Advertisement

Immunogenetics

, Volume 69, Issue 8–9, pp 605–616 | Cite as

The roles of MHC class II genes and post-translational modification in celiac disease

  • Ludvig M. SollidEmail author
Review
Part of the following topical collections:
  1. Topical Collection on MHC/KIR in Health and Disease

Abstract

Our increasing understanding of the etiology of celiac disease, previously considered a simple food hypersensitivity disorder caused by an immune response to cereal gluten proteins, challenges established concepts of autoimmunity. HLA is a chief genetic determinant, and certain HLA-DQ allotypes predispose to the disease by presenting posttranslationally modified (deamidated) gluten peptides to CD4+ T cells. The deamidation of gluten peptides is mediated by transglutaminase 2. Strikingly, celiac disease patients generate highly disease-specific autoantibodies to the transglutaminase 2 enzyme. The dual role of transglutaminase 2 in celiac disease is hardly coincidental. This paper reviews the genetic mapping and involvement of MHC class II genes in disease pathogenesis, and discusses the evidence that MHC class II genes, via the involvement of transglutaminase 2, influence the generation of celiac disease-specific autoantibodies.

Keywords

MHC class II Post-translational Celiac disease 

Notes

Acknowledgements

The work in the author’s laboratory was supported by grants from the Research Council of Norway through its Centers of Excellence funding scheme (project number 179573/V40); by grants from the South-Eastern Norway Regional Health Authority; by the European Commission (grant ERC-2010-Ad-268541); and by Stiftelsen KG Jebsen. The author thanks former and present members of his laboratory as well as collaborators for invaluable contributions to the research. He also thanks numerous celiac disease patients for their donation of biological samples, thus making critical experiments possible.

