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PMID: 19935805 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Tissue-mediated control of immunopathology in coeliac disease.

Nature reviews. Immunology ·Vol. 9 ·No. 12 ·2009-12-00 ·Pages 858-70

Jabri B, Sollid LM

Abstract

Coeliac disease is an inflammatory disorder with autoimmune features that is characterized by destruction of the intestinal epithelium and remodelling of the intestinal mucosa following the ingestion of dietary gluten. A common feature of coeliac disease and many organ-specific autoimmune diseases is a central role for T cells in causing tissue destruction. In this Review, we discuss the emerging hypothesis that, in coeliac disease, intestinal tissue inflammation--induced either by infectious agents or by gluten--is crucial for activating T cells and eliciting their tissue-destructive effector functions.

MeSH Terms
Animals Autoimmune Diseases/genetics,immunology Celiac Disease/genetics,immunology Genetic Predisposition to Disease Glutens/immunology Humans Inflammation/immunology Lymphocyte Activation/immunology T-Lymphocytes/immunology
Chemicals
Glutens
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Jabri Bana
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. bjabri@bsd.uchicago.edu
Sollid Ludvig M
References (116)
116 references, click to expand
  1. Peripheral deletion of antigen-reactive T cells in oral tolerance.
    Nature. 1995 Jul 13;376(6536):177-80 PMID: 7603570
  2. 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 Feb 21;191(4):603-12 PMID: 10684852
  3. 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. 2009 Oct;10(10):1096-101 PMID: 19718029
  4. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.
    Gastroenterology. 2003 Sep;125(3):730-45 PMID: 12949719
  5. NKG2D blockade prevents autoimmune diabetes in NOD mice.
    Immunity. 2004 Jun;20(6):757-67 PMID: 15189740
  6. HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice.
    J Immunol. 2002 Nov 15;169(10):5595-600 PMID: 12421937
  7. Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients.
    J Exp Med. 1993 Jul 1;178(1):187-96 PMID: 8315377
  8. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.
    Gastroenterology. 2008 Jul;135(1):194-204.e3 PMID: 18485912
  9. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase.
    Eur J Immunol. 2001 May;31(5):1317-23 PMID: 11465088
  10. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease.
    J Clin Invest. 2006 Aug;116(8):2226-36 PMID: 16878175
  11. Wheat gluten causes dendritic cell maturation and chemokine secretion.
    J Immunol. 2004 Aug 1;173(3):1925-33 PMID: 15265926
  12. 5-lipoxygenase: cellular biology and molecular pharmacology.
    Curr Drug Targets Inflamm Allergy. 2002 Mar;1(1):23-44 PMID: 14561204
  13. Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes.
    Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15849-54 PMID: 19805228
  14. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.
    Gut. 2009 Aug;58(8):1078-83 PMID: 19240061
  15. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes.
    J Immunol. 2007 Jan 15;178(2):732-9 PMID: 17202333
  16. Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease.
    Gut. 2008 Jul;57(7):887-92 PMID: 17965065
  17. NKG2 receptor-mediated regulation of effector CTL functions in the human tissue microenvironment.
    Curr Top Microbiol Immunol. 2006;298:139-56 PMID: 16323414
  18. Expression of nonclassical class I molecules by intestinal epithelial cells.
    Inflamm Bowel Dis. 2007 Mar;13(3):298-307 PMID: 17238179
  19. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway.
    J Immunol. 2009 Jun 1;182(11):6763-70 PMID: 19454671
  20. Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells.
    J Immunol. 2009 Jun 15;182(12):7440-50 PMID: 19494267
  21. Retinoic acid: an educational "vitamin elixir" for gut-seeking T cells.
    Immunity. 2004 Oct;21(4):458-60 PMID: 15485623
  22. Development of type 1 diabetes mellitus during interferon alfa therapy for chronic HCV hepatitis.
    Lancet. 1992 Aug 29;340(8818):548 PMID: 1354296
  23. Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease.
    Gut. 2007 Apr;56(4):480-8 PMID: 16891357
  24. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity.
