at 'gluten-free' food labeling. Accessed 21 February 2012
  71. 71.
    European Union (2009) Commission Regulation (EC) No. 41/2009. Official Journal of the European UnionGoogle Scholar
  72. 72.
    Thompson T, Mendez E (2008) Commercial assays to assess gluten content of gluten-free foods: why they are not created equal. J Am Diet Assoc 108(10):1682–1687PubMedCrossRefGoogle Scholar
  73. 73.
    Shewry PR, And T, Kasarda DD (1992) Cereal proteins and coeliac disease. In: Marsh MN (ed) Coeliac disease. Blackwell Scientific, OxfordGoogle Scholar
  74. 74.
    Shewry PR, Halford NG (2002) Cereal seed storage proteins: structures, properties and role in grain utilization. J Exp Bot 53(370):947–958PubMedCrossRefGoogle Scholar
  75. 75.
    Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV (2000) In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med 6(3):337–342PubMedCrossRefGoogle Scholar
  76. 76.
    Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, Tatham A, Henderson K, Mannering SI, Gianfrani C, Jewell DP, Hill AV, McCluskey J, Rossjohn J, Anderson RP (2010) Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med 2(41):41ra51PubMedCrossRefGoogle Scholar
  77. 77.
    Arentz-Hansen H, Korner R, Molberg O, Quarsten H, Vader W, Kooy YM, Lundin KE, Koning F, Roepstorff P, Sollid LM, McAdam SN (2000) 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 191(4):603–612PubMedCrossRefGoogle Scholar
  78. 78.
    Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, Picard J, Osman M, Quaratino S, Londei M (2003) Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362(9377):30–37PubMedCrossRefGoogle Scholar
  79. 79.
    Denery-Papini S, Nicolas Y, Popineau Y (1999) Efficiency and limitations of immunochemical assays for the testing of gluten-free foods. J Cereal Sci 30(2):121–131CrossRefGoogle Scholar
  80. 80.
    Valdes I, Garcia E, Llorente M, Mendez E (2003) Innovative approach to low-level gluten determination in foods using a novel sandwich enzyme-linked immunosorbent assay protocol. Eur J Gastroenterol Hepatol 15(5):465–474PubMedCrossRefGoogle Scholar
  81. 81.
    Murray JA, Watson T, Clearman B, Mitros F (2004) Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease. Am J Clin Nutr 79(4):669–673PubMedGoogle Scholar
  82. 82.
    Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI (2003) Risk of malignancy in patients with celiac disease. Am J Med 115(3):191–195PubMedCrossRefGoogle Scholar
  83. 83.
    Singh J, Whelan K (2011) Limited availability and higher cost of gluten-free foods. J Hum Nutr Diet 24(5):479–486PubMedCrossRefGoogle Scholar
  84. 84.
    Hall NJ, Rubin G, Charnock A (2009) Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment Pharmacol Ther 30(4):315–330PubMedCrossRefGoogle Scholar
  85. 85.
    Bardella MT, Velio P, Cesana BM, Prampolini L, Casella G, Di Bella C, Lanzini A, Gambarotti M, Bassotti G, Villanacci V (2007) Coeliac disease: a histological follow-up study. Histopathology 50(4):465–471PubMedCrossRefGoogle Scholar
  86. 86.
    Kaukinen K, Peraaho M, Lindfors K, Partanen J, Woolley N, Pikkarainen P, Karvonen AL, Laasanen T, Sievanen H, Maki M, Collin P (2007) Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease. Aliment Pharmacol Ther 25(10):1237–1245PubMedCrossRefGoogle Scholar
  87. 87.
    Vahedi K, Mascart F, Mary JY, Laberenne JE, Bouhnik Y, Morin MC, Ocmant A, Velly C, Colombel JF, Matuchansky C (2003) Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol 98(5):1079–1087PubMedCrossRefGoogle Scholar
  88. 88.
