Gliadin Peptides Activate Blood Monocytes from Patients with Celiac Disease

To elucidate the role of innate immune responses in celiac disease, we investigated the effect of gliadin on blood monocytes from patients with celiac disease. Gliadin induced substantial TNF-α and IL-8 production by monocytes from patients with active celiac disease, lower levels by monocytes from patients with inactive celiac disease, and even lower levels by monocytes from healthy donors. In healthy donor monocytes gliadin induced IL-8 from monocytes expressing HLA-DQ2 and increased monocyte expression of the costimulatory molecules CD80 and CD86, the dendritic cell marker CD83, and the activation marker CD40. Gliadin also increased DNA binding activity of NF-κB p50 and p65 subunits in monocytes from celiac patients, and NF-κB inhibitors reduced both DNA binding activity and cytokine production. Thus, gliadin activation of HLA-DQ2+ monocytes leading to chemokine and proinflammatory cytokine production may contribute to the host innate immune response in celiac disease.

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  1. 1

    Trier JS: Celiac sprue. N Engl J Med 325:1709–1719, 1991

    PubMed  CAS  Article  Google Scholar 

  2. 2

    Marsh MN: Gluten, major histocompatibility complex, and the small intestine. A molecular and immunbiologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 102:330–354, 1992

    PubMed  CAS  Google Scholar 

  3. 3

    Maki M, Collin P: Coeliac disease. Lancet 349:1755–1759, 1997

    PubMed  Article  CAS  Google Scholar 

  4. 4

    Schuppan D: Current concepts of celiac disease pathogenesis. Gastroenterology 119:234–242, 2000

    PubMed  Article  CAS  Google Scholar 

  5. 5

    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 169:345–350, 1989

    PubMed  Article  CAS  Google Scholar 

  6. 6

    Sollid LM: Coeliac disease: Dissecting a complex inflammatory disorder. Nat Rev Immunol 2:647–655, 2002

    PubMed  Article  CAS  Google Scholar 

  7. 7

    Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Solid LM, Jahnsen J, Scott H, Brandtzaeg P: Gluten induced an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 115:551–563, 1998

    PubMed  Article  CAS  Google Scholar 

  8. 8

    Strober W, Fuss IJ: Gluten-sensitive enteropathy and other immunologically mediated enteropaties. In Mucosal Immunology, PL Ogra, J Mestecky, ME Lamm (eds). San Diego, CA, Academic, 1999, pp 1101–1128

    Google Scholar 

  9. 9

    Eiras P, Leon F, Camarero C, Lombardia M, Roldan E, Bootello A, Roy G: Intestinal intraepithelial lymphocytes contain a CD3-CD7+ subset expressing natural killer markers and a singular pattern of adhesion molecules. Scand J Immunol 52:1–6, 2000

    PubMed  Article  CAS  Google Scholar 

  10. 10

    Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, Verkarre V, Fodil N, Bahram S, Cerf-Bensussan N, Caillat-Zucman S: A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21:367–377, 2004

    PubMed  Article  Google Scholar 

  11. 11

    Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Laner LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B: Coordinated introduction by IL-15 of TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21:357–366, 2004

    PubMed  Article  CAS  Google Scholar 

  12. 12

    Sollid LM: Intraepithelial lymphocytes in celiac disease: Licence to kill revealed. Immunity 21:303–304, 2004

    PubMed  CAS  Google Scholar 

  13. 13

    Gianfrani C, Auricchio S, Troncone R: Adaptive and innate immune response in celiac disease. Immunol Lett 99:141–145, 2005

    PubMed  Article  CAS  Google Scholar 

  14. 14

    Ciccocioppo R, Di Sabatino A, Corazza GR: The immune recognition of gluten in celiac disease. Clin Exp Immunol 140:408–416, 2005

    PubMed  Article  CAS  Google Scholar 

  15. 15

    Valeski JE, Kumar V, Beutner EH, Lerner A, Chorzelski TP: Immunology of coeliac disease: Tissue and species specificity of endomysial and reticulin antibodies. Int Arch Allergy Appl Immunol 93:1–7, 1990