References

  1. 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 6:337–342CrossRefPubMedGoogle Scholar
  2. Anderson RP, van Heel DA, Tye-Din JA, Barnardo M, Salio M, Jewell DP, Hill AV (2005) T cells in peripheral blood after gluten challenge in coeliac disease. Gut 54:1217–1223CrossRefPubMedPubMedCentralGoogle Scholar
  3. Araya M, Mondragon A, Perez-Bravo F, Roessler JL, Alarcon T, Rios G, Bergenfreid C (2000) Celiac disease in a Chilean population carrying Amerindian traits. J Pediatr Gastroenterol Nutr 31:381–386CrossRefPubMedGoogle Scholar
  4. Arentz-Hansen H, Körner R, Molberg Ø, Quarsten H, Vader W, Kooy YM, Lundin KEA, Koning F, Roepstorff P, Sollid LM, McAdam SN (2000) The intestinal T cell response to α-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 191:603–612CrossRefPubMedPubMedCentralGoogle Scholar
  5. Arentz-Hansen H, McAdam SN, Molberg Ø, Fleckenstein B, Lundin KE, Jorgensen TJ, Jung G, Roepstorff P, Sollid LM (2002) Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 123:803–809CrossRefPubMedGoogle Scholar
  6. Ballew JT, Murray JA, Collin P, Maki M, Kagnoff MF, Kaukinen K, Daugherty PS (2013) Antibody biomarker discovery through in vitro directed evolution of consensus recognition epitopes. Proc Natl Acad Sci U S A 110:19330–19335CrossRefPubMedPubMedCentralGoogle Scholar
  7. van Belzen MJ, Koeleman BP, Crusius JB, Meijer JW, Bardoel AF, Pearson PL, Sandkuijl LA, Houwen RH, Wijmenga C (2004) Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients. Genes Immun 5:215–220CrossRefPubMedGoogle Scholar
  8. Berg LJ, Frank GD, Davis MM (1990) The effects of MHC gene dosage and allelic variation on T cell receptor selection. Cell 60:1043–1053CrossRefPubMedGoogle Scholar
  9. Bergseng E, Dørum S, Arntzen MO, Nielsen M, Nygard S, Buus S, de Souza GA, Sollid LM (2015) Different binding motifs of the celiac disease-associated HLA molecules DQ2.5, DQ2.2, and DQ7.5 revealed by relative quantitative proteomics of endogenous peptide repertoires. Immunogenetics 67:73–84CrossRefPubMedGoogle Scholar
  10. Betuel H, Gebuhrer L, Descos L, Percebois H, Minaire Y, Bertrand J (1980) Adult celiac disease associated with HLA-DRw3 and -DRw7. Tissue Antigens 15:231–238CrossRefPubMedGoogle Scholar
  11. Bodd M, Ráki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KE, Sollid LM (2010) HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol 3:594–601CrossRefPubMedGoogle Scholar
  12. Bodd M, Kim CY, Lundin KE, Sollid LM (2012) T-cell response to gluten in patients with HLA-DQ2.2 reveals requirement of peptide-MHC stability in celiac disease. Gastroenterology 142:552–561CrossRefPubMedGoogle Scholar
  13. Bolognesi E, Karell K, Percopo S, Coto I, Greco L, Mantovani V, Suoraniemi E, Partanen J, Mustalahti K, Maki M, Momigliano-Richiardi P (2003) Additional factor in some HLA DR3/DQ2 haplotypes confers a fourfold increased genetic risk of celiac disease. Tissue Antigens 61:308–316CrossRefPubMedGoogle Scholar
  14. Broughton SE, Petersen J, Theodossis A, Scally SW, Loh KL, Thompson A, van Bergen J, Kooy-Winkelaar Y, Henderson KN, Beddoe T, Tye-Din JA, Mannering SI, Purcell AW, McCluskey J, Anderson RP, Koning F, Reid HH, Rossjohn J (2012) Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. Immunity 37:611–621CrossRefPubMedGoogle Scholar
  15. Christophersen A, Risnes LF, Bergseng E, Lundin KE, Sollid LM, Qiao SW (2016) Healthy HLA-DQ2.5+ subjects lack regulatory and memory T cells specific for immunodominant gluten epitopes of celiac disease. J Immunol 196:2819–2826CrossRefPubMedGoogle Scholar
  16. Congia M, Frau F, Lampis R, Frau R, Mele R, Cucca F, Muntoni F, Porcu S, Boi F, Contu L et al (1992) A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201. Tissue Antigens 39:78–83CrossRefPubMedGoogle Scholar
  17. Cook L, Munier CM, Seddiki N, van Bockel D, Ontiveros N, Hardy MY, Gillies JK, Levings MK, Reid HH, Peterson J, Rossjohn J, Anderson RP, Zaunders JJ, Tye-Din JA, Kelleher AD (2017) Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in celiac disease. J Allergy Clin Immunol. doi: 10.1016/j.jaci.2017.02.015
