The Intestinal T Cell Response to {alpha}-Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

doi:10.1084/jem.191.4.603

This Article

	Full Text
	Full Text (PDF, 173K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Arentz-Hansen, H.
	Articles by McAdam, S. N.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Arentz-Hansen, H.
	Articles by McAdam, S. N.


Social Bookmarking

	What's this?

© The Rockefeller University Press, 0022-1007/2000/2/603/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 4, February 21, 2000 603-612

Original Article

The Intestinal T Cell Response to ${alpha}$ -Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

Helene Arentz-Hansen^a, Roman Körner^b, Øyvind Molberg^a, Hanne Quarsten^a, Willemijn Vader^d, Yvonne M.C. Kooy^d, Knut E.A. Lundin^a,c, Frits Koning^d, Peter Roepstorff^b, Ludvig M. Sollid^a, and Stephen N. McAdam^a
^a From the Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway
^b Department of Molecular Biology, Odense University, DK-5230 Odense M, Denmark
^c Department of Gastroenterology, Ullevaal Hospital, 0407 Oslo, Norway
^d Department of Immunohaematology and Blood Bank, Leiden University Hospital, 2300 RC Leiden, The Netherlands

Correspondence to: Stephen N. McAdam, Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway. Tel:47-22-86-85-52 Fax:47-22-20-36-93 E-mail:stephenm{at}labmed.uio.no.

The great majority of patients that are intolerant of wheatgluten protein due to celiac disease (CD) are human histocompatibilityleukocyte antigen (HLA)-DQ2⁺, and the remaining few normallyexpress HLA-DQ8. These two class II molecules are chiefly responsiblefor the presentation of gluten peptides to the gluten-specificT cells that are found only in the gut of CD patients but notof controls. Interestingly, tissue transglutaminase (tTG)-mediateddeamidation of gliadin plays an important role in recognitionof this food antigen by intestinal T cells. Here we have usedrecombinant antigens to demonstrate that the intestinal T cellresponse to ${alpha}$ -gliadin in adult CD is focused on two immunodominant,DQ2-restricted peptides that overlap by a seven-residue fragmentof gliadin. We show that tTG converts a glutamine residue withinthis fragment into glutamic acid and that this process is criticalfor T cell recognition. Gluten-specific T cell lines from 16different adult patients all responded to one or both of thesedeamidated peptides, indicating that these epitopes are highlyrelevant to disease pathology. Binding studies showed that thedeamidated peptides displayed an increased affinity for DQ2,a molecule known to preferentially bind peptides containingnegatively charged residues. Interestingly, the modified glutamineis accommodated in different pockets of DQ2 for the differentepitopes. These results suggest modifications of anchor residuesthat lead to an improved affinity for major histocompatibilitycomplex (MHC), and altered conformation of the peptide–MHCcomplex may be a critical factor leading to T cell responsesto gliadin and the oral intolerance of gluten found in CD.