    PubMed  CAS  Google Scholar 

  16. 16

    Karpati S, Burgin-Wolff A, Krieg T, Meurer M, Stolz W, Braun-Flaco O: Binding to human jejunum of serum IgA antibody from children with coeliac disease. Lancet 336:1335–1338, 1990

    PubMed  Article  CAS  Google Scholar 

  17. 17

    Volta U, Molinaro N, Fratangelo D, Bianchi FB: IgA antibodies to jejunum. Specific immunity directed against target organ of gluten-sensitive enteropathy. Dig Dis Sci 39:1924–1929, 1994

    PubMed  Article  CAS  Google Scholar 

  18. 18

    Ascher H, Hahn-Zoric M, Hanson LA, Kilander AF, Nilsson LA, Tlaskalova H: Value of serological markers for clinic diagnosis and population studies of coeliac disease. Scand J Gastroenterol 31:61–67, 1996

    PubMed  CAS  Google Scholar 

  19. 19

    Karska K, Tuckova L, Steiner L, Tlaskalova-Hogenova H, Michalak M: Calreticulin—the potential autoantigen in celiac disease. Biochem Biophys Res Commun 209:597–605, 1995

    PubMed  Article  CAS  Google Scholar 

  20. 20

    Dieterich W, Laag E, Schopper H, Volta U, Ferguson A, Gillett H, Riecken EO, Schuppan D: Autoantibodies to tissue transglutaminase as predictor of coeliac disease. Gastroenterology 115:1317–1321, 1998

    PubMed  Article  CAS  Google Scholar 

  21. 21

    Stulik J, Hernychova L, Porkertova S, Pozler O, Tuckova L, Sanchez D, Bures J: Identification of new celiac disease autoantigens using proteomic analysis. Proteomics 3:951–956, 2003

    PubMed  Article  CAS  Google Scholar 

  22. 22

    Sollid LM, Jabri B: Is celiac disease an autoimmune disorder? Curr Opin Immunol 17:595–600, 2005

    PubMed  Article  CAS  Google Scholar 

  23. 23

    Tuckova L, Flegelova Z, Tlaskalova-Hogenova H, Zidek Z: Activation of macrophages by food antigens: Enhancing effect of gluten on nitric oxide and cytokine production. J Leukoc Biol 67:312–318, 2000

    PubMed  CAS  Google Scholar 

  24. 24

    Tuckova L, Novotna J, Novak P, Flegelova Z, Kveton T, Jelinkova L, Zidek Z, Man P, Tlaskalova-Hogenova H, Bezouska K, Havlicek V: Activation of macrophages by gliadin fragments: Isolation and characterization of active peptide. J Leukoc Biol 71:625–631, 2002

    PubMed  CAS  Google Scholar 

  25. 25

    Novak P, Man P, Tuckova L, Tlaskalova-Hoqenova H, Bezouska K, Havlicek V: Monitoring of in vitro deamidation of gliadin peptic fragments by mass spectrometry may reflect one of the molecular mechanisms taking place in celiac disease development. J Mass Spectrom 37:507–511, 2002.

    PubMed  Article  CAS  Google Scholar 

  26. 26

    De Stefano D, Maiuri MC, Iovine B, Ialenti A, Bevilacqua MA, Carnuccio R: The role of NF-kappa B, IRF-1, and STAT-1 alpha transcription factors in the iNOS gene induction by gliadin and IFN-gamma in RAW 264.7 macrophages. J Mol Med 84:65–74, 2006

    PubMed  Article  CAS  Google Scholar 

  27. 27

    Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, Picard J, Osman M, Quaratinos S, Londei M: Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362:30–37, 2003

    PubMed  Article  CAS  Google Scholar 

  28. 28

    Maiuri MC, De Stefano D, Mele G, Iovine B, Bevilacqua MA, Greco L, Auricchio S, Carnuccio R: Gliadin increases iNOS gene expression in interferon-gamma-stimulated RAW 264.7 cells through a mechanism involving NF-kappa B. Naunyn Schmiedebergs Arch Pharmacol 368:63–71, 2003

