Serum cytokine elevations in celiac disease: association with disease presentation.

Celiac disease (CD) is an autoimmune disorder that is triggered by an immune response to gluten in genetically predisposed individuals. Although considered a primary gastrointestinal disease, CD is now known to have widespread systemic manifestations. We attempted to define the nature and role of systemic cytokine levels in the pathophysiology of CD. Multiplex cytokine assays were performed on four different groups of adult patients; patients with active CD (ACD), patients on a gluten-free diet (GFD) with positive TTG IgA antibodies, patients on a GFD with negative antibodies, and those with refractory CD (RCD). The results were compared with values in healthy adult controls. Patients with active CD and those on GFD with positive antibodies had significantly higher levels of proinflammatory cytokines, such as interferon-gamma, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6 and IL-8, and also T(h)-2 cytokines such as IL-4 and IL-10, compared with normal controls and patients on GFD without antibodies. Interestingly patients on GFD for less than 1 year had significantly higher levels of both proinflammatory cytokines and T(h)2 cytokines compared with the patients on GFD for more than 1 year. In addition, a statistically significant correlation between levels of TTG IgA titers and serum levels of T(h)-2 cytokines IL-4 (p < 0.001), IL-10 (p < 0.001) and inflammatory cytokines such as IL-1alpha (p < 0.001), IL-1beta (p < 0.005), and IL-8 (p < 0.05) was observed.

[1]  A. Fasano,et al.  Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. , 2001, Gastroenterology.

[2]  P. Green,et al.  Extraintestinal manifestations of celiac disease , 2006, Current gastroenterology reports.

[3]  J. Adams,et al.  Interleukin 1 beta down-regulates collagen and augments collagenase expression in human intestinal smooth muscle cells. , 1996, Gastroenterology.

[4]  W. Scherbaum,et al.  Antibodies to Human Recombinant Tissue Transglutaminase Measured by Radioligand Assay: Evidence for High Diagnostic Sensitivity for Celiac Disease , 1999, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[5]  Murphy Pm.  Neutrophil receptors for interleukin-8 and related CXC chemokines. , 1997 .

[6]  P. Ciclitira,et al.  Raised pro-inflammatory cytokines interleukin 6 and tumour necrosis factor alpha in coeliac disease mucosa detected by immunohistochemistry. , 1994, Gut.

[7]  C. Wijmenga,et al.  The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility. , 2004, Journal of autoimmunity.

[8]  D. Schuppan,et al.  Autoantibodies to tissue transglutaminase as predictors of celiac disease. , 1998, Gastroenterology.

[9]  M. Kagnoff,et al.  Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge , 1997, Clinical and experimental immunology.

[10]  M. Černá,et al.  Gliadin Peptides Activate Blood Monocytes from Patients with Celiac Disease , 2007, Journal of Clinical Immunology.

[11]  J. Peteiro-Cartelle,et al.  Increased Serum Levels of Interleukin‐2 and Soluble Interleukin‐2 Receptor in Celiac Disease , 1991, Journal of pediatric gastroenterology and nutrition.

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

[13]  D. Lio,et al.  Gluten Stimulation Induces an in vitro Expansion of Peripheral Blood Tγδ Cells from HLA-DQ2-Positive Subjects of Families of Patients with Celiac Disease , 1998, Experimental and Clinical Immunogenetics.

[14]  E. Bonifacio,et al.  Comparison of tissue transglutaminase-specific antibody assays with established antibody measurements for coeliac disease. , 1999, Journal of autoimmunity.

[15]  G. Corazza,et al.  Plasma cytokine profiles in patients with celiac disease and selective IgA deficiency , 2003, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[16]  O. Hernell,et al.  Concomitant increase of IL-10 and pro-inflammatory cytokines in intraepithelial lymphocyte subsets in celiac disease. , 2007, International immunology.

[17]  J. Gordon.  CD23 and B cell activation , 1992, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[18]  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.

[19]  E. Broide,et al.  Lack of Correlation between Disease Activity and Decreased Stimulated Secretion of IL-10 in Lymphocytes from Patients with Celiac Disease , 2002, Scandinavian journal of gastroenterology.

[20]  T. Mosmann,et al.  Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies , 1987, The Journal of experimental medicine.

[21]  Frits Koning,et al.  Celiac disease--sandwiched between innate and adaptive immunity. , 2006, Human Immunology.

[22]  P. Murphy.  Neutrophil receptors for interleukin-8 and related CXC chemokines. , 1997, Seminars in hematology.

[23]  E. Savilahti,et al.  Inflammatory cytokines in small intestinal mucosa of patients with potential coeliac disease , 2002, Clinical and experimental immunology.

[24]  R. Coffman,et al.  Control of isotype switching by T cells and cytokines. , 1991, Current opinion in immunology.

[25]  G. A. Limb,et al.  Cytokine mRNA expression in the mucosa of treated coeliac patients after wheat peptide challenge. , 1995, Gut.

