Advertisement

Digestive Diseases and Sciences

, Volume 53, Issue 2, pp 500–505 | Cite as

Co-Occurrence of IgA Antibodies Against Ethanol Metabolites and Tissue Transglutaminase in Alcohol Consumers: Correlation with Proinflammatory Cytokines and Markers of Fibrogenesis

  • Heidi Koivisto
  • Johanna Hietala
  • Petra Anttila
  • Onni Niemelä
Original Paper

Abstract

IgA antibodies to tissue transglutaminase have been suggested to be specific indicators of celiac disease. However, no studies have addressed the relationships between such antibodies and alcohol abuse, which is also a common cause of IgA-isotype immune responses and tissue injury in the gastrointestinal tract and liver. Here, measurements of specific IgAs against tissue transglutaminase and proteins modified by acetaldehyde, the first metabolite of ethanol, showed significantly higher levels of both antibodies in alcoholic liver disease patients than in healthy controls or heavy drinkers without liver disease. These antibodies also significantly co-occurred in heavy drinkers without liver disease, moderate drinkers, and abstainers, and correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis. The data suggests a link between such immune responses, perturbations in cytokine profiles and fibrogenesis, which should be implicated in studies on the pathogenesis and diagnosis of ethanol-induced tissue injury and celiac disease.

Keywords

Alcohol Autoimmunity Celiac disease Gut Liver disease 

Notes

Acknowledgement

The studies were supported in part by the Finnish Foundation for Alcohol Studies.