    Nachman F, Sugai E, Vazquez H, Gonzalez A, Andrenacci P, Niveloni S, Mazure R, Smecuol E, Moreno ML, Hwang HJ, Sanchez MI, Maurino E, Bai JC (2011) Serological tests for celiac disease as indicators of long-term compliance with the gluten-free diet. Eur J Gastroenterol Hepatol 23(6):473–480PubMedGoogle Scholar
  89. 89.
    Gray AM, Papanicolas IN (2010) Impact of symptoms on quality of life before and after diagnosis of coeliac disease: results from a UK population survey. BMC Health Serv Res 10:105PubMedCrossRefGoogle Scholar
  90. 90.
    Hauser W, Gold J, Stein J, Caspary WF, Stallmach A (2006) Health-related quality of life in adult coeliac disease in Germany: results of a national survey. Eur J Gastroenterol Hepatol 18(7):747–754PubMedCrossRefGoogle Scholar
  91. 91.
    Midhagen G, Hallert C (2003) High rate of gastrointestinal symptoms in celiac patients living on a gluten-free diet: controlled study. Am J Gastroenterol 98(9):2023–2026PubMedCrossRefGoogle Scholar
  92. 92.
    Garcia-Manzanares A, Lucendo AJ (2011) Nutritional and dietary aspects of celiac disease. Nutr Clin Pract 26(2):163–173PubMedCrossRefGoogle Scholar
  93. 93.
    van den Broeck HC, van Herpen TW, Schuit C, Salentijn EM, Dekking L, Bosch D, Hamer RJ, Smulders MJ, Gilissen LJ, van der Meer IM (2009) Removing celiac disease-related gluten proteins from bread wheat while retaining technological properties: a study with Chinese Spring deletion lines. BMC Plant Biol 9:41PubMedCrossRefGoogle Scholar
  94. 94.
    Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, Drijfhout JW, Jonker H, van Soest L, Smulders MJ, Bosch D, Gilissen LJ, Koning F (2005) Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology 129(3):797–806PubMedCrossRefGoogle Scholar
  95. 95.
    Mitea C, Salentijn EM, van Veelen P, Goryunova SV, van der Meer IM, van den Broeck HC, Mujico JR, Monserrat V, Gilissen LJ, Drijfhout JW, Dekking L, Koning F, Smulders MJ (2010) A universal approach to eliminate antigenic properties of alpha-gliadin peptides in celiac disease. PLoS One 5(12):e15637PubMedCrossRefGoogle Scholar
  96. 96.
    Gil-Humanes J, Piston F, Tollefsen S, Sollid LM, Barro F (2010) Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference. Proc Natl Acad Sci USA 107(39):17023–17028PubMedCrossRefGoogle Scholar
  97. 97.
    Di Cagno R, De Angelis M, Auricchio S, Greco L, Clarke C, De Vincenzi M, Giovannini C, D'Archivio M, Landolfo F, Parrilli G, Minervini F, Arendt E, Gobbetti M (2004) Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appl Environ Microbiol 70(2):1088–1096PubMedCrossRefGoogle Scholar
  98. 98.
    Di Cagno R, Barbato M, Di Camillo C, Rizzello CG, De Angelis M, Giuliani G, De Vincenzi M, Gobbetti M, Cucchiara S (2010) Gluten-free sourdough wheat baked goods appear safe for young celiac patients: a pilot study. J Pediatr Gastroenterol Nutr 51(6):777–783PubMedCrossRefGoogle Scholar
  99. 99.
    Gianfrani C, Siciliano RA, Facchiano AM, Camarca A, Mazzeo MF, Costantini S, Salvati VM, Maurano F, Mazzarella G, Iaquinto G, Bergamo P, Rossi M (2007) Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology 133(3):780–789PubMedCrossRefGoogle Scholar
  100. 100.
    Matysiak-Budnik T, Candalh C, Cellier C, Dugave C, Namane A, Vidal-Martinez T, Cerf-Bensussan N, Heyman M (2005) Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Gastroenterology 129(3):786–796PubMedCrossRefGoogle Scholar
  101. 101.