    Immunity. 2002 Apr;16(4):559-69 PMID: 11970879
  25. Interleukin 15 mediates epithelial changes in celiac disease.
    Gastroenterology. 2000 Oct;119(4):996-1006 PMID: 11040186
  26. Abnormal intestinal intraepithelial lymphocytes in refractory sprue.
    Gastroenterology. 1998 Mar;114(3):471-81 PMID: 9496937
  27. Friendly and dangerous signals: is the tissue in control?
    Nat Immunol. 2007 Jan;8(1):11-3 PMID: 17179963
  28. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches.
    Science. 2009 Mar 13;323(5920):1488-92 PMID: 19286559
  29. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal.
    Immunol Today. 1999 Dec;20(12):561-7 PMID: 10562707
  30. The yin and yang of intestinal epithelial cells in controlling dendritic cell function.
    J Exp Med. 2007 Oct 1;204(10):2253-7 PMID: 17893197
  31. Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-alpha therapy.
    Clin Endocrinol (Oxf). 1996 Jun;44(6):635-42 PMID: 8759175
  32. Increase in gamma/delta T cell receptor bearing lymphocytes in normal small bowel mucosa in latent coeliac disease.
    Gut. 1991 Nov;32(11):1412-4 PMID: 1836446
  33. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer.
    J Exp Med. 1989 Jan 1;169(1):345-50 PMID: 2909659
  34. Fcgamma receptors as regulators of immune responses.
    Nat Rev Immunol. 2008 Jan;8(1):34-47 PMID: 18064051
  35. Gliadin peptides activate blood monocytes from patients with celiac disease.
    J Clin Immunol. 2007 Mar;27(2):201-9 PMID: 17260166
  36. 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):330-54 PMID: 1727768
  37. A Structural basis for the association of DAP12 with mouse, but not human, NKG2D.
    J Immunol. 2004 Aug 15;173(4):2470-8 PMID: 15294961
  38. Detecting shared pathogenesis from the shared genetics of immune-related diseases.
    Nat Rev Genet. 2009 Jan;10(1):43-55 PMID: 19092835
  39. Interleukin 18 and associated markers of T helper cell type 1 activity in coeliac disease.
    Gut. 2002 Feb;50(2):186-90 PMID: 11788557
  40. Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding.
    J Immunol. 1994 May 1;152(9):4663-70 PMID: 8157979
  41. Rotavirus and celiac disease: clues to the pathogenesis and perspectives on prevention.
    J Pediatr Gastroenterol Nutr. 2007 May;44(5):527-8 PMID: 17460483
  42. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes.
    Nat Immunol. 2001 Jun;2(6):501-7 PMID: 11376336
  43. A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease.
    Immunity. 2007 Jul;27(1):23-34 PMID: 17629515
  44. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease.
    J Exp Med. 2008 Jan 21;205(1):143-54 PMID: 18166587
  45. 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. 2005 Jul 1;175(1):254-61 PMID: 15972656
  46. In siblings of celiac children, rectal gluten challenge reveals gluten sensitization not restricted to celiac HLA.
    Gastroenterology. 1996 Aug;111(2):318-24 PMID: 8690196
  47. On the HLA-DQ(alpha 1*0501, beta 1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201.
    Tissue Antigens. 1993 Apr;41(4):173-7 PMID: 8362409
  48. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design.
    Nat Rev Immunol. 2006 Aug;6(8):595-601 PMID: 16868550
  49. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.
    Nature. 1987 Oct 15-21;329(6140):599-604 PMID: 3309680
  50. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation.
    Nat Immunol. 2008 Mar;9(3):282-91 PMID: 18204450
  51. The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides.
    Gastroenterology. 2002 Jun;122(7):1729-37 PMID: 12055577
  52. NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice.
    Proc Natl Acad Sci U S A. 2007 May 1;104(18):7512-5 PMID: 17463084
  53. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity.
    J Immunol. 1998 Aug 15;161(4):1585-8 PMID: 9712018
  54. 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. 2003 Oct 14;100(21):12390-5 PMID: 14530392
  55. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases.
    Cell. 2004 May 28;117(5):561-74 PMID: 15163405
  56. Concordance, disease progression, and heritability of coeliac disease in Italian twins.
    Gut. 2006 Jun;55(6):803-8 PMID: 16354797
  57. Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice.
    Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9374-9 PMID: 12082183
  58. The immune system evolved to discriminate infectious nonself from noninfectious self.
    Immunol Today. 1992 Jan;13(1):11-6 PMID: 1739426
  59. Shared and distinct genetic variants in type 1 diabetes and celiac disease.
    N Engl J Med. 2008 Dec 25;359(26):2767-77 PMID: 19073967
  60. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease.
    Gastroenterology. 2000 May;118(5):867-79 PMID: 10784586
  61. Refractory coeliac disease.
    Best Pract Res Clin Gastroenterol. 2005 Jun;19(3):413-24 PMID: 15925846
  62. Oral tolerance.
    Immunol Rev. 2005 Aug;206:232-59 PMID: 16048553
  63. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.
    Nat Genet. 2001 Jan;27(1):18-20 PMID: 11137992
  64. Classification of intractable diarrhea in infancy using clinical and immunohistological criteria.
    Gastroenterology. 1990 Oct;99(4):1037-43 PMID: 2203660
  65. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells.
    Nature. 2003 Jul 3;424(6944):88-93 PMID: 12840763
  66. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases.
    Immunol Rev. 1999 Feb;167:257-74 PMID: 10319267
  67. Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease.
    Gastroenterology. 2007 Mar;132(3):994-1008 PMID: 17324400
  68. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease.
    Lancet. 2003 Jul 5;362(9377):30-7 PMID: 12853196
  69. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease.
    Gastroenterology. 1998 Sep;115(3):551-63 PMID: 9721152
  70. Gliadin regulates the NK-dendritic cell cross-talk by HLA-E surface stabilization.
    J Immunol. 2007 Jul 1;179(1):372-81 PMID: 17579058
  71. A unique dendritic cell subset accumulates in the celiac lesion and efficiently activates gluten-reactive T cells.
    Gastroenterology. 2006 Aug;131(2):428-38 PMID: 16890596
  72. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet.
    Gut. 1993 Feb;34(2):208-14 PMID: 8432475
  73. Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children.
    Bone Marrow Transplant. 2002 Feb;29(3):223-30 PMID: 11859394
  74. TCR specificity dictates CD94/NKG2A expression by human CTL.
    Immunity. 2002 Oct;17(4):487-99 PMID: 12387742
  75. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.
    J Exp Med. 2001 Jan 15;193(2):219-31 PMID: 11208862
  76. A quantitative analysis of transglutaminase 2-mediated deamidation of gluten peptides: implications for the T-cell response in celiac disease.
    J Proteome Res. 2009 Apr;8(4):1748-55 PMID: 19239248
  77. Celiac disease.
    N Engl J Med. 2007 Oct 25;357(17):1731-43 PMID: 17960014
  78. 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. 1994 Dec;41(4):285-91 PMID: 7883596
  79. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.
    Science. 2007 Jul 13;317(5835):256-60 PMID: 17569825
  80. Structure of celiac disease-associated HLA-DQ8 and non-associated HLA-DQ9 alleles in complex with two disease-specific epitopes.
    Int Immunol. 2000 Aug;12(8):1157-66 PMID: 10917890
  81. Unique peptide binding characteristics of the disease-associated DQ(alpha 1*0501, beta 1*0201) vs the non-disease-associated DQ(alpha 1*0201, beta 1*0202) molecule.
    Immunogenetics. 1997;46(6):484-92 PMID: 9321428
  82. Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury.
    PLoS One. 2008 Mar 26;3(3):e1861 PMID: 18365016
  83. Transglutaminases: crosslinking enzymes with pleiotropic functions.
    Nat Rev Mol Cell Biol. 2003 Feb;4(2):140-56 PMID: 12563291
  84. The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease.
    Nature. 2008 Nov 27;456(7221):534-8 PMID: 19037317
  85. 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):188-92 PMID: 1293082
  86. Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease.
    J Clin Invest. 2008 Jan;118(1):281-93 PMID: 18064301
  87. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis.
    Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9452-7 PMID: 12878725
  88. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15.
