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In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope

Nature Medicinevolume 6pages337342 (2000) | Download Citation



Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200–1:300)1 that is induced by dietary exposure to wheat gliadins2 (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (α1*0501, β1*0201), which is present in over 90% of CD patients3. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones4,5,6 and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge7,8,9, it has been unclear whether a ‘dominant’ T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57–73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses10, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56–75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.

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  1. 1

    Hin, H., Bird, G., Fisher, P., Mahy, N. & Jewell, D. Coeliac disease in primary care: case finding study. Br. Med. J. 318, 164–167 (1999).

  2. 2

    Kendall, M., Schneider, R., Cox, P. & Hawkins, C. Gluten subfractionation in coeliac disease. Lancet 2, 1065–1067 (1972).

  3. 3

    Sollid, L.M., Thorsby, E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterol. 105, 910–922 (1993).

  4. 4

    Molberg, O. 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. 46, 103–109 (1997).

  5. 5

    van der Wal, Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J. Immunol. 161, 1585–1588 (1998).

  6. 6

    Sjostrom, H. 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. 48, 111–115 (1998).

  7. 7

    Mantzaris, G. & Jewell, D. In vivo toxicity of a synthetic dodecapeptide from A gliadin in patients with coeliac disease. Scand. J. Gastroenterol. 26, 392–398 (1991).

  8. 8

    de Ritis, G. et al. In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in celiac disease. Gastroenterology 94, 41–49 (1988).

  9. 9

    Mauri, L. et al. In vitro activities of A-gliadin-related synthetic peptides. Scand. J. Gastroenterol. 31, 247–253 (1996).

  10. 10

    Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Med. 4, 713–717 (1998).

  11. 11

    Kasarda, D. et al. Nucleic acid (cDNA) and amino acid sequence of α-type gliadins from wheat (Tricetum aestivum). Proc. Natl. Acad. Sci. USA 81, 4712–4716 (1984).

  12. 12

    Gutgemann, I., Fahrer, A., Altman, J., Davis, M. & Chien, Y-h. Induction of rapid T cell activation and tolerance by systemic presentation of orally administered antigen. Immunity 8, 667–673 (1998).

  13. 13

    Greenbergm, C.S., Birckbichlerm, P. & Ricem, R. Transglutaminases: multifunctional cross-linking enzymes that stablize tissues. FASEB J. 5, 3071–3077 (1991).

  14. 14

    Lehmann, P.V., Forsthuber, T., Miller, A. & Serzarz, E.E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 359, 155–157 (1992).

  15. 15

    Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).

  16. 16

    Lahat, N. et al. Cytokine profile in coeliac disease. Scand. J. Immunol. 49, 441–446 (1999).

  17. 17

    Vartdal, F. et al. The binding motif of the disease associated HLA-DQ (α1*0501, β1*0201) molecule. Eur. J. Immunol. 26, 2764–2772 (1996).

  18. 18

    Ward, R. Codex alimentarius- the proposed gluten-free standard (position paper) (The Coeliac Society of the United Kingdom, High Wycombe, UK, 1999).

  19. 19

    Bunce, M. et al. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 46, 355–367 (1995).

  20. 20

    Olerup, O., Aldener, A. & Fogdell, A. HLA-DQB1 and DQA1 typing by PCR amplification with sequence-specific primers in 2 hours. Tissue Antigens 41, 119–134 (1993).

  21. 21

    Mullighan, C.G., Bunce, M. & Welsh, K.I. High-resolution HLA-DQB1 typing using the polymerase chain reaction and sequence-specific primers. Tissue Antigens. 50, 688–692 (1997).

  22. 22

    Plebanski, M. et al. Protection from Plasmodium berghei infection by priming and boosting T cells to a single class I restricted epitope with recombinant carriers suitable for human use. Eur. J. Immunol. 28, 4345–4355 (1998).

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We thank A. Willis for HPLC and amino-acid analysis; G. Bird and H. Griffith for assays of antibody against endomysium; M. Bunce for tissue typing; A. Pathan and A. Lalvani for the gift of antibodies against class II; A. Connell for dietary advice; and J. Simmons and A. Ellis for referring subjects for the study. R.P.A. was supported by a CJ Martin/Menzies Fellowship from the National Health and Medical Research Council of Australia 987001. A.V.S.H. is a Wellcome Trust Principal Research Fellow. The work was supported by the Coeliac Society of the United Kingdom and Isis Innovation (University of Oxford, UK).

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  1. Nuffield Department of Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK

    • Robert P. Anderson
    • , Pilar Degano
    • , Andrew J. Godkin
    •  & Adrian V.S. Hill
  2. Nuffield Department of Medicine, Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK

    • Robert P. Anderson
    •  & Derek P. Jewell


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Correspondence to Robert P. Anderson.

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