    Pyle GG, Paaso B, Anderson BE, Allen DD, Marti T, Li Q, Siegel M, Khosla C, Gray GM (2005) Effect of pretreatment of food gluten with prolyl endopeptidase on gluten-induced malabsorption in celiac sprue. Clin Gastroenterol Hepatol 3(7):687–694PubMedCrossRefGoogle Scholar
  102. 102.
    Gass J, Bethune MT, Siegel M, Spencer A, Khosla C (2007) Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology 133(2):472–480PubMedCrossRefGoogle Scholar
  103. 103.
    Ehren J, Govindarajan S, Moron B, Minshull J, Khosla C (2008) Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng Des Sel 21(12):699–707PubMedCrossRefGoogle Scholar
  104. 104.
    Siegel M, Garber ME, Spencer AG, Botwick W, Kumar P, Williams RN, Kozuka K, Shreeniwas R, Pratha V, Adelman DC (2012) Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci 57:440–450PubMedCrossRefGoogle Scholar
  105. 105.
    Tye-Din JA, Anderson RP, Ffrench RA, Brown GJ, Hodsman P, Siegel M, Botwick W, Shreeniwas R (2010) The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol 134(3):289–295PubMedCrossRefGoogle Scholar
  106. 106.
    Lähdeaho M-L, Kaukinen K, Laurila K, Marcantonio A, Adelman D, Mäki M (2011) ALV003, A novel glutenase, attenuates gluten-induced small intestinal mucosal injury in celiac disease patients: a randomised controlled phase 2A clinical trial. Accessed 21 February 2012
  107. 107.
    Tack GJ, van de Water JM, Kooy-Winkelaar EM, van Bergen J, Meijer GA, von Blomberg BM, Schreurs MW, Bruins MJ, Edens L, Mulder CJ, Koning F (2010) Can prolyl endoprotease enzyme treatment mitigate the toxic effect of gluten in coeliac patients? Gastroenterology 138(5):S-54CrossRefGoogle Scholar
  108. 108.
    Ehren J, Morón B, Martin E, Bethune MT, Gray GM, Khosla C (2009) A food-grade enzyme preparation with modest gluten detoxification properties. PLoS One 4(7):e6313PubMedCrossRefGoogle Scholar
  109. 109.
    Pinier M, Verdu EF, Nasser-Eddine M, David CS, Vezina A, Rivard N, Leroux JC (2009) Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology 136(1):288–298PubMedCrossRefGoogle Scholar
  110. 110.
    Pinier M, Fuhrmann G, Galipeau HJ, Rivard N, Murray JA, David CS, Drasarova H, Tuckova L, Leroux JC, Verdu EF (2012) The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues. Gastroenterology 142:316–25.e1-12PubMedCrossRefGoogle Scholar
  111. 111.
    Assimakopoulos SF, Papageorgiou I, Charonis A (2011) Enterocytes’ tight junctions: from molecules to diseases. World J Gastrointest Pathophysiol 2(6):123–137PubMedCrossRefGoogle Scholar
  112. 112.
    van Elburg RM, Uil JJ, Mulder CJ, Heymans HS (1993) Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut 34(3):354–357PubMedCrossRefGoogle Scholar
  113. 113.
    Schulzke JD, Bentzel CJ, Schulzke I, Riecken EO, Fromm M (1998) Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res 43(4 Pt 1):435–441PubMedCrossRefGoogle Scholar
  114. 114.
    Wolters VM, Alizadeh BZ, Weijerman ME, Zhernakova A, van Hoogstraten IM, Mearin ML, Wapenaar MC, Wijmenga C, Schreurs MW (2010) Intestinal barrier gene variants may not explain the increased levels of antigliadin antibodies, suggesting other mechanisms than altered permeability. Hum Immunol 71(4):392–396PubMedCrossRefGoogle Scholar
  115. 115.
    Fasano A, Baudry B, Pumplin DW, Wasserman SS, Tall BD, Ketley JM, Kaper JB (1991) Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci USA 88(12):5242–5246PubMedCrossRefGoogle Scholar
  116. 116.