  18. DeMarchi M, Borelli I, Olivetti E, Richiardi P, Wright P, Ansaldi N, Barbera C, Santini B (1979) Two HLA-D and DR alleles are associated with coeliac disease. Tissue Antigens 14:309–316CrossRefPubMedGoogle Scholar
  19. Di Niro R, Mesin L, Zheng NY, Stamnaes J, Morrissey M, Lee JH, Huang M, Iversen R, du Pre MF, Qiao SW, Lundin KE, Wilson PC, Sollid LM (2012) High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18:441–445CrossRefPubMedPubMedCentralGoogle Scholar
  20. Dicke WK (1950) Coeliac disease. Investigations of the harmful effects of certain types of cereal on patients suffering from coeliac disease. Thesis. University of UtrechtGoogle Scholar
  21. 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 3:797–801CrossRefPubMedGoogle Scholar
  22. Dørum S, Arntzen MO, Qiao SW, Holm A, Koehler CJ, Thiede B, Sollid LM, Fleckenstein B (2010) The preferred substrates for transglutaminase 2 in a complex wheat gluten digest are peptide fragments harboring celiac disease T-cell epitopes. PLoS One 5:e14056CrossRefPubMedPubMedCentralGoogle Scholar
  23. Dørum S, Steinsbø Ø, Bergseng E, Arntzen MO, de Souza GA, Sollid LM (2016) Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes. Sci Rep 6:25565CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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 42:295–302CrossRefPubMedPubMedCentralGoogle Scholar
  25. Falchuk ZM, Rogentine GN, Strober W (1972) Predominance of histocompatibility antigen HL-A8 in patients with gluten-sensitive enteropathy. J Clin Invest 51:1602–1605CrossRefPubMedPubMedCentralGoogle Scholar
  26. Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM (2009) Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol 10:1096–1101CrossRefPubMedGoogle Scholar
  27. Fleckenstein B, Molberg Ø, Qiao SW, Schmid DG, Von Der MF, Elgstoen K, Jung G, Sollid LM (2002) 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 277:34109–34116CrossRefPubMedGoogle Scholar
  28. Fleckenstein B, Qiao SW, Larsen MR, Jung G, Roepstorff P, Sollid LM (2004) Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides. J Biol Chem 279:17607–17616CrossRefPubMedGoogle Scholar
  29. Gianfrani C, Levings MK, Sartirana C, Mazzarella G, Barba G, Zanzi D, Camarca A, Iaquinto G, Giardullo N, Auricchio S, Troncone R, Roncarolo MG (2006) Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol 177:4178–4186CrossRefPubMedGoogle Scholar
  30. Godkin A, Friede T, Davenport M, Stevanovic S, Willis A, Jewell D, Hill A, Rammensee HG (1997) Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8 (DQ 3.2). Int Immunol 9:905–911CrossRefPubMedGoogle Scholar
  31. Gutierrez-Achury HJ (2015) HLA and other tales: The different perspectives of celiac disease. Thesis. University of GroningenGoogle Scholar
  32. Gutierrez-Achury J, Zhernakova A, Pulit SL, Trynka G, Hunt KA, Romanos J, Raychaudhuri S, van Heel DA, Wijmenga C, de Bakker PI (2015) Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nat Genet 47:577–578CrossRefPubMedPubMedCentralGoogle Scholar
  33. Han A, Newell EW, Glanville J, Fernandez-Becker N, Khosla C, Chien YH, Davis MM (2013) Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease. Proc Natl Acad Sci U S A 110:13073–13078CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D, Gwilliam R, Takeuchi F, McLaren WM, Holmes GK, Howdle PD, Walters JR, Sanders DS, Playford RJ, Trynka G, Mulder CJ, Mearin ML, Verbeek WH, 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 40:395–402CrossRefPubMedPubMedCentralGoogle Scholar
  35. Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP, Diagnosis EWGoCD, Committee EG, European Society for Pediatric Gastroenterology H, Nutrition (2012) European Society for Pediatric Gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54:136–160CrossRefPubMedGoogle Scholar
  36. Iversen R, du Pré MF, Di Niro R, Sollid LM (2015) Igs as substrates for transglutaminase 2: implications for autoantibody production in celiac disease. J Immunol 195:5159–5168CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jabri B, Chen X, Sollid LM (2014) How T cells taste gluten in celiac disease. Nat Struct Mol Biol 21:429–431CrossRefPubMedGoogle Scholar
