Search tips
Search criteria 


Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1993 July 1; 178(1): 187–196.
PMCID: PMC2191064

Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients


Celiac disease (CD) is most probably an immunological disease, precipitated in susceptible individuals by ingestion of wheat gliadin and related proteins from other cereals. The disease shows a strong human HLA association predominantly to the cis or trans encoded HLA- DQ(alpha 1*0501,beta 1*0201) (DQ2) heterodimer. T cell recognition of gliadin presented by this DQ heterodimer may thus be of immunopathogenic importance in CD. We therefore challenged small intestinal biopsies from adult CD patients on a gluten-free diet in vitro with gluten (containing both gliadin and other wheat proteins), and isolated activated CD25+ T cells. Polyclonal T cell lines and a panel of T cell clones recognizing gluten were established. They recognized the gliadin moiety of gluten, but not proteins from other cereals. Inhibition studies with anti-HLA antibodies demonstrated predominant antigen presentation by HLA-DQ molecules. The main antigen- presenting molecule was established to be the CD-associated DQ(alpha 1*0501, beta 1*0201) heterodimer. The gluten-reactive T cell clones were CD4+, CD8-, and carried diverse combinations of T cell receptor (TCR) V alpha and V beta chains. The findings suggest preferential mucosal presentation of gluten-derived peptides by HLA-DQ(alpha 1*0501, beta 1*0201) in CD, which may explain the HLA association.