    Wang W, Uzzau S, Goldblum SE, Fasano A (2000) Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 113(Pt 24):4435–4440PubMedGoogle Scholar
  117. 117.
    Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum SE (2000) Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 355(9214):1518–1519PubMedCrossRefGoogle Scholar
  118. 118.
    Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB (2007) 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 26(5):757–766PubMedCrossRefGoogle Scholar
  119. 119.
    Menard S, Lebreton C, Schumann M, Matysiak-Budnik T, Dugave C, Bouhnik Y, Malamut G, Cellier C, Allez M, Crenn P, Schulzke JD, Cerf-Bensussan N, Heyman M (2012) Paracellular versus transcellular intestinal permeability to gliadin peptides in active celiac disease. Am J Pathol 180(2):608–615PubMedCrossRefGoogle Scholar
  120. 120.
    Vader W, Kooy Y, Van Veelen P, De Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F (2002) The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122(7):1729–1737PubMedCrossRefGoogle Scholar
  121. 121.
    Qiao SW, Bergseng E, Molberg O, Jung G, Fleckenstein B, Sollid LM (2005) Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J Immunol 175(1):254–261PubMedGoogle Scholar
  122. 122.
    Molberg O, McAdam S, Lundin KE, Kristiansen C, Arentz-Hansen H, Kett K, Sollid LM (2001) T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol 31(5):1317–1323PubMedCrossRefGoogle Scholar
  123. 123.
    Siegel M, Khosla C (2007) Transglutaminase 2 inhibitors and their therapeutic role in disease states. Pharmacol Ther 115(2):232–245PubMedCrossRefGoogle Scholar
  124. 124.
    Jeitner TM, Delikatny EJ, Ahlqvist J, Capper H, Cooper AJ (2005) Mechanism for the inhibition of transglutaminase 2 by cystamine. Biochem Pharmacol 69(6):961–970PubMedCrossRefGoogle Scholar
  125. 125.
    De Laurenzi V, Melino G (2001) Gene disruption of tissue transglutaminase. Mol Cell Biol 21(1):148–155PubMedCrossRefGoogle Scholar
  126. 126.
    Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Rispo A, Griffin M, Issekutz T, Quaratino S, Londei M (2005) Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 129(5):1400–1413PubMedCrossRefGoogle Scholar
  127. 127.
    Sollid LM, Khosla C (2011) Novel therapies for coeliac disease. J Intern Med 269(6):604–613PubMedCrossRefGoogle Scholar
  128. 128.
    Siegel M, Strnad P, Watts RE, Choi K, Jabri B, Omary MB, Khosla C (2008) Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PLoS One 3(3):e1861PubMedCrossRefGoogle Scholar
  129. 129.
    Dafik L, Albertelli M, Stamnaes J, Sollid LM, Khosla C (2012) Activation and inhibition of transglutaminase 2 in mice. PLoS One 7(2):e30642PubMedCrossRefGoogle Scholar
  130. 130.
    Sykulev Y, Joo M, Vturina I, Tsomides TJ, Eisen HN (1996) Evidence that a single peptide–MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 4(6):565–571PubMedCrossRefGoogle Scholar
  131. 131.
    Juse U, van de Wal Y, Koning F, Sollid LM, Fleckenstein B (2010) Design of new high-affinity peptide ligands for human leukocyte antigen-DQ2 using a positional scanning peptide library. Hum Immunol 71(5):475–481PubMedCrossRefGoogle Scholar
  132. 132.
    Kapoerchan VV, Wiesner M, Hillaert U, Drijfhout JW, Overhand M, Alard P, van der Marel GA, Overkleeft HS, Koning F (2010) Design, synthesis and evaluation of high-affinity binders for the celiac disease associated HLA-DQ2 molecule. Mol Immunol 47(5):1091–1097PubMedCrossRefGoogle Scholar
  133. 133.
    Stepniak D, Wiesner M, de Ru AH, Moustakas AK, Drijfhout JW, Papadopoulos GK, van Veelen PA, Koning F (2008) Large-scale characterization of natural ligands explains the unique gluten-binding properties of HLA-DQ2. J Immunol 180(5):3268–3278PubMedGoogle Scholar
  134. 134.