Key Words: HLA-DQ2, modification, gluten, oral tolerance, mucosal immunity

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

Iismaa, S. E., Mearns, B. M., Lorand, L., Graham, R. M. (2009). Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders. Physiol. Rev. 89: 991-1023 [Abstract] [Full Text]
de Kauwe, A. L., Chen, Z., Anderson, R. P., Keech, C. L., Price, J. D., Wijburg, O., Jackson, D. C., Ladhams, J., Allison, J., McCluskey, J. (2009). Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-Transgenic Mice Expressing Specific Anti-Gliadin CD4+ T Cells. J. Immunol. 182: 7440-7450 [Abstract] [Full Text]
Bethune, M. T., Siegel, M., Howles-Banerji, S., Khosla, C. (2009). Interferon-{gamma} Released by Gluten-Stimulated Celiac Disease-Specific Intestinal T Cells Enhances the Transepithelial Flux of Gluten Peptides. J. Pharmacol. Exp. Ther. 329: 657-668 [Abstract] [Full Text]
Camarca, A., Anderson, R. P., Mamone, G., Fierro, O., Facchiano, A., Costantini, S., Zanzi, D., Sidney, J., Auricchio, S., Sette, A., Troncone, R., Gianfrani, C. (2009). Intestinal T Cell Responses to Gluten Peptides Are Largely Heterogeneous: Implications for a Peptide-Based Therapy in Celiac Disease. J. Immunol. 182: 4158-4166 [Abstract] [Full Text]
Shewry, P. R. (2009). Wheat. J Exp Bot 60: 1537-1553 [Abstract] [Full Text]
Mitea, C., Kooy-Winkelaar, Y., van Veelen, P., de Ru, A., Drijfhout, J. W, Koning, F., Dekking, L. (2008). Fine specificity of monoclonal antibodies against celiac disease-inducing peptides in the gluteome. Am. J. Clin. Nutr. 88: 1057-1066 [Abstract] [Full Text]
Van Herpen, T. W. J. M., Riley, M., Sparks, C., Jones, H. D., Gritsch, C., Dekking, E. H., Hamer, R. J., Bosch, D., Salentijn, E. M. J., Smulders, M. J. M., Shewry, P. R., Gilissen, L. J. W. J. (2008). Detailed Analysis of the Expression of an Alpha-gliadin Promoter and the Deposition of Alpha-gliadin Protein During Wheat Grain Development. ANN BOT (LOND) 102: 331-342 [Abstract] [Full Text]
Tunheim, G., Schjetne, K. W., Rasmussen, I. B., Sollid, L. M., Sandlie, I., Bogen, B. (2008). Recombinant antibodies for delivery of antigen: a single loop between {beta}-strands in the constant region can accommodate long, complex and tandem T cell epitopes. Int Immunol 20: 295-306 [Abstract] [Full Text]
Stepniak, D., Wiesner, M., de Ru, A. H., Moustakas, A. K., Drijfhout, J. W., Papadopoulos, G. K., van Veelen, P. A., Koning, F. (2008). Large-Scale Characterization of Natural Ligands Explains the Unique Gluten-Binding Properties of HLA-DQ2. J. Immunol. 180: 3268-3278 [Abstract] [Full Text]
Silano, M., Di Benedetto, R., Maialetti, F., De Vincenzi, A., Calcaterra, R., Trecca, A., De Vincenzi, M. (2008). A 10-residue peptide from durum wheat promotes a shift from a Th1-type response toward a Th2-type response in celiac disease. Am. J. Clin. Nutr. 87: 415-423 [Abstract] [Full Text]
Matysiak-Budnik, T., Moura, I. C., Arcos-Fajardo, M., Lebreton, C., Menard, S., Candalh, C., Ben-Khalifa, K., Dugave, C., Tamouza, H., van Niel, G., Bouhnik, Y., Lamarque, D., Chaussade, S., Malamut, G., Cellier, C., Cerf-Bensussan, N., Monteiro, R. C., Heyman, M. (2008). Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. JEM 205: 143-154 [Abstract] [Full Text]