[26]  A. Šedivá,et al.  Gliadin Fragments Induce Phenotypic and Functional Maturation of Human Dendritic Cells1 , 2005, The Journal of Immunology.

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

[28]  F. León,et al.  Cytokine Production by Intestinal Intraepithelial Lymphocyte Subsets in Celiac Disease , 2005, Digestive Diseases and Sciences.

[29]  M. Sata,et al.  Interleukin-6 trans-signaling in inflammatory bowel disease. , 2006, Cytokine & growth factor reviews.

[30]  I. Korponay-Szabó,et al.  Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. , 1998, Gastroenterology.

[31]  K. Lundin,et al.  Gluten activation of peripheral blood T cells induces a Th0‐like cytokine pattern in both coeliac patients and controls , 1996, Clinical and experimental immunology.

[32]  A. Mauviel.  Cytokine regulation of metalloproteinase gene expression , 1993, Journal of cellular biochemistry.

[33]  L. Sollid.  Molecular basis of celiac disease. , 2000, Annual review of immunology.

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

[35]  R. Pujol-Borrell,et al.  Human intestinal αβ IEL clones in celiac disease show reduced IL-10 synthesis and enhanced IL-2 production , 2006 .

[36]  W. Paul,et al.  Regulation of IgG1 and IgE Production by Interleukin 4 , 1988, Immunological reviews.

[37]  G. Oberhuber,et al.  The histopathology of coeliac disease: time for a standardized report scheme for pathologists. , 1999, European journal of gastroenterology & hepatology.

[38]  J. Spencer,et al.  Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine , 1988, The Journal of experimental medicine.

[39]  J. Abrams,et al.  Seronegative Celiac Disease: Increased Prevalence with Lesser Degrees of Villous Atrophy , 2004, Digestive Diseases and Sciences.

[40]  J. Abrams,et al.  Utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[41]  D. Barbieri,et al.  Serum Soluble Interleukin-2 Receptor, Interleukin-6, and Tumor Necrosis Factor-&agr; Levels in Children with Celiac Disease: Response to Treatment , 2002, Journal of pediatric gastroenterology and nutrition.

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

[43]  D. Schuppan,et al.  Identification of tissue transglutaminase as the autoantigen of celiac disease , 1997, Nature Medicine.

[44]  A. Lerner,et al.  TH1/TH2 cytokine profile in celiac disease. , 1997, Israel journal of medical sciences.

[45]  G. A. Limb,et al.  Detection of interferon gamma mRNA in the mucosa of patients with coeliac disease by in situ hybridisation. , 1994, Gut.

[46]  P. Ciclitira,et al.  Analysis of interleukin-4 and interleukin-10 and their association with the lymphocytic infiltrate in the small intestine of patients with coeliac disease. , 1996, Gut.

[47]  I. Nakshabendi,et al.  Immunohistochemical analysis of mucosal gamma-interferon production in coeliac disease. , 1992, Gut.

[48]  A. Torsoli,et al.  Identification of a new coeliac disease subgroup: antiendomysial and anti‐transglutaminase antibodies of IgG class in the absence of selective IgA deficiency , 2001, Journal of internal medicine.

[49]  Is coeliac disease prevalent among adolescent psychiatric patients? , 2002, Acta paediatrica.

[50]  R. Coffman,et al.  Two types of mouse helper T-cell clone Implications for immune regulation. , 1987, Immunology today.

[51]  M. Mäki,et al.  Phenotypical characterization of peripheral blood T cells in patients with coeliac disease: elevation of antigen-primed CD45RO+ T lymphocytes. , 1995, Immunology.

[52]  E. Smecuol,et al.  Pre- and Post-Treatment Serum Levels of Cytokines IL-1β, IL-6, and IL-1 Receptor Antagonist in Celiac Disease. Are They Related to the Associated Osteopenia? , 1998, American Journal of Gastroenterology.

[53]  R. Streilein,et al.  Serum IL-8 in patients with dermatitis herpetiformis is produced in response to dietary gluten. , 2007, The Journal of investigative dermatology.

[54]  C. Gianfrani,et al.  Adaptive and innate immune responses in celiac disease. , 2005, Immunology letters.

[55]  C. Dinarello,et al.  Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. , 1998, International reviews of immunology.

[56]  H. Stein,et al.  Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease , 1999, Gut.

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

[58]  F. Cataldo,et al.  Increased Prevalence of Autoimmune Diseases in First-Degree Relatives of Patients With Celiac Disease , 2003, Journal of pediatric gastroenterology and nutrition.

[59]  B. V. von Blomberg,et al.  Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice , 1999, American Journal of Gastroenterology.

[60]  D. Lio,et al.  Gluten stimulation induces an in vitro expansion of peripheral blood T gamma delta cells from HLA-DQ2-positive subjects of families of patients with celiac disease. , 1998, Experimental and clinical immunogenetics.

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

[62]  S. Melgar,et al.  Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. , 2002, Gastroenterology.