    Juse U, Arntzen M, Hojrup P, Fleckenstein B, Sollid LM (2011) Assessing high affinity binding to HLA-DQ2.5 by a novel peptide library based approach. Bioorg Med Chem 19(7):2470–2477PubMedCrossRefGoogle Scholar
  135. 135.
    Huan J, Meza-Romero R, Mooney JL, Vandenbark AA, Offner H, Burrows GG (2011) Single-chain recombinant HLA-DQ2.5/peptide molecules block alpha2-gliadin-specific pathogenic CD4+ T-cell proliferation and attenuate production of inflammatory cytokines: a potential therapy for celiac disease. Mucosal Immunol 4(1):112–120PubMedCrossRefGoogle Scholar
  136. 136.
    Beaurepaire C, Smyth D, McKay DM (2009) Interferon-gamma regulation of intestinal epithelial permeability. J Interferon Cytokine Res 29(3):133–144PubMedCrossRefGoogle Scholar
  137. 137.
    Reinisch W, de Villiers W, Bene L, Simon L, Racz I, Katz S, Altorjay I, Feagan B, Riff D, Bernstein CN, Hommes D, Rutgeerts P, Cortot A, Gaspari M, Cheng M, Pearce T, Sands BE (2010) Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 16(2):233–242PubMedGoogle Scholar
  138. 138.
    Utech M, Ivanov AI, Samarin SN, Bruewer M, Turner JR, Mrsny RJ, Parkos CA, Nusrat A (2005) Mechanism of IFN-gamma-induced endocytosis of tight junction proteins: myosin II-dependent vacuolarization of the apical plasma membrane. Mol Biol Cell 16(10):5040–5052PubMedCrossRefGoogle Scholar
  139. 139.
    Hahmann C, Schroeter T (2010) Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity. Cell Mol Life Sci 67(2):171–177PubMedCrossRefGoogle Scholar
  140. 140.
    Ciccocioppo R, Di Sabatino A, Bauer M, Della Riccia DN, Bizzini F, Biagi F, Cifone MG, Corazza GR, Schuppan D (2005) Matrix metalloproteinase pattern in celiac duodenal mucosa. Lab Invest 85(3):397–407PubMedCrossRefGoogle Scholar
  141. 141.
    Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT (1997) A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 158(4):1582–1590PubMedGoogle Scholar
  142. 142.
    Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE (2004) Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group Trial E2196. J Clin Oncol 22(23):4683–4690PubMedCrossRefGoogle Scholar
  143. 143.
    Gege C, Bao B, Bluhm H, Boer J, Gallagher BM, Korniski B, Powers TS, Steeneck C, Taveras AG, Baragi VM (2012) Discovery and evaluation of a non-Zn chelating, selective matrix metalloproteinase 13 (MMP-13) inhibitor for potential intra-articular treatment of osteoarthritis. J Med Chem 55:709–716PubMedCrossRefGoogle Scholar
  144. 144.
    Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI, Ebert EC, Vierra MA, Goodman SB, Genovese MC, Wardlaw AJ, Greenberg HB, Parker CM, Butcher EC, Andrew DP, Agace WW (2000) Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J Exp Med 192(5):761–768PubMedCrossRefGoogle Scholar
  145. 145.
    Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G, Agace WW (2002) CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. J Clin Invest 110(8):1113–1121PubMedGoogle Scholar
  146. 146.
    Rivera-Nieves J, Ho J, Bamias G, Ivashkina N, Ley K, Oppermann M, Cominelli F (2006) Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis. Gastroenterology 131(5):1518–1529PubMedCrossRefGoogle Scholar
  147. 147.
    Walters MJ, Wang Y, Lai N, Baumgart T, Zhao BN, Dairaghi DJ, Bekker P, Ertl LS, Penfold ME, Jaen JC, Keshav S, Wendt E, Pennell A, Ungashe S, Wei Z, Wright JJ, Schall TJ (2010) Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. J Pharmacol Exp Ther 335(1):61–69PubMedCrossRefGoogle Scholar
  148. 148.