References

  1. 1.
    Cho E, Smith-Warner SA, Ritz J, van den Brandt PA, Colditz GA, Folsom AR, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Holmberg L, Kim DH, Malila N, Miller AB, Pietinen P, Rohan TE, Sellers TA, Speizer FE, Willett WC, Wolk A, Hunter DJ (2004) Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 140:603–613PubMedGoogle Scholar
  2. 2.
    Laheij RJ, Verlaan M, Van Oijen MG, De Doelder MS, Dejong CA, Jansen JB (2004) Gastrointestinal symptoms and ethanol metabolism in alcoholics. Dig Dis Sci 49:1007–1011PubMedCrossRefGoogle Scholar
  3. 3.
    Lieber CS (1995) Medical disorders of alcoholism. N Engl J Med 333:1058–1065PubMedCrossRefGoogle Scholar
  4. 4.
    Seitz HK, Salaspuro M, Savolainen M, Haber P, Ishii H, Teschke R, Moshage H, Lieber CS (2005) From alcohol toxicity to treatment. Alcohol Clin Exp Res 29:1341–1350PubMedCrossRefGoogle Scholar
  5. 5.
    Rajendram R, Preedy VR (2005) Effect of alcohol consumption on the gut. Dig Dis 23:214–221PubMedCrossRefGoogle Scholar
  6. 6.
    Salaspuro MP (2003) Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci 40:183–208PubMedCrossRefGoogle Scholar
  7. 7.
    Seitz HK, Gartner U, Egerer G, Simanowski UA (1994) Ethanol metabolism in the gastrointestinal tract and its possible consequences. Alcohol Alcohol Suppl 2:157–162PubMedGoogle Scholar
  8. 8.
    Visapää JP, Jokelainen K, Nosova T, Salaspuro M (1998) Inhibition of intracolonic acetaldehyde production and alcoholic fermentation in rats by ciprofloxacin. Alcohol Clin Exp Res 22:1161–1164PubMedCrossRefGoogle Scholar
  9. 9.
    Latvala J, Hietala J, Koivisto H, Järvi K, Anttila P, Niemelä O (2005) Immune responses to ethanol metabolites and cytokine profiles differentiate alcoholics with or without liver disease. Am J Gastroenterol 100:1303–1310PubMedCrossRefGoogle Scholar
  10. 10.
    Tuma DJ, Klassen LW (1992) Immune responses to acetaldehyde-protein adducts: role in alcoholic liver disease. Gastroenterology 103:1969–1973PubMedGoogle Scholar
  11. 11.
    Worrall S, de Jersey J, Shanley BC, Wilce PA (1991) Antibodies against acetaldehyde-modified epitopes: an elevated IgA response in alcoholics. Eur J Clin Invest 21:90–95PubMedCrossRefGoogle Scholar
  12. 12.
    Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396PubMedCrossRefGoogle Scholar
  13. 13.
    Martin A, Romito G, Pepe I, De Vivo G, Merola MR, Limatola A, Gentile V (2006) Transglutaminase-catalyzed reactions responsible for the pathogenesis of celiac disease and neurodegenerative diseases: from basic biochemistry to clinic. Curr Med Chem 13:1895–1902PubMedCrossRefGoogle Scholar
  14. 14.
    Green PH, Jabri B (2006) Celiac disease. Annu Rev Med 57:207–221PubMedCrossRefGoogle Scholar
  15. 15.
    Wodzinska JM (2005) Transglutaminases as targets for pharmacological inhibition. Mini Rev Med Chem 5:279–292PubMedGoogle Scholar
  16. 16.
    Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3:797–801PubMedCrossRefGoogle Scholar
  17. 17.
    Chand N, Mihas AA (2006) Celiac disease: current concepts in diagnosis and treatment. J Clin Gastroenterol 40:3–14PubMedCrossRefGoogle Scholar
  18. 18.
    Hourigan CS (2006) The molecular basis of coeliac disease. Clin Exp Med 6:53–59PubMedCrossRefGoogle Scholar
  19. 19.
    Mäki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, Ilonen J, Laurila K, Dahlbom I, Hansson T, Höpfl P, Knip M (2003) Prevalence of celiac disease among children in Finland. N Engl J Med 348:2517–2524PubMedCrossRefGoogle Scholar
  20. 20.
    Sanders DS, Hurlstone DP (2005) Do patients with unrecognized coeliac disease present as an emergency? Eur J Emerg Med 12:303–305PubMedCrossRefGoogle Scholar
  21. 21.
    Orrego H, Israel Y, Blake JE, Medline A (1983) Assessment of prognostic factors in alcoholic liver disease: toward a global quantitative expression of severity. Hepatology 3:896–905PubMedCrossRefGoogle Scholar
  22. 22.
    Orrego H, Blake JE, Blendis LM, Medline A (1987) Prognosis of alcoholic cirrhosis in the presence and absence of alcoholic hepatitis. Gastroenterology 92:208–214PubMedGoogle Scholar
  23. 23.
    Hietala J, Koivisto H, Latvala J, Anttila P, Niemelä O (2006) IgAs against acetaldehyde-modified red cell protein as a marker of ethanol consumption in male alcoholic subjects, moderate drinkers, and abstainers. Alcohol Clin Exp Res 30:1693–1698PubMedCrossRefGoogle Scholar
  24. 24.
    Carroccio A, Vitale G, Di Prima L, Chifari N, Napoli S, La Russa C, Gulotta G, Averna MR, Montalto G, Mansueto S, Notarbartolo A (2002) Comparison of anti-transglutaminase ELISAs and an anti-endomysial antibody assay in the diagnosis of celiac disease: a prospective study. Clin Chem 48:1546–1550PubMedGoogle Scholar
  25. 25.
    Koop I, Ilchmann R, Izzi L, Adragna A, Koop H, Barthelmes H (2000) Detection of autoantibodies against tissue transglutaminase in patients with celiac disease and dermatitis herpetiformis. Am J Gastroenterol 95:2009–2014PubMedCrossRefGoogle Scholar
  26. 26.
    Sulkanen S, Halttunen T, Laurila K, Kolho KL, Korponay-Szabó IR, Sarnesto A, Savilahti E, Collin P, Mäki M (1998) Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology 115:1322–1328PubMedCrossRefGoogle Scholar
  27. 27.
    Lo Iacono O, Petta S, Venezia G, Di Marco V, Tarantino G, Barbaria F, Mineo C, De Lisi S, Almasio PL, Craxì A (2005) Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: is it always coeliac disease?. Am J Gastroenterol 100:2472–2477PubMedCrossRefGoogle Scholar
  28. 28.