    PubMed  Article  CAS  Google Scholar 

  29. 29

    Jelinkova L, Tuckova L, Cinova J, Flegelova Z, Tlaskalova-Hogenova H: Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappa B. FEBS Lett 571:81–85, 2004

    PubMed  Article  CAS  Google Scholar 

  30. 30

    Palová-Jelínková L, Roková D, Pecharová B, Bartova J, Sediva A, Tlaskalova-Hogenova H, Spisek R, Tuckova L: Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol 175:7038–7045, 2005

    PubMed  Google Scholar 

  31. 31

    Walker-Smith JA, Guandalini S, Schmitz J, Working Group of European Society of Paediatric Gastroenterology and Nutrition: Revised criteria of diagnosis of coeliac disease. Arch Dis Child 65:909–911, 1990

    Article  Google Scholar 

  32. 32

    Mazzarella G, Maglio M, Paparo F, Nardone G, Stefanile R, Greco L, van de Wal Y, Kooy Y, Koning F, Auricchio S: An immunodominant DQ-8 restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA DQ-8 positive but not HLA-DQ8 negative coeliac patients. Gut 52:57–62, 2003

    PubMed  Article  CAS  Google Scholar 

  33. 33

    Olerup O, Zatterquist H: HLA DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 h: An alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 39:225–235, 1992

    Google Scholar 

  34. 34

    Zetterquist H, Olerup O: Identification of HLA-DRB1*04, DRB1*07 and DRB1*09 alleles by PCR amplification with sequence-specific primers (PCR-SSP) in 2 h. Hum Immunol 34:64–74, 1992

    Google Scholar 

  35. 35

    Holm S: A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70, 1979

    Google Scholar 

  36. 36

    Jelinkova L, Tuckova L, Sanchez D, Krupickova S, Pozler O, Nevoral J, Kotalova R, Tlaskalova-Hogenova H: Increased levels of cirulating ICAM-1, E-selectin and IL-2 receptors in celiac disease. Dig Dis Sci 45:398–402, 2000

    PubMed  Article  CAS  Google Scholar 

  37. 37

    Merendino RA, Di Pasquale G, Sturniolo GC, Ruello A, Albanese V, Minciullo PL, Di Mauro S, Gangemi S: Relationship between IL-18 and sICAM-1 serum levels in patients affected by coeliac disease: Preliminary considerations. Immunol Lett 85:257–260, 2003

    PubMed  Article  CAS  Google Scholar 

  38. 38

    Romaldini CC, Barbieri D, Okay TS, Raiz R Jr, Cancado EL: Serum soluble interleukin-2 receptor, interleukin-6, and tumor necrosis factor-alpha levels in children with coeliac disease: Response to treatment. J Pediatr Gastroenterol Nutr 35:513–517, 2002

    PubMed  Article  CAS  Google Scholar 

  39. 39

    Cataldo F, Lio D, Marino V, Scola L, Crivello A, Corazza GR, Working Group of the SIGEP, Working Group of “Club del Tenue”: Plasma cytokine profiles in patients with celiac disease and selective IgA deficiency. Pediatr Allergy Immunol 14:320–324, 2003

    Google Scholar 

  40. 40

    Pace E, Gjomarkaj M, Melis M, Profita M, Spatafora M, Vignola A, Bonsignore G, Mody CH: Interleukin-8 induces lymphocyte chemotaxis into the pleural space. Role of pleural macrophages. Am J Respir Crit Care Med 159:1592–1599, 1999

    PubMed  CAS  Google Scholar 

  41. 41

    Roth SJ, Carr MW, Springer TA: C-C chemokines, but not the C-X-C chemokines interleukin-8 and interferon-g inducible protein-10, stimulate transendothelial chemotaxis of T lymphocytes. Eur J Immunol 25:3482–3488, 1995

    PubMed  CAS  Google Scholar 

  42. 42

    Issekutz AC, Meager A, Otterness I, Issekutz TB: The role of tumour necrosis factor-a and IL-1 in polymorphonuclear leucocyte and T lymphocyte recruitment to joint inflammation in adjuvant arthritis. Clin Exp Immunol 97:26–32, 1994