    Davenport RJ, Munday JR (2007) Alpha4-integrin antagonism—an effective approach for the treatment of inflammatory diseases? Drug Discov Today 12(13–14):569–576PubMedCrossRefGoogle Scholar
  149. 149.
    Guagnozzi D, Caprilli R (2008) Natalizumab in the treatment of Crohn's disease. Biologics 2(2):275–284PubMedGoogle Scholar
  150. 150.
    Thomas S, Baumgart DC (2012) Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis. Inflammopharmacology 20:1–18PubMedCrossRefGoogle Scholar
  151. 151.
    Parikh A, Leach T, Wyant T, Scholz C, Sankoh S, Mould DR, Ponich T, Fox I, Feagan BG (2011) Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis. doi:10.1002/ibd.21896
  152. 152.
    Larche M, Wraith DC (2005) Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat Med 11(4 Suppl):S69–76PubMedCrossRefGoogle Scholar
  153. 153.
    Brown GJ, Daveson J, Marjason JK, Ffrench RA, Smith D, Sullivan M, Tye-Din JA, Anderson RP (2011) A phase I study to determine safety, tolerability and bioactivity of nexvax2® in HLA DQ2+ volunteers with celiac disease following a long-term, strict gluten-free diet. Gastroenterology 140 Supplement 1 (5):S-437–438Google Scholar
  154. 154.
    Tollefsen S, Arentz-Hansen H, Fleckenstein B, Molberg O, Raki M, Kwok WW, Jung G, Lundin KE, Sollid LM (2006) HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest 116(8):2226–2236PubMedCrossRefGoogle Scholar
  155. 155.
    Huibregtse IL, Snoeck V, de Creus A, Braat H, De Jong EC, Van Deventer SJ, Rottiers P (2007) Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology 133(2):517–528PubMedCrossRefGoogle Scholar
  156. 156.
    Huibregtse IL, Marietta EV, Rashtak S, Koning F, Rottiers P, David CS, van Deventer SJ, Murray JA (2009) Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice. J Immunol 183(4):2390–2396PubMedCrossRefGoogle Scholar
  157. 157.
    Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346(22):1692–1698PubMedCrossRefGoogle Scholar
  158. 158.
    Utset TO, Auger JA, Peace D, Zivin RA, Xu D, Jolliffe L, Alegre ML, Bluestone JA, Clark MR (2002) Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J Rheumatol 29(9):1907–1913PubMedGoogle Scholar
  159. 159.
    Abraham M, Karni A, Dembinsky A, Miller A, Gandhi R, Anderson D, Weiner HL (2008) In vitro induction of regulatory T cells by anti-CD3 antibody in humans. J Autoimmun 30(1–2):21–28PubMedCrossRefGoogle Scholar
  160. 160.
    da Cunha AP, Weiner HL (2012) Induction of immunological tolerance by oral anti-CD3. Clin Dev Immunol 2012:425021PubMedGoogle Scholar
  161. 161.
    Ilan Y, Zigmond E, Lalazar G, Dembinsky A, Ben Ya'acov A, Hemed N, Kasis I, Axelrod E, Zolotarov L, Klein A, El Haj M, Gandhi R, Baecher-Allan C, Wu H, Murugaiyan G, Kivisakk P, Farez MF, Quintana FJ, Khoury SJ, Weiner HL (2010) Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells. J Clin Immunol 30(1):167–177PubMedCrossRefGoogle Scholar
  162. 162.
    Okada H, Kuhn C, Feillet H, Bach JF (2010) The 'hygiene hypothesis' for autoimmune and allergic diseases: an update. Clin Exp Immunol 160(1):1–9PubMedCrossRefGoogle Scholar
  163. 163.
    Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, Bresolin N, Sironi M (2009) Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 206(6):1395–1408PubMedCrossRefGoogle Scholar
  164. 164.
