Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL-15 and IL-21 in CD.

[1]  J. Murray,et al.  Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. , 2003, Archives of internal medicine.

[2]  A Steinle,et al.  Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. , 1999, Science.

[3]  L. Maiuri,et al.  Interleukin 15 mediates epithelial changes in celiac disease. , 2000, Gastroenterology.

[4]  G. Corazza,et al.  Coeliac disease , 2005, Journal of Clinical Pathology.

[5]  Scott F. Saccone,et al.  A Genome-Wide Association Study of Psoriasis and Psoriatic Arthritis Identifies New Disease Loci , 2008, PLoS genetics.

[6]  W. Leonard,et al.  Interleukin-21: basic biology and implications for cancer and autoimmunity. , 2008, Annual review of immunology.

[7]  G. Bhagat,et al.  Small intestinal CD8 + TCRγδ + NKG2A + intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease , 2008 .

[8]  M. Neurath,et al.  Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance , 1996, The Journal of experimental medicine.

[9]  E. Ebert Interleukin 15 is a potent stimulant of intraepithelial lymphocytes. , 1998, Gastroenterology.

[10]  Anita B. Roberts,et al.  REGULATION OF IMMUNE RESPONSES BY TGF-β* , 1998 .

[11]  T. Macdonald,et al.  Immunity, Inflammation, and Allergy in the Gut , 2005, Science.

[12]  Roepstorff,et al.  Identification of a Gliadin T‐Cell Epitope in Coeliac Disease: General Importance of Gliadin Deamidation for Intestinal T‐Cell Recognition , 1998, Scandinavian journal of immunology.

[13]  T. Macdonald,et al.  A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. , 2007, Gastroenterology.

[14]  G. Corazza,et al.  Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease. , 2007, Gastroenterology.

[15]  L. Greco,et al.  HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. , 2003, Human immunology.

[16]  R. Jian,et al.  Selective expansion of intraepithelial lymphocytes expressing the HLA-E–specific natural killer receptor CD94 in celiac disease☆☆☆ , 2000, Gastroenterology.

[17]  Gerstein,et al.  Cytokine Profile in Coeliac Disease , 1999, Scandinavian journal of immunology.

[18]  P. Krajči,et al.  Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. , 1995, Gut.

[19]  K. Lundin,et al.  Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. , 1998, Gastroenterology.

[20]  T. Macdonald,et al.  Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease , 2007, Gut.

[21]  E. Ebert Interleukin 21 up‐regulates perforin‐mediated cytotoxic activity of human intra‐epithelial lymphocytes , 2009, Immunology.

[22]  I. Julkunen,et al.  IFN‐α regulates IL‐21 and IL‐21R expression in human NK and T cells , 2004 .

[23]  T. Macdonald,et al.  Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa , 2004, Gut.

[24]  P. Lionetti,et al.  Role of interferon α in promoting T helper cell type 1 responses in the small intestine in coeliac disease , 2001, Gut.

[25]  R. Flavell,et al.  Abrogation of TGFβ Signaling in T Cells Leads to Spontaneous T Cell Differentiation and Autoimmune Disease , 2000 .

[26]  Govind Bhagat,et al.  Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. , 2004, Immunity.

[27]  G. Proetzel,et al.  Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease , 1992, Nature.

[28]  Scott R. Presnell,et al.  Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function , 2000, Nature.

[29]  P. Deloukas,et al.  A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 , 2007, Nature Genetics.

[30]  P. Lionetti,et al.  Differing patterns of transforming growth factor-beta expression in normal intestinal mucosa and in active celiac disease. , 1999, Journal of pediatric gastroenterology and nutrition.

[31]  P. Bingley,et al.  Undiagnosed coeliac disease at age seven: population based prospective birth cohort study , 2004, BMJ : British Medical Journal.

[32]  T. Macdonald,et al.  Smad7 in TGF-β-mediated negative regulation of gut inflammation , 2004 .

[33]  T. Macdonald,et al.  Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. , 2001, The Journal of clinical investigation.

[34]  N. Cerf-Bensussan,et al.  Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease. , 2007, Gastroenterology.

[35]  L. Sollid Coeliac disease: dissecting a complex inflammatory disorder , 2002, Nature Reviews Immunology.

[36]  L. Greco,et al.  The first large population based twin study of coeliac disease , 2002, Gut.

[37]  B. Jabri,et al.  NKG2 receptor-mediated regulation of effector CTL functions in the human tissue microenvironment. , 2006, Current topics in microbiology and immunology.

[38]  L. Sollid,et al.  HLA in coeliac disease: unravelling the complex genetics of a complex disorder. , 2003, Tissue antigens.

[39]  Jorma Ilonen,et al.  Prevalence of Celiac disease among children in Finland. , 2003, The New England journal of medicine.

[40]  E. Kistner,et al.  Reprogramming of CTLs into natural killer–like cells in celiac disease , 2006, The Journal of experimental medicine.

[41]  A. Gunturi,et al.  The role of TCR stimulation and TGF‐β in controlling the expression of CD94/NKG2A receptors on CD8 T cells , 2005, European journal of immunology.

[42]  David S Sanders,et al.  Newly identified genetic risk variants for celiac disease related to the immune response , 2008, Nature Genetics.

[43]  V. Raia,et al.  Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease , 2003, The Lancet.

[44]  Bernhard Schmierer,et al.  TGFβ–SMAD signal transduction: molecular specificity and functional flexibility , 2007, Nature Reviews Molecular Cell Biology.

[45]  T. Macdonald,et al.  Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21 , 2006, Gut.

[46]  T. Macdonald,et al.  IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes1 , 2007, The Journal of Immunology.

[47]  J. Rioux,et al.  Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis , 2009, Gut.

[48]  Seiamak Bahram,et al.  A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. , 2004, Immunity.

[49]  I. McInnes,et al.  Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. , 2004, Current opinion in pharmacology.

[50]  Vahid Asnafi,et al.  Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. , 2003, Gastroenterology.

[51]  Ying E Zhang,et al.  Non-Smad pathways in TGF-β signaling , 2009, Cell Research.

[52]  E. Bottinger,et al.  A mechanism of suppression of TGF–β/SMAD signaling by NF-κB/RelA , 2000, Genes & Development.

[53]  J. Massagué,et al.  Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway , 1999, Nature.

[54]  N. Cerf-Bensussan,et al.  Celiac disease: from oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis , 2009, Mucosal Immunology.

[55]  R. Winchester,et al.  TCR specificity dictates CD94/NKG2A expression by human CTL. , 2002, Immunity.

[56]  G. Ciliberto,et al.  The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells , 2009, The Journal of experimental medicine.

[57]  Jun Wu,et al.  An activating immunoreceptor complex formed by NKG2D and DAP10. , 1999, Science.