    J Exp Med. 2009 Mar 16;206(3):707-19 PMID: 19237603
  89. Onset of coeliac disease during treatment with interferon for chronic hepatitis C.
    Lancet. 2000 Oct 28;356(9240):1494-5 PMID: 11081540
  90. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia.
    J Exp Med. 2005 Jun 6;201(11):1793-803 PMID: 15939793
  91. Intraepithelial T cells of the TcR gamma/delta+ CD8- and V delta 1/J delta 1+ phenotypes are increased in coeliac disease.
    Scand J Immunol. 1989 Dec;30(6):665-72 PMID: 2481336
  92. T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells.
    J Immunol. 2002 Aug 1;169(3):1236-40 PMID: 12133944
  93. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment.
    J Immunol. 2001 Nov 15;167(10):5527-30 PMID: 11698420
  94. CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.
    Gut. 1998 Aug;43(2):187-9 PMID: 10189842
  95. Post-translational protein modifications in antigen recognition and autoimmunity.
    Trends Immunol. 2001 Aug;22(8):443-9 PMID: 11473834
  96. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.
    Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4175-9 PMID: 15020763
  97. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.
    J Exp Med. 2007 Aug 6;204(8):1757-64 PMID: 17620361
  98. Identification of tissue transglutaminase as the autoantigen of celiac disease.
    Nat Med. 1997 Jul;3(7):797-801 PMID: 9212111
  99. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.
    Immunity. 2004 Sep;21(3):367-77 PMID: 15357948
  100. Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis?
    J Immunol. 2000 Aug 15;165(4):2240-50 PMID: 10925312
  101. HLA in coeliac disease: unravelling the complex genetics of a complex disorder.
    Tissue Antigens. 2003 Feb;61(2):105-17 PMID: 12694579
  102. Autoantibodies in coeliac disease: tissue transglutaminase--guilt by association?
    Gut. 1997 Dec;41(6):851-2 PMID: 9462222
  103. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation.
    Nat Rev Immunol. 2005 Sep;5(9):688-98 PMID: 16138102
  104. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.
    Nat Genet. 2007 Jul;39(7):827-9 PMID: 17558408
  105. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease.
    Nat Med. 1998 Jun;4(6):713-7 PMID: 9623982
  106. Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis.
    Gastroenterology. 2008 Apr;134(4):1017-27 PMID: 18395083
  107. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.
    Immunity. 2004 Sep;21(3):357-66 PMID: 15357947
  108. Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease.
    Gastroenterology. 2007 Oct;133(4):1175-87 PMID: 17919493
  109. Role of interferon alpha in promoting T helper cell type 1 responses in the small intestine in coeliac disease.
    Gut. 2001 Mar;48(3):425-9 PMID: 11171837
  110. Specificity of tissue transglutaminase explains cereal toxicity in celiac disease.
    J Exp Med. 2002 Mar 4;195(5):643-9 PMID: 11877487
  111. Dendritic cells and cytokines in human inflammatory and autoimmune diseases.
    Cytokine Growth Factor Rev. 2008 Feb;19(1):41-52 PMID: 18258476
  112. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies.
    J Clin Invest. 1998 Jan 1;101(1):273-81 PMID: 9421490
  113. 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. 1997 Sep;46(3):103-9 PMID: 9315123
  114. 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. 2003 Apr;64(4):469-77 PMID: 12651074
  115. Self-recognition of CD1 by gamma/delta T cells: implications for innate immunity.
    J Exp Med. 2000 Mar 20;191(6):937-48 PMID: 10727456
  116. Newly identified genetic risk variants for celiac disease related to the immune response.
    Nat Genet. 2008 Apr;40(4):395-402 PMID: 18311140
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri2670
Email
bjabri@bsd.uchicago.edu
Published
2009-12-00
Pages
858-70
Language
English
Region
England
NLM ID
101124169
Subset
IM
Grants
NIDDK NIH HHS · P30DK42086 · United States
NIDDK NIH HHS · R01DK063158 · United States
NIDDK NIH HHS · R01DK58727 · United States
External Links
PubMed source DOI: 10.1038/nri2670 View journal details
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