    Tjellstrom B, Stenhammar L, Hogberg L, Falth-Magnusson K, Magnusson KE, Midtvedt T, Sundqvist T, Norin E (2005) Gut microflora associated characteristics in children with celiac disease. Am J Gastroenterol 100(12):2784–2788PubMedCrossRefGoogle Scholar
  165. 165.
    Schippa S, Iebba V, Barbato M, Di Nardo G, Totino V, Checchi MP, Longhi C, Maiella G, Cucchiara S, Conte MP (2010) A distinctive 'microbial signature' in celiac pediatric patients. BMC Microbiol 10:175PubMedCrossRefGoogle Scholar
  166. 166.
    Lindfors K, Blomqvist T, Juuti-Uusitalo K, Stenman S, Venalainen J, Maki M, Kaukinen K (2008) Live probiotic Bifidobacterium lactis bacteria inhibit the toxic effects induced by wheat gliadin in epithelial cell culture. Clin Exp Immunol 152(3):552–558PubMedCrossRefGoogle Scholar
  167. 167.
    D'Arienzo R, Maurano F, Luongo D, Mazzarella G, Stefanile R, Troncone R, Auricchio S, Ricca E, David C, Rossi M (2008) Adjuvant effect of Lactobacillus casei in a mouse model of gluten sensitivity. Immunol Lett 119(1–2):78–83PubMedCrossRefGoogle Scholar
  168. 168.
    D'Arienzo R, Maurano F, Lavermicocca P, Ricca E, Rossi M (2009) Modulation of the immune response by probiotic strains in a mouse model of gluten sensitivity. Cytokine 48(3):254–259PubMedCrossRefGoogle Scholar
  169. 169.
    Elliott DE, Weinstock JV (2012) Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci 1247:83–96PubMedCrossRefGoogle Scholar
  170. 170.
    Daveson AJ, Jones DM, Gaze S, McSorley H, Clouston A, Pascoe A, Cooke S, Speare R, Macdonald GA, Anderson R, McCarthy JS, Loukas A, Croese J (2011) Effect of hookworm infection on wheat challenge in celiac disease—a randomised double-blinded placebo controlled trial. PLoS One 6(3):e17366PubMedCrossRefGoogle Scholar
  171. 171.
    Brar P, Lee S, Lewis S, Egbuna I, Bhagat G, Green PH (2007) Budesonide in the treatment of refractory celiac disease. Am J Gastroenterol 102(10):2265–2269PubMedCrossRefGoogle Scholar
  172. 172.
    Cino M, Greenberg GR (2002) Bone mineral density in Crohn's disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy. Am J Gastroenterol 97(4):915–921PubMedCrossRefGoogle Scholar
  173. 173.
    Jamma S, Leffler DA, Dennis M, Najarian RM, Schuppan DB, Sheth S, Kelly CP (2011) Small intestinal release mesalamine for the treatment of refractory celiac disease type I. J Clin Gastroenterol 45(1):30–33PubMedCrossRefGoogle Scholar
  174. 174.
    Tack GJ, Verbeek WH, Al-Toma A, Kuik DJ, Schreurs MW, Visser O, Mulder CJ (2011) Evaluation of Cladribine treatment in refractory celiac disease type II. World J Gastroenterol 17(4):506–513PubMedCrossRefGoogle Scholar
  175. 175.
    Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B (2010) IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 120(6):2131–2143PubMedCrossRefGoogle Scholar
  176. 176.
    Yokoyama S, Watanabe N, Sato N, Perera PY, Filkoski L, Tanaka T, Miyasaka M, Waldmann TA, Hiroi T, Perera LP (2009) Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes. Proc Natl Acad Sci USA 106(37):15849–15854PubMedCrossRefGoogle Scholar
  177. 177.
    Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, Petersen LJ, Beurskens FJ, Schuurman J, van de Winkel JG, Parren PW, Gracie JA, Jongbloed S, Liew FY, McInnes IB (2005) Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum 52(9):2686–2692PubMedCrossRefGoogle Scholar
  178. 178.