Full Text

The Full Text of this article is available as a PDF (941K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Trier JS. Celiac sprue. N Engl J Med. 1991 Dec 12;325(24):1709–1719. [PubMed]
  • Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology. 1992 Jan;102(1):330–354. [PubMed]
  • Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med. 1989 Jan 1;169(1):345–350. [PMC free article] [PubMed]
  • Lundin KE, Sollid LM, Qvigstad E, Markussen G, Gjertsen HA, Ek J, Thorsby E. T lymphocyte recognition of a celiac disease-associated cis- or trans-encoded HLA-DQ alpha/beta-heterodimer. J Immunol. 1990 Jul 1;145(1):136–139. [PubMed]
  • Kagnoff MF, Harwood JI, Bugawan TL, Erlich HA. Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6274–6278. [PubMed]
  • Crabtree JE, Heatley RV, Juby LD, Howdle PD, Losowsky MS. Serum interleukin-2-receptor in coeliac disease: response to treatment and gluten challenge. Clin Exp Immunol. 1989 Sep;77(3):345–348. [PubMed]
  • Fais S, Maiuri L, Pallone F, De Vincenzi M, De Ritis G, Troncone R, Auricchio S. Gliadin induced changes in the expression of MHC-class II antigens by human small intestinal epithelium. Organ culture studies with coeliac disease mucosa. Gut. 1992 Apr;33(4):472–475. [PMC free article] [PubMed]
  • Halstensen TS, Hvatum M, Scott H, Fausa O, Brandtzaeg P. Association of subepithelial deposition of activated complement and immunoglobulin G and M response to gluten in celiac disease. Gastroenterology. 1992 Mar;102(3):751–759. [PubMed]
  • Halstensen TS, Scott H, Farstad IN, Michaelsen TE, Brandtzaeg P. In situ two- and three-color immunofluorescence staining of mucosal T-cells in celiac disease. Increase of TCR gamma/delta+CD8- and TCR alpha/beta+CD45R0+ intraepithelial lymphocytes and IL-2R+ TCR alpha/beta+CD4+CD45R0+ lamina propria lymphocytes. Prog Histochem Cytochem. 1992;26(1-4):201–210. [PubMed]
  • Sturgess RP, Ellis HJ, Ciclitira PJ. Cereal chemistry, molecular biology, and toxicity in coeliac disease. Gut. 1991 Sep;32(9):1055–1060. [PMC free article] [PubMed]
  • FRAZER AC, FLETCHER RF, ROSS CA, SHAW B, SAMMONS HG, SCHNEIDER R. Gluten-induced enteropathy: the effect of partially digested gluten. Lancet. 1959 Sep 5;2(7097):252–255. [PubMed]
  • Kasarda DD, Okita TW, Bernardin JE, Baecker PA, Nimmo CC, Lew EJ, Dietler MD, Greene FC. Nucleic acid (cDNA) and amino acid sequences of alpha-type gliadins from wheat (Triticum aestivum). Proc Natl Acad Sci U S A. 1984 Aug;81(15):4712–4716. [PubMed]
  • Wieser H, Belitz HD, Ashkenazi A. Amino-acid sequence of the coeliac active gliadin peptide B 3142. Z Lebensm Unters Forsch. 1984 Nov;179(5):371–376. [PubMed]
  • Okita TW, Cheesbrough V, Reeves CD. Evolution and heterogeneity of the alpha-/beta-type and gamma-type gliadin DNA sequences. J Biol Chem. 1985 Jul 5;260(13):8203–8213. [PubMed]
  • Lea T, Smeland E, Funderud S, Vartdal F, Davies C, Beiske K, Ugelstad J. Characterization of human mononuclear cells after positive selection with immunomagnetic particles. Scand J Immunol. 1986 Apr;23(4):509–519. [PubMed]
  • Lundin KE, Ovigstad E, Sollid LM, Gjertsen HA, Gaudernack G, Thorsby E. Positive selection of Tac- (CD25) positive cells following T-cell activation. Use of immunomagnetic separation and implications for T-cell cloning. J Immunogenet. 1989 Apr;16(2):185–191. [PubMed]
  • Gaudernack G, Lundin KE. Rapid immunomagnetic phenotyping of cells. J Immunogenet. 1989 Apr;16(2):169–175. [PubMed]
  • Kimura A, Dong RP, Harada H, Sasazuki T. DNA typing of HLA class II genes in B-lymphoblastoid cell lines homozygous for HLA. Tissue Antigens. 1992 Jul;40(1):5–12. [PubMed]
  • Kwok WW, Schwarz D, Nepom BS, Hock RA, Thurtle PS, Nepom GT. HLA-DQ molecules form alpha-beta heterodimers of mixed allotype. J Immunol. 1988 Nov 1;141(9):3123–3127. [PubMed]
  • Hansen T, Lundin KE, Markussen G, Thorsby E. T cell receptor usage by HLA-DQw8-specific T cell clones. Int Immunol. 1992 Aug;4(8):931–934. [PubMed]
  • Spurkland A, Sollid LM, Polanco I, Vartdal F, Thorsby E. HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7. Hum Immunol. 1992 Nov;35(3):188–192. [PubMed]