  38. Johansen BH, Jensen T, Thorpe CJ, Vartdal F, Thorsby E, Sollid LM (1996a) Both α and β chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with β chain residues being most influential. Immunogenetics 45:142–150CrossRefPubMedGoogle Scholar
  39. Johansen BH, Vartdal F, Eriksen JA, Thorsby E, Sollid LM (1996b) Identification of a putative motif for binding of peptides to HLA-DQ2. Int Immunol 8:177–182CrossRefPubMedGoogle Scholar
  40. Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM, Partanen J (2003) 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 64:469–477CrossRefPubMedGoogle Scholar
  41. Kaur G, Sarkar N, Bhatnagar S, Kumar S, Rapthap CC, Bhan MK, Mehra NK (2002) Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes. HumImmunol 63:677–682Google Scholar
  42. Keuning JJ, Pena AS, van Leeuwen A, van Hooff JP, van Rood JJ (1976) HLA-DW3 associated with coeliac disease. Lancet 1:506–508CrossRefPubMedGoogle Scholar
  43. Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM (2004) Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A 101:4175–4179CrossRefPubMedPubMedCentralGoogle Scholar
  44. Kwok WW, Domeier ML, Raymond FC, Byers P, Nepom GT (1996) Allele-specific motifs characterize HLA-DQ interactions with a diabetes-associated peptide derived from glutamic acid decarboxylase. J Immunol 156:2171–2177PubMedGoogle Scholar
  45. Louka AS, Lie BA, Talseth B, Ascher H, Ek J, Gudjonsdottir AH, Sollid LM (2003) Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles. Immunogenetics 55:339–343CrossRefPubMedGoogle Scholar
  46. Lundin KEA, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O, Thorsby E, Sollid LM (1993) Gliadin-specific, HLA-DQ(α1*0501,β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med 178:187–196CrossRefPubMedGoogle Scholar
  47. Lundin KEA, Scott H, Fausa O, Thorsby E, Sollid LM (1994) T cells from the small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac disease patient preferentially recognize gliadin when presented by DQ8. Hum Immunol 41:285–291CrossRefPubMedGoogle Scholar
  48. Mearin ML, Biemond I, Pena AS, Polanco I, Vazquez C, Schreuder GT, de Vries RR, van Rood JJ (1983) HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease. Gut 24:532–537CrossRefPubMedPubMedCentralGoogle Scholar
  49. Meeuwisse GW (1970) European society for paediatric gastroenterology meeting in Interlaken September 18, 1969. Acta Paediat Scand 59:461–463CrossRefGoogle Scholar
  50. Molberg Ø, 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 4:713–717CrossRefPubMedGoogle Scholar
  51. Nilsen EM, Lundin KEA, Krajci P, Scott H, Sollid LM, Brandtzaeg P (1995) Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 37:766–776CrossRefPubMedPubMedCentralGoogle Scholar
  52. Osman AA, Gunnel T, Dietl A, Uhlig HH, Amin M, Fleckenstein B, Richter T, Mothes T (2000) B cell epitopes of gliadin. Clin Exp Immunol 121:248–254CrossRefPubMedPubMedCentralGoogle Scholar
  53. Pantazes RJ, Reifert J, Bozekowski J, Ibsen KN, Murray JA, Daugherty PS (2016) Identification of disease-specific motifs in the antibody specificity repertoire via next-generation sequencing. Sci Rep 6:30312CrossRefPubMedPubMedCentralGoogle Scholar
  54. Petersen J, Montserrat V, Mujico JR, Loh KL, Beringer DX, van Lummel M, Thompson A, Mearin ML, Schweizer J, Kooy-Winkelaar Y, van Bergen J, Drijfhout JW, Kan WT, La Gruta NL, Anderson RP, Reid HH, Koning F, Rossjohn J (2014) T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat Struct Mol Biol 21:480–488CrossRefPubMedGoogle Scholar
  55. Petersen J, van Bergen J, Loh KL, Kooy-Winkelaar Y, Beringer DX, Thompson A, Bakker SF, Mulder CJ, Ladell K, McLaren JE, Price DA, Rossjohn J, Reid HH, Koning F (2015) Determinants of gliadin-specific T cell selection in celiac disease. J Immunol 194:6112–6122CrossRefPubMedGoogle Scholar
  56. Petersen J, Kooy-Winkelaar Y, Loh KL, Tran M, van Bergen J, Koning F, Rossjohn J, Reid HH (2016) Diverse T cell receptor gene usage in HLA-DQ8-associated celiac disease converges into a consensus binding solution. Structure 24:1643–1657CrossRefPubMedGoogle Scholar