    Morris JC, Janik JE, White JD, Fleisher TA, Brown M, Tsudo M, Goldman CK, Bryant B, Petrus M, Top L, Lee CC, Gao W, Waldmann TA (2006) Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia. Proc Natl Acad Sci USA 103(2):401–406PubMedCrossRefGoogle Scholar
  179. 179.
    Kjellev S, Haase C, Lundsgaard D, Urso B, Tornehave D, Markholst H (2007) Inhibition of NKG2D receptor function by antibody therapy attenuates transfer-induced colitis in SCID mice. Eur J Immunol 37(5):1397–1406PubMedCrossRefGoogle Scholar
  180. 180.
    Kline RM, Neudorf SM, Baron HI (2007) Correction of celiac disease after allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia. Pediatrics 120(4):e1120–1122PubMedCrossRefGoogle Scholar
  181. 181.
    Hoekstra JH, Groot-Loonen JJ, van der Weij A, Hoogerbrugge PM, Kooy Y, Koning F (2010) Successful treatment of coeliac disease by allogeneic haematopoietic stem cell transplantation. J Pediatr Gastroenterol Nutr 51(6):793–794PubMedCrossRefGoogle Scholar
  182. 182.
    Bargetzi MJ, Schonenberger A, Tichelli A, Fried R, Cathomas G, Signer E, Speck B, Gratwohl A (1997) Celiac disease transmitted by allogeneic non-T cell-depleted bone marrow transplantation. Bone Marrow Transplant 20(7):607–609PubMedCrossRefGoogle Scholar
  183. 183.
    Al-Toma A, Verbeek WH, Visser OJ, Kuijpers KC, Oudejans JJ, Kluin-Nelemans HC, Mulder CJ, Huijgens PC (2007) Disappointing outcome of autologous stem cell transplantation for enteropathy-associated T-cell lymphoma. Dig Liver Dis 39(7):634–641PubMedCrossRefGoogle Scholar
  184. 184.
    Zhao J, de Vera J, Narushima S, Beck EX, Palencia S, Shinkawa P, Kim KA, Liu Y, Levy MD, Berg DJ, Abo A, Funk WD (2007) R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 132(4):1331–1343PubMedCrossRefGoogle Scholar
  185. 185.
    Gee S (1888) On the coeliac affliction. St Bartholomew's Hospital Reports 24:17–20Google Scholar
  186. 186.
    Lo W, Sano K, Lebwohl B, Diamond B, Green PH (2003) Changing presentation of adult celiac disease. Dig Dis Sci 48(2):395–398PubMedCrossRefGoogle Scholar
  187. 187.
    Rao AS, Camilleri M, Eckert DJ, Busciglio I, Burton DD, Ryks M, Wong BS, Lamsam J, Singh R, Zinsmeister AR (2011) Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome–diarrhea and controls. Am J Physiol Gastrointest Liver Physiol 301(5):G919–928PubMedCrossRefGoogle Scholar
  188. 188.
    Rondonotti E, Spada C, Cave D, Pennazio M, Riccioni ME, De Vitis I, Schneider D, Sprujevnik T, Villa F, Langelier J, Arrigoni A, Costamagna G, de Franchis R (2007) Video capsule enteroscopy in the diagnosis of celiac disease: a multicenter study. Am J Gastroenterol 102(8):1624–1631PubMedCrossRefGoogle Scholar
  189. 189.
    Collin P, Rondonotti E, Lundin KE, Spada C, Keuchel M, Kaukinen K, De Franchis R, Jacobs MA, Villa F, Mulder CJ (2012) Video capsule endoscopy in celiac disease: current clinical practice. J Dig Dis 13(2):94–99PubMedCrossRefGoogle Scholar
  190. 190.
    Ch'ng CL, Jones MK, Kingham JG (2007) Celiac disease and autoimmune thyroid disease. Clin Med Res 5(3):184–192PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Christopher S. McAllister
    • 1
  • Martin F. Kagnoff
    • 1
  1. 1.Department of MedicineUniversity of CaliforniaLa JollaUSA

Personalised recommendations