    Vecchi M, Folli C, Donato MF, Formenti S, Arosio E, de Franchis R (2003) High rate of positive anti-tissue transglutaminase antibodies in chronic liver disease. Role of liver decompensation and of the antigen source. Scand J Gastroenterol 38:50–54PubMedCrossRefGoogle Scholar
  29. 29.
    Villalta D, Crovatto M, Stella S, Tonutti E, Tozzoli R, Bizzaro N (2005) False positive reactions for IgA and IgG anti-tissue transglutaminase antibodies in liver cirrhosis are common and method-dependent. Clin Chim Acta 356:102–109PubMedCrossRefGoogle Scholar
  30. 30.
    Dieterich W, Esslinger B, Trapp D, Hahn E, Huff T, Seilmeier W, Wieser H, Schuppan D (2006) Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease. Gut 55:478–484PubMedCrossRefGoogle Scholar
  31. 31.
    Gianfrani C, Auricchio S, Troncone R (2005) Adaptive and innate immune responses in celiac disease. Immunol Lett 99:141–145PubMedCrossRefGoogle Scholar
  32. 32.
    Hansson T, Dannaeus A, Klareskog L (1999) Cytokine-producing cells in peripheral blood of children with coeliac disease secrete cytokines with a type 1 profile. Clin Exp Immunol 116:246–250PubMedCrossRefGoogle Scholar
  33. 33.
    Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR (2005) Recent advances in alcohol-induced adduct formation. Alcohol Clin Exp Res 29:1310–1316PubMedCrossRefGoogle Scholar
  34. 34.
    Israel Y, Hurwitz E, Niemelä O, Arnon R (1986) Monoclonal and polyclonal antibodies against acetaldehyde-containing epitopes in acetaldehyde-protein adducts. Proc Natl Acad Sci USA 83:7923–7927PubMedCrossRefGoogle Scholar
  35. 35.
    Niemelä O (2001) Distribution of ethanol-induced protein adducts in vivo: relationship to tissue injury. Free Radic Biol Med 31:1533–1538PubMedCrossRefGoogle Scholar
  36. 36.
    Tuma DJ, Newman MR, Donohue TM Jr, Sorrell MF (1987) Covalent binding of acetaldehyde to proteins: participation of lysine residues. Alcohol Clin Exp Res 11:579–584PubMedCrossRefGoogle Scholar
  37. 37.
    Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, Eisenbarth GS (1999) One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J Autoimmun 13:143–148PubMedCrossRefGoogle Scholar
  38. 38.
    Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou J (2006) Cytokines and alcohol. Alcohol Clin Exp Res 30:720–730PubMedCrossRefGoogle Scholar
  39. 39.
    Hill DB, Marsano LS, McClain CJ (1993) Increased plasma interleukin-8 concentrations in alcoholic hepatitis. Hepatology 18:576–580PubMedCrossRefGoogle Scholar
  40. 40.
    Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI (1991) Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology 13:267–276PubMedGoogle Scholar
  41. 41.
    McClain CJ, Cohen DA (1989) Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 9:349–351PubMedCrossRefGoogle Scholar
  42. 42.
    Neuman MG, Brenner DA, Rehermann B, Taieb J, Chollet-Martin S, Cohard M, Garaud JJ, Poynard T, Katz GG, Cameron RG, Shear NH, Gao B, Takamatsu M, Yamauchi M, Ohata M, Saito S, Maeyama S, Uchikoshi T, Toda G, Kumagi T, Akbar SM, Abe M, Michitaka K, Horiike N, Onji M (2001) Mechanisms of alcoholic liver disease: cytokines. Alcohol Clin Exp Res 25:251S–253SPubMedGoogle Scholar
  43. 43.
    Bird GL, Sheron N, Goka AK, Alexander GJ, Williams RS (1990) Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med 112:917–920PubMedGoogle Scholar
  44. 44.
    Felver ME, Mezey E, McGuire M, Mitchell MC, Herlong HF, Veech GA, Veech RL (1990) Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res 14:255–259PubMedCrossRefGoogle Scholar
  45. 45.
    Huang YS, Chan CY, Wu JC, Pai CH, Chao Y, Lee SD (1996) Serum levels of interleukin-8 in alcoholic liver disease: relationship with disease stage, biochemical parameters and survival. J Hepatol 24:377–384PubMedCrossRefGoogle Scholar
  46. 46.
    McClain C, Barve S, Joshi-Barve S, Song Z, Deaciuc I, Chen T, Hill D (2005) Dysregulated cytokine metabolism, altered hepatic methionine metabolism and proteasome dysfunction in alcoholic liver disease. Alcohol Clin Exp Res 29:180S–188SPubMedCrossRefGoogle Scholar
  47. 47.
    Swiatkowska-Stodulska R, Bakowska A, Drobinska-Jurowiecka A (2006) Interleukin-8 in the blood serum of patients with alcoholic liver disease. Med Sci Monit 12:CR215–CR220PubMedGoogle Scholar
  48. 48.
    Colantoni A, Idilman R, De Maria N, La Paglia N, Belmonte J, Wezeman F, Emanuele N, Van Thiel DH, Kovacs EJ, Emanuele MA (2003) Hepatic apoptosis and proliferation in male and female rats fed alcohol: role of cytokines. Alcohol Clin Exp Res 27:1184–1189PubMedCrossRefGoogle Scholar
  49. 49.
    Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG (1997) Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26:1530–1537PubMedCrossRefGoogle Scholar
  50. 50.
    Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG (1999) Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117:942–952PubMedCrossRefGoogle Scholar
  51. 51.
    Joshi-Barve S, Barve SS, Butt W, Klein J, McClain CJ (2003) Inhibition of proteasome function leads to NF-kappaB-independent IL-8 expression in human hepatocytes. Hepatology 38:1178–1187PubMedCrossRefGoogle Scholar
  52. 52.
    Stephens P, Grenard P, Aeschlimann P, Langley M, Blain E, Errington R, Kipling D, Thomas D, Aeschlimann D (2004) Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses. J Cell Sci 117:3389–3403PubMedCrossRefGoogle Scholar
  53. 53.
    Metzger MH, Heier M, Mäki M, Bravi E, Schneider A, Löwel H, Illig T, Schuppan D, Wichmann HE (2006) Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989–1998. Eur J Epidemiol 21:359–365PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Heidi Koivisto
    • 1