  57. Pisapia L, Camarca A, Picascia S, Bassi V, Barba P, Del Pozzo G, Gianfrani C (2016) HLA-DQ2.5 genes associated with celiac disease risk are preferentially expressed with respect to non-predisposing HLA genes: implication for anti-gluten T cell response. J Autoimmun 70:63–72CrossRefPubMedGoogle Scholar
  58. Ploski R, Ek J, Thorsby E, Sollid LM (1993) On the HLA-DQ(α1*0501, β1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201. Tissue Antigens 41:173–177CrossRefPubMedGoogle Scholar
  59. Qiao SW, Bergseng E, Molberg Ø, 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 175:254–261CrossRefPubMedGoogle Scholar
  60. Qiao SW, Ráki M, Gunnarsen KS, Løset GA, Lundin KE, Sandlie I, Sollid LM (2011) Posttranslational modification of gluten shapes TCR usage in celiac disease. J Immunol 187:3064–3071CrossRefPubMedGoogle Scholar
  61. Qiao SW, Christophersen A, Lundin KE, Sollid LM (2014) Biased usage and preferred pairing of α- and β-chains of TCRs specific for an immunodominant gluten epitope in coeliac disease. Int Immunol 26:13–19CrossRefPubMedGoogle Scholar
  62. Ráki M, Fallang LE, Brottveit M, Bergseng E, Quarsten H, Lundin KE, Sollid LM (2007) Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc Natl Acad Sci U S A 104:2831–2836CrossRefPubMedPubMedCentralGoogle Scholar
  63. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50CrossRefPubMedGoogle Scholar
  64. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787CrossRefPubMedGoogle Scholar
  65. Shan L, Molberg Ø, Parrot I, Hausch F, Filiz F, Gray GM, Sollid LM, Khosla C (2002) Structural basis for gluten intolerance in celiac sprue. Science 297:2275–2279CrossRefPubMedGoogle Scholar
  66. Sjöström H, Lundin KEA, Molberg Ø, Körner R, McAdam SN, Anthonsen D, Quarsten H, Noren O, Roepstorff P, Thorsby E, Sollid LM (1998) Identification of a gliadin T-cell epitope in coeliac disease: general importance of gliadin deamidation for intestinal T-cell recognition. Scand J Immunol 48:111–115CrossRefPubMedGoogle Scholar
  67. Solheim BG, Albrechtsen D, Thorsby E, Thune P (1977) Strong association between an HLA-Dw3 associated B cell alloantigen and dermatitis herpetiformis. Tissue Antigens 10:114–118CrossRefPubMedGoogle Scholar
  68. Sollid LM, Jabri B (2013) Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 13:294–302CrossRefPubMedGoogle Scholar
  69. 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 α/β heterodimer. J Exp Med 169:345–350CrossRefPubMedGoogle Scholar
  70. Sollid LM, Molberg Ø, McAdam S, Lundin KEA (1997) Autoantibodies in coeliac disease: tissue transglutaminase--guilt by association? Gut 41:851–852CrossRefPubMedPubMedCentralGoogle Scholar
  71. Sollid LM, Qiao SW, Anderson RP, Gianfrani C, Koning F (2012) Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics 64:455–460CrossRefPubMedPubMedCentralGoogle Scholar
  72. Spurkland A, Sollid LM, Polanco I, Vartdal F, Thorsby E (1992) HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7. Hum Immunol 35:188–192CrossRefPubMedGoogle Scholar
  73. Stamnaes J, Iversen R, du Pre MF, Chen X, Sollid LM (2015) Enhanced B-cell receptor recognition of the autoantigen transglutaminase 2 by efficient catalytic self-multimerization. PLoS One 10:e0134922CrossRefPubMedPubMedCentralGoogle Scholar
  74. Steinsbø Ø, Henry Dunand CJ, Huang M, Mesin L, Salgado-Ferrer M, Lundin KE, Jahnsen J, Wilson PC, Sollid LM (2014) Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat Commun 5:4041CrossRefPubMedPubMedCentralGoogle Scholar
  75. Stepniak D, Vader LW, Kooy Y, van Veelen PA, Moustakas A, Papandreou NA, Eliopoulos E, Drijfhout JW, Papadopoulos GK, Koning F (2005) T-cell recognition of HLA-DQ2-bound gluten peptides can be influenced by an N-terminal proline at p-1. Immunogenetics 57:8–15CrossRefPubMedGoogle Scholar
  76. Stokes PL, Asquith P, Holmes GK, Mackintosh P, Cooke WT (1972) Histocompatibility antigens associated with adult coeliac disease. Lancet 2:162–164CrossRefGoogle Scholar
  77. Thomson G, Robinson WP, Kuhner MK, Joe S, MacDonald MJ, Gottschall JL, Barbosa J, Rich SS, Bertrams J, Baur MP et al (1988) Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 43:799–816PubMedPubMedCentralGoogle Scholar