Mitea, C, Havenaar, R, Drijfhout, J W., Edens, L, Dekking, L, Koning, F (2008). Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for coeliac disease. Gut 57: 25-32 [Abstract] [Full Text]
Rizzello, C. G., De Angelis, M., Di Cagno, R., Camarca, A., Silano, M., Losito, I., De Vincenzi, M., De Bari, M. D., Palmisano, F., Maurano, F., Gianfrani, C., Gobbetti, M. (2007). Highly Efficient Gluten Degradation by Lactobacilli and Fungal Proteases during Food Processing: New Perspectives for Celiac Disease. Appl. Environ. Microbiol. 73: 4499-4507 [Abstract] [Full Text]
Barone, M. V, Gimigliano, A., Castoria, G., Paolella, G., Maurano, F., Paparo, F., Maglio, M., Mineo, A., Miele, E., Nanayakkara, M., Troncone, R., Auricchio, S. (2007). Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut 56: 480-488 [Abstract] [Full Text]
Raki, M., Fallang, L.-E., Brottveit, M., Bergseng, E., Quarsten, H., Lundin, K. E. A., Sollid, L. M. (2007). Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc. Natl. Acad. Sci. USA 104: 2831-2836 [Abstract] [Full Text]
Stepniak, D., Spaenij-Dekking, L., Mitea, C., Moester, M., de Ru, A., Baak-Pablo, R., van Veelen, P., Edens, L., Koning, F. (2006). Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease. Am. J. Physiol. Gastrointest. Liver Physiol. 291: G621-G629 [Abstract] [Full Text]
van Heel, D A, West, J (2006). Recent advances in coeliac disease. Gut 55: 1037-1046 [Full Text]
Dieterich, W, Esslinger, B, Trapp, D, Hahn, E, Huff, T, Seilmeier, W, Wieser, H, Schuppan, D (2006). Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease. Gut 55: 478-484 [Abstract] [Full Text]
Anderson, R P, van Heel, D A, Tye-Din, J A, Jewell, D P, Hill, A V S (2006). Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease. Gut 55: 485-491 [Abstract] [Full Text]
Senger, S., Maurano, F., Mazzeo, M. F., Gaita, M., Fierro, O., David, C. S., Troncone, R., Auricchio, S., Siciliano, R. A., Rossi, M. (2005). Identification of Immunodominant Epitopes of {alpha}-Gliadin in HLA-DQ8 Transgenic Mice following Oral Immunization. J. Immunol. 175: 8087-8095 [Abstract] [Full Text]
Anderson, R P, van Heel, D A, Tye-Din, J A, Barnardo, M, Salio, M, Jewell, D P, Hill, A V S (2005). T cells in peripheral blood after gluten challenge in coeliac disease. Gut 54: 1217-1223 [Abstract] [Full Text]
Qiao, S.-W., Bergseng, E., Molberg, O., Jung, G., Fleckenstein, B., Sollid, L. M. (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: 254-261 [Abstract] [Full Text]
Bergseng, E., Xia, J., Kim, C.-Y., Khosla, C., Sollid, L. M. (2005). Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule. J. Biol. Chem. 280: 21791-21796 [Abstract] [Full Text]
Herzog, J., Maekawa, Y., Cirrito, T. P., Illian, B. S., Unanue, E. R. (2005). Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells. Proc. Natl. Acad. Sci. USA 102: 7928-7933 [Abstract] [Full Text]
Moss, C. X., Matthews, S. P., Lamont, D. J., Watts, C. (2005). Asparagine Deamidation Perturbs Antigen Presentation on Class II Major Histocompatibility Complex Molecules. J. Biol. Chem. 280: 18498-18503 [Abstract] [Full Text]
Marti, T., Molberg, O., Li, Q., Gray, G. M., Khosla, C., Sollid, L. M. (2005). Prolyl Endopeptidase-Mediated Destruction of T Cell Epitopes in Whole Gluten: Chemical and Immunological Characterization. J. Pharmacol. Exp. Ther. 312: 19-26 [Abstract] [Full Text]
