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14 T CELL RESPONSES TO GLUTEN PEPTIDES non-deamidated gluten were also observed. These results indicate that a large proportion of the gluten specific responses are directed to deamidated gluten but that responses to non-deamidated gluten are also common. Extensive testing of the T cell clones against the 3 known HLA-DQ2 restricted T cell stimulatory gliadin derived peptides indicated that the large majority of the T cell clones did not respond to these peptides, and were thus likely reactive towards yet unidentified gluten peptides. To characterize these novel peptides we have used two different methods. First, we purified and characterized T cell stimulatory gluten epitopes from pepsin/trypsin digests of (tTG-) gluten by rpHPLC and mass 1-2 spectrometry as described . This method led to the characterization of 3 novel T cell stimulatory peptides. Second, we tested the T cell clones against a set of 250 synthetic gluten peptides, representing gliadin and glutenin sequences. This method led to the identification of 3 additional novel T cell stimulatory peptides. Subsequently we tested the response of the T cell clones to the identified peptides in deamidated and non-deamidated form. The T cell response towards 3 peptides required prior deamidation. In contrast, the response to 2 peptides was found to be largely indifferent to deamidation. Finally, deamidation abolished the response to the sixth peptide. Thus, the effect of deamidation by tTG on gluten specific T cell stimulation is heterogeneous and can be positive, neutral and negative. Subsequently the gluten specific T cell clones of all patients were tested against the 3-5 previously characterized HLA-DQ2 restricted gluten peptides as well as against the peptides reported in the present study. While responses to some peptides were found in one patient only, responses to other peptides were found in various patients and these may thus represent more immunodominant peptides. T cell responses towards the a- gliadin peptides which have been reported to be immunodominant in adult patients were found in three paediatric patients, among whom the identical twins. In these 9 patients we observed 8 distinct reactivity patterns towards the gluten peptides (Table). Altogether, these results indicate a highly diverse response against the gluten peptides. These results indicate a discrepancy between the specificity of adult and paediatric gluten specific T cell responses. While immunodominant responses to a particular a- gliadin peptide are found in adult patients, the response in paediatric patients appears more diverse. Our results also indicate that T cell responses to peptides other than the immunodominant a-gliadin peptide can lead to disease. Moreover, our results demonstrate that responses to non-deamidated peptides are frequently found, suggesting that native gluten peptides are immunogenic in celiac disease patients. The discrepancy between the specificity of the adult and paediatric gluten specific T cell response could be explained by a deamidation driven narrowing of the gluten response towards immunodominant T cell stimulatory peptides after initiation of disease by responses towards a diverse repertoire of gluten peptides. Acknowledgements This study was financially supported by the European Community project no. BMH CT-98, a grant from the Dutch Digestive Disease Foundation and the University of Leiden.
T CELL RESPONSES TO GLUTEN PEPTIDES 15 DB JB NB SB JP NP MS NV SV Glia- Glia- Glia- Glia- 2a 20a 9a 1g Glia- 30g Glt- 17 Glt- 156 Glu- 5 Glu- 21 Table. Overview of paediatric T cell responses to gluten peptides. References 1. Van de Wal Y, Kooy YM, Van Veelen PA, Pena AS, Mearin LM, Molberg O, 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: 10050-4. 2. Van de Wal Y. Kooy YM, Van Veelen P, Vader W, August SA, Drijfhout JW, et al. Glutenin is involved in the gluten-driven mucosal T cell response. Eur J Immunol 1999; 29: 3133- 9. 3. Sjostrom H, Lundin KE, Molberg O, Korner R, McAdam SN, Anthonsen D, 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: 111-5. 4. Arentz-Hansen H, Korner R, Molberg O, Quarsten H, Vader W, Kooy YM, 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: 603-12. 5. Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV. 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: 337-42. 6. Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998; 4: 713-7. 7. Van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998; 161: 1585-8. 8. Quarsten H, Molberg O, Fugger L, McAdam SN, Sollid LM. HLA binding and T cell recognition of a tissue transglutaminase - modified gliadin epitope. Eur J Immunol 1999; 29: 2506-14. 9. Van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning F. Peptide binding characteristics of the coeliac disease-associated DQ(alpha1*0501, beta1*0201) molecule. Immunogenetics 1996; 44: 246-53. 10. Vartdal F, Johansen B.H., Friede T, Thorpe CJ, Stevanovic S, Eriksen JE, et al. The peptide binding motif of the disease associated HLA-DQ (alpha 1* 0501, beta 1* 0201) molecule. Eur J Immunol 1996; 26: 2764-72. 11. Kwok WW. Domeier ML, Raymond FC, Byers P, Nepom GT. Allele-specific motifs characterize HLA-DQ interactions with a diabetes - associated peptide derived from glutamic acid decarboxylase. J Immunol. 1996; 156: 2171-7.
Page 1: Perspectives on Coeliac Disease Vol
Page 4: The AIC Meeting was held in the Aul
Page 8 and 9: Italian Coeliac Society, Via Picott
Page 11 and 12: Preface Coeliac disease (CD) is a u
Page 13: Contents Current understanding of t
Page 16 and 17: 2 THE BASIS OF COELIAC DISEASE hapl
Page 18 and 19: 4 THE BASIS OF COELIAC DISEASE 1 pr
Page 20 and 21: 6 THE BASIS OF COELIAC DISEASE spre
Page 22 and 23: 8 THE BASIS OF COELIAC DISEASE Ackn
Page 24 and 25: 10 THE BASIS OF COELIAC DISEASE glu
Page 27: Catassi C, Fasano A, Corazza GR (ed
Page 32 and 33: 18 A DOMINANT EPITOPE IN GLUTEN PEP
Page 42 and 43: 28 ROLE OF A-GLIADIN 31-49 PEPTIDE
Page 45 and 46: Catassi C, Fasano A, Corazza GR (ed
Page 47 and 48: COELIAC DISEASE IN THE SAHARAWI 33
Page 55: COELIAC DISEASE IN THE SAHARAWI 41
Page 58 and 59: 44 INFANT FEEDING PRACTICES AND COE
Page 66 and 67: Age (years) 52 INFANT FEEDING PRACT
Page 76 and 77: 62 MECHANISMS OF ORAL TOLERANCE the
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64 MECHANISMS OF ORAL TOLERANCE pot
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66 MECHANISMS OF ORAL TOLERANCE Epi
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68 MECHANISMS OF ORAL TOLERANCE typ
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70 MECHANISMS OF ORAL TOLERANCE 51
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72 MECHANISMS OF ORAL TOLERANCE 23.
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Catassi C, Fasano A, Corazza GR (ed
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GENETICALLY DETOXIFIED GRAINS 77 to
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• • GENETICALLY DETOXIFIED GRAI
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GENETICALLY DETOXIFIED GRAINS 81 3.
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IMMUNOTHERAPY OF COELIAC DISEASE 85
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IMMUNOTHERAPY OF COELIAC DISEASE 87
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RECENT ADVANCES ON GLUTEN TOXICITY
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Index A Antiendomysium antibodies (
Page 109:
INDEX 95 W Wheat, 7, 23, 27, 31, 53
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