  78. Tighe MR, Hall MA, Ashkenazi A, Siegler E, Lanchbury JS, Ciclitira PJ (1993) Celiac disease among Ashkenazi Jews from Israel. A study of the HLA class II alleles and their associations with disease susceptibility. Hum Immunol 38:270–276CrossRefPubMedGoogle Scholar
  79. Tollefsen S, Arentz-Hansen H, Fleckenstein B, Molberg Ø, Ráki 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 116:2226–2236CrossRefPubMedPubMedCentralGoogle Scholar
  80. Tosi R, Vismara D, Tanigaki N, Ferrara GB, Cicimarra F, Buffolano W, Follo D, Auricchio S (1983) Evidence that celiac disease is primarily associated with a DC locus allelic specificity. ClinImmunol Immunopathol 28:395–404CrossRefGoogle Scholar
  81. Trabace S, Giunta A, Rosso M, Marzorati D, Cascino I, Tettamanti A, Mazzilli MC, Gandini E (1984) HLA-ABC and DR antigens in celiac disease. A study in a pediatric Italian population. Vox Sang 46:102–106CrossRefPubMedGoogle Scholar
  82. 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 43:1193–1201CrossRefPubMedPubMedCentralGoogle Scholar
  83. 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 2:41ra51CrossRefPubMedGoogle Scholar
  84. Vader LW, de Ru A, van Der WY, Kooy YM, Benckhuijsen W, Mearin ML, Drijfhout JW, van Veelen P, Koning F (2002a) Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med 195:643–649CrossRefPubMedPubMedCentralGoogle Scholar
  85. Vader W, Kooy Y, van Veelen P, de Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F (2002b) The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122:1729–1737CrossRefPubMedGoogle Scholar
  86. 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 Natl Acad Sci U S A 100:12390–12395CrossRefPubMedPubMedCentralGoogle Scholar
  87. Vartdal F, Johansen BH, Friede T, Thorpe CJ, Stevanovic S, Eriksen JA, Sletten K, Thorsby E, Rammensee HG, Sollid LM (1996) The peptide binding motif of the disease associated HLA-DQ(α1*0501, β1*0201) molecule. Eur J Immunol 26:2764–2772CrossRefPubMedGoogle Scholar
  88. van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning F (1996) Peptide binding characteristics of the coeliac disease-associated DQ(α1*0501, β1*0201) molecule. Immunogenetics 44:246–253CrossRefPubMedGoogle Scholar
  89. van de Wal Y, Kooy YC, Drijfhout JW, Amons R, Papadopoulos GK, Koning F (1997) Unique peptide binding characteristics of the disease-associated DQ(α1*0501, β1*0201) vs the non-disease-associated DQ(α1*0201, β1*0202) molecule. Immunogenetics 46:484–492CrossRefPubMedGoogle Scholar
  90. van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, Koning F (1998a) Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 161:1585–1588PubMedGoogle Scholar
  91. van de Wal Y, Kooy YM, van Veelen PA, Pena SA, Mearin LM, Molberg Ø, Lundin KEA, Sollid LM, Mutis T, Benckhuijsen WE, Drijfhout JW, Koning F (1998b) Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc Natl Acad Sci U S A 95:10050–10054CrossRefPubMedPubMedCentralGoogle Scholar
  92. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi JK (1990) Revised criteria for diagnosis of coeliac disease. Arch Dis Child 65:909–911CrossRefGoogle Scholar
  93. Withoff S, Li Y, Jonkers I, Wijmenga C (2016) Understanding celiac disease by genomics. Trends Genet 32:295–308CrossRefPubMedGoogle Scholar
  94. Witt CS, Price P, Kaur G, Cheong K, Kanga U, Sayer D, Christiansen F, Mehra NK (2002) Common HLA-B8-DR3 haplotype in northern India is different from that found in Europe. Tissue Antigens 60:474–480CrossRefPubMedGoogle Scholar
  95. Xia J, Siegel M, Bergseng E, Sollid LM, Khosla C (2006) Inhibition of HLA-DQ2-mediated antigen presentation by analogues of a high affinity 33-residue peptide from α2-gliadin. J Am Chem Soc 128:1859–1867CrossRefPubMedPubMedCentralGoogle Scholar
  96. Xia J, Bergseng E, Fleckenstein B, Siegel M, Kim CY, Khosla C, Sollid LM (2007) Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorg Med Chem 15:6565–6573CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Centre for Immune Regulation, KG Jebsen Coeliac Disease Research Centre, Department of ImmunologyUniversity of Oslo and Oslo University Hospital-RikshospitaletOsloNorway

Personalised recommendations