Piper, J. L., Gray, G. M., Khosla, C. (2004). Effect of Prolyl Endopeptidase on Digestive-Resistant Gliadin Peptides in Vivo. J. Pharmacol. Exp. Ther. 311: 213-219 [Abstract] [Full Text]
Spaenij-Dekking, E H A, Kooy-Winkelaar, E M C, Nieuwenhuizen, W F, Drijfhout, J W, Koning, F (2004). A novel and sensitive method for the detection of T cell stimulatory epitopes of {alpha}/{beta}- and {gamma}-gliadin. Gut 53: 1267-1273 [Abstract] [Full Text]
Bateman, E A L, Ferry, B L, Hall, A, Misbah, S A, Anderson, R, Kelleher, P (2004). IgA antibodies of coeliac disease patients recognise a dominant T cell epitope of A-gliadin. Gut 53: 1274-1278 [Abstract] [Full Text]
Qiao, S.-W., Bergseng, E., Molberg, O., Xia, J., Fleckenstein, B., Khosla, C., Sollid, L. M. (2004). Antigen Presentation to Celiac Lesion-Derived T Cells of a 33-Mer Gliadin Peptide Naturally Formed by Gastrointestinal Digestion. J. Immunol. 173: 1757-1762 [Abstract] [Full Text]
Nikulina, M., Habich, C., Flohe, S. B., Scott, F. W., Kolb, H. (2004). Wheat Gluten Causes Dendritic Cell Maturation and Chemokine Secretion. J. Immunol. 173: 1925-1933 [Abstract] [Full Text]
Fleckenstein, B., Qiao, S.-W., Larsen, M. R., Jung, G., Roepstorff, P., Sollid, L. M. (2004). Molecular Characterization of Covalent Complexes between Tissue Transglutaminase and Gliadin Peptides. J. Biol. Chem. 279: 17607-17616 [Abstract] [Full Text]
Kim, C.-Y., Quarsten, H., Bergseng, E., Khosla, C., Sollid, L. M. (2004). Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc. Natl. Acad. Sci. USA 101: 4175-4179 [Abstract] [Full Text]
Lillicrap, M. S., Duggleby, R. C., Goodall, J. C., Gaston, J. S. H. (2004). T cell recognition of a highly conserved epitope in heat shock protein 60: self-tolerance maintained by TCR distinguishing between asparagine and aspartic acid. Int Immunol 16: 405-414 [Abstract] [Full Text]
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: 1088-1096 [Abstract] [Full Text]
Fraser, J S, Engel, W, Ellis, H J, Moodie, S J, Pollock, E L, Wieser, H, Ciclitira, P J (2003). Coeliac disease: in vivo toxicity of the putative immunodominant epitope. Gut 52: 1698-1702 [Abstract] [Full Text]
Dieterich, W, Trapp, D, Esslinger, B, Leidenberger, M, Piper, J, Hahn, E, Schuppan, D (2003). Autoantibodies of patients with coeliac disease are insufficient to block tissue transglutaminase activity. Gut 52: 1562-1566 [Abstract] [Full Text]
Vader, W., Stepniak, D., Kooy, Y., Mearin, L., Thompson, A., van Rood, J. J., 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. USA 100: 12390-12395 [Abstract] [Full Text]
Leung, P. S. C., Quan, C., Park, O., Van de Water, J., Kurth, M. J., Nantz, M. H., Ansari, A. A., Coppel, R. L., Lam, K. S., Gershwin, M. E. (2003). Immunization with a Xenobiotic 6-Bromohexanoate Bovine Serum Albumin Conjugate Induces Antimitochondrial Antibodies. J. Immunol. 170: 5326-5332 [Abstract] [Full Text]
Gianfrani, C., Troncone, R., Mugione, P., Cosentini, E., De Pascale, M., Faruolo, C., Senger, S., Terrazzano, G., Southwood, S., Auricchio, S., Sette, A. (2003). Celiac Disease Association with CD8+ T Cell Responses: Identification of a Novel Gliadin-Derived HLA-A2-Restricted Epitope. J. Immunol. 170: 2719-2726 [Abstract] [Full Text]
Lundin, K E A, Sollid, L M (2003). Gliadin peptide specific intestinal T cells in coeliac disease. Gut 52: 162-162 [Full Text]