    PubMed  CAS  Article  Google Scholar 

  43. 43

    Issekutz TB: Effects of six different cytokines on lymphocyte adherence to microvascular endothelium and in vivo lymphocyte migration in the rat. J Immunol 144:2140–2146, 1990

    PubMed  CAS  Google Scholar 

  44. 44

    Ding Z, Xiong K, Issekutz TB: Chemokines stimulate human T lymphocyte transendothelial migration to utilize VLA-4 in addition to LFA-1. J Leukoc Biol 69:458–466, 2001

    PubMed  CAS  Google Scholar 

  45. 45

    Sturgess RP, Macartney, JC, Makgoba MW, Hung CH, Haskard DO, Ciclitira PJ: Differential upregulation of intercellular adhesion molecule-1 in coeliac disease. Clin Exp Immunol 82:489–492, 1990

    PubMed  CAS  Article  Google Scholar 

  46. 46

    Pober JS, Gimbrone MA Jr, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, Springer TA: Overlapping patterns of activation of human endothelial cells by interleukin-1, tumor necrosis factor, and immune interferon. J Immunol 137:1893–1896, 1986

    PubMed  CAS  Google Scholar 

  47. 47

    Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Tacar M, Iacono G, Carroccio A, D’Agate C, Not T, Zampini L, Catáis C, Fasano A: Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 41:408–419, 2006

    PubMed  Article  CAS  Google Scholar 

  48. 48

    Sander GR, Cummins AG, Henshall T, Powell BC: Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett 579:4851–4855, 2005

    PubMed  Article  CAS  Google Scholar 

  49. 49

    Thomas KE, Sapone A, Fasano A, Vogel SN: Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in celiac disease. J Immunol 176:2512–2521, 2006

    PubMed  CAS  Google Scholar 

  50. 50

    Ghosh S, May MJ, Kopp EB: NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Ann Rev Immunol 16:225–260, 1998

    Article  CAS  Google Scholar 

  51. 51

    Maiuri MC, De Stefano D, Mele G, Fecarotta S, Greco L, Troncone R, Carnuccio R: Nuclear factor kappa B is activated in small intestinal mucosa of celiac patients. J Mol Med 81:373–379, 2003

    PubMed  CAS  Google Scholar 

  52. 52

    Baldwin AS: The NF-kappa B and I kappa B proteins: New discoveries and insights. Ann Rev Immunol 14:649–683, 1996

    Article  CAS  Google Scholar 

  53. 53

    Snyder JG, Prewitt R, Campsen J, Britt LD: PDTC and Mg132, inhibitors of NF-kappa B, block endotoxin induced vasodilatation of isolated rat skeletal muscle arterioles. Shock 17:304–307, 2002

    PubMed  Article  Google Scholar 

  54. 54

    Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, Orenstein JM, Smith PD: Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 115:66–75, 2005

    PubMed  Article  CAS  Google Scholar 

  55. 55

    Smythies LE, Maheshwari A, Clements R, Eckhoff D, Novak L, Vu HL, Mosteller-Barnum M, Sellers M, Smith PD: Mucosal IL-8 and TGF-b recruit blood monocytes: Evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leuk Biol 80:492–499, 2006

    Article  CAS  Google Scholar 

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This work was supported by the Grant Agency of the Czech Republic (Grants 310/05/2245 and 310/03/H147); the Grant Agency of the Czech Academy of Sciences (Grants AA5020210, AA5020205, 1QS500200572, and B5020407); the Grant Agency of the Ministry of Education (MSM 0021620814, GA UK 30/2006), Mininstry of Agriculture 1B53002 and Institutional Research Concept (Grant AV0Z50200510); and the National Institutes of Health (U.S.) (DK-74033, DK-47322, DK-54495, HD-41361, and DK-064400); the Crohn’s and Colitis Foundation of America; and the Research Service of the Veterans Administration

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CINOVA, J., PALOVÁ-JELÍNKOVÁ, L., SMYTHIES, L. et al. Gliadin Peptides Activate Blood Monocytes from Patients with Celiac Disease. J Clin Immunol 27, 201–209 (2007).

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  • Celiac disease
  • Innate immunity
  • Blood monocytes