  • Mantovani V, Corazza GR, Bragliani M, Frisoni M, Zaniboni MG, Gasbarrini G. Asp57-negative HLA DQ beta chain and DQA1*0501 allele are essential for the onset of DQw2-positive and DQw2-negative coeliac disease. Clin Exp Immunol. 1993 Jan;91(1):153–156. [PubMed]
  • Cohen JA, Essayan DM, Zweiman B, Lisak RP. Limiting dilution analysis of the frequency of antigen-reactive lymphocytes isolated from the central nervous system of Lewis rats with experimental allergic encephalomyelitis. Cell Immunol. 1987 Aug;108(1):203–213. [PubMed]
  • Zeitz M, Quinn TC, Graeff AS, James SP. Mucosal T cells provide helper function but do not proliferate when stimulated by specific antigen in lymphogranuloma venereum proctitis in nonhuman primates. Gastroenterology. 1988 Feb;94(2):353–366. [PubMed]
  • Halstensen TS, Brandtzaeg P. Activated T lymphocytes in the celiac lesion: non-proliferative activation (CD25) of CD4+ alpha/beta cells in the lamina propria but proliferation (Ki-67) of alpha/beta and gamma/delta cells in the epithelium. Eur J Immunol. 1993 Feb;23(2):505–510. [PubMed]
  • MacDonald TT, Spencer J. Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine. J Exp Med. 1988 Apr 1;167(4):1341–1349. [PMC free article] [PubMed]
  • Scott H, Sollid LM, Fausa O, Brandtzaeg P, Thorsby E. Expression of major histocompatibility complex class II subregion products by jejunal epithelium in patients with coeliac disease. Scand J Immunol. 1987 Nov;26(5):563–571. [PubMed]
  • Lechler RI, Norcross MA, Germain RN. Qualitative and quantitative studies of antigen-presenting cell function by using I-A-expressing L cells. J Immunol. 1985 Nov;135(5):2914–2922. [PubMed]
  • Acha-Orbea H, Mitchell DJ, Timmermann L, Wraith DC, Tausch GS, Waldor MK, Zamvil SS, McDevitt HO, Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. [PubMed]
  • Hansen T, Rønningen KS, Ploski R, Kimura A, Thorsby E. Coding region polymorphisms of human T-cell receptor V beta 6.9 and V beta 21.4. Scand J Immunol. 1992 Aug;36(2):285–290. [PubMed]
  • Ciclitira PJ, Evans DJ, Fagg NL, Lennox ES, Dowling RH. Clinical testing of gliadin fractions in coeliac patients. Clin Sci (Lond) 1984 Mar;66(3):357–364. [PubMed]
  • Wieser H, Belitz HD, Idar D, Ashkenazi A. Coeliac activity of the gliadin peptides CT-1 and CT-2. Z Lebensm Unters Forsch. 1986 Feb;182(2):115–117. [PubMed]
  • Kagnoff MF, Austin RK, Hubert JJ, Bernardin JE, Kasarda DD. Possible role for a human adenovirus in the pathogenesis of celiac disease. J Exp Med. 1984 Nov 1;160(5):1544–1557. [PMC free article] [PubMed]
  • Friis SU, Norén O, Sjöström H, Gudmand-Høyer E. Patients with coeliac disease have a characteristic gliadin antibody pattern. Clin Chim Acta. 1986 Mar 16;155(2):133–141. [PubMed]
  • Jos J, de Tand MF, Arnaud-Battandier F, Boissel JP, Popineau Y, Wajcman H. Separation of pure toxic peptides from a beta-gliadin subfraction using high-performance liquid chromatography. Clin Chim Acta. 1983 Oct 31;134(1-2):189–198. [PubMed]
  • Wieser H, Springer G, Belitz HD, Ashkenazi A, Idar D. Toxicity of different wheat gliadins in coeliac disease. Z Lebensm Unters Forsch. 1982;175(5):321–326. [PubMed]
  • Wieser H, Seilmeier W, Belitz HD. Vergleichende Untersuchungen über partielle Aminosäuresequenzen von Prolaminen und Glutelinen verschiedener Getreidearten. VII. Aminosäuresequenzen von Prolaminpeptiden. Z Lebensm Unters Forsch. 1987 May;184(5):366–373. [PubMed]
  • Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, McDermott M, Sinha AA, Timmerman L, Steinman L, et al. A molecular basis for MHC class II--associated autoimmunity. Science. 1988 May 20;240(4855):1003–1009. [PubMed]
  • Möller E, Böhme J, Valugerdi MA, Ridderstad A, Olerup O. Speculations on mechanisms of HLA associations with autoimmune diseases and the specificity of "autoreactive" T lymphocytes. Immunol Rev. 1990 Dec;118:5–19. [PubMed]
  • Altmann DM, Sansom D, Marsh SG. What is the basis for HLA-DQ associations with autoimmune disease? Immunol Today. 1991 Aug;12(8):267–270. [PubMed]
  • Deem RL, Shanahan F, Targan SR. Triggered human mucosal T cells release tumour necrosis factor-alpha and interferon-gamma which kill human colonic epithelial cells. Clin Exp Immunol. 1991 Jan;83(1):79–84. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press