Ellis, H J, Pollock, E L, Engel, W, Fraser, J S, Rosen-Bronson, S, Wieser, H, Ciclitira, P J (2003). Investigation of the putative immunodominant T cell epitopes in coeliac disease. Gut 52: 212-217 [Abstract] [Full Text]
Mazzarella, G, Maglio, M, Paparo, F, Nardone, G, Stefanile, R, Greco, L, van de Wal, Y, Kooy, Y, Koning, F, Auricchio, S, Troncone, R (2003). An immunodominant DQ8 restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients. Gut 52: 57-62 [Abstract] [Full Text]
Vlad, A. M., Muller, S., Cudic, M., Paulsen, H., Otvos, L. Jr., Hanisch, F.-G., Finn, O. J. (2002). Complex Carbohydrates Are Not Removed During Processing of Glycoproteins by Dendritic Cells: Processing of Tumor Antigen MUC1 Glycopeptides for Presentation to Major Histocompatibility Complex Class II-restricted T Cells. JEM 196: 1435-1446 [Abstract] [Full Text]
Parrot, I., Huang, P. C., Khosla, C. (2002). Circular Dichroism and Nuclear Magnetic Resonance Spectroscopic Analysis of Immunogenic Gluten Peptides and Their Analogs. J. Biol. Chem. 277: 45572-45578 [Abstract] [Full Text]
Black, K. E., Murray, J. A., David, C. S. (2002). HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice. J. Immunol. 169: 5595-5600 [Abstract] [Full Text]
Hausch, F., Shan, L., Santiago, N. A., Gray, G. M., Khosla, C. (2002). Intestinal digestive resistance of immunodominant gliadin peptides. Am. J. Physiol. Gastrointest. Liver Physiol. 283: G996-G1003 [Abstract] [Full Text]
Shan, L., Molberg, O., Parrot, I., Hausch, F., Filiz, F., Gray, G. M., Sollid, L. M., Khosla, C. (2002). Structural Basis for Gluten Intolerance in Celiac Sprue. Science 297: 2275-2279 [Abstract] [Full Text]
Fleckenstein, B., Molberg, O., Qiao, S.-W., Schmid, D. G., von der Mulbe, F., Elgstoen, K., Jung, G., Sollid, L. M. (2002). Gliadin T Cell Epitope Selection by Tissue Transglutaminase in Celiac Disease. ROLE OF ENZYME SPECIFICITY AND pH INFLUENCE ON THE TRANSAMIDATION VERSUS DEAMIDATION REACTIONS. J. Biol. Chem. 277: 34109-34116 [Abstract] [Full Text]
Ivarsson, A., Hernell, O., Stenlund, H., Persson, L. A. (2002). Breast-feeding protects against celiac disease. Am. J. Clin. Nutr. 75: 914-921 [Abstract] [Full Text]
Vader, L. W., de Ru, A., van der Wal, Y., Kooy, Y. M.C., Benckhuijsen, W., Mearin, M. L., Drijfhout, J. W., van Veelen, P., Koning, F. (2002). Specificity of Tissue Transglutaminase Explains Cereal Toxicity in Celiac Disease. JEM 195: 643-649 [Abstract] [Full Text]
Quarsten, H., McAdam, S. N., Jensen, T., Arentz-Hansen, H., Lundin, K. E. A., Sollid, L. M. (2001). Staining of Celiac Disease-Relevant T Cells by Peptide-DQ2 Multimers. J. Immunol. 167: 4861-4868 [Abstract] [Full Text]
Cucca, F., Lampis, R., Congia, M., Angius, E., Nutland, S., Bain, S. C., Barnett, A. H., Todd, J. A. (2001). A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum Mol Genet 10: 2025-2037 [Abstract] [Full Text]
Appel, H., Seth, N. P., Gauthier, L., Wucherpfennig, K. W. (2001). Anergy Induction by Dimeric TCR Ligands. J. Immunol. 166: 5279-5285 [Abstract] [Full Text]
McADAM, S N, SOLLID, L M (2000). Getting to grips with gluten. Gut 47: 743-745 [Full Text]

Original Article

The Intestinal T Cell Response to -Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

The Intestinal T Cell Response to ${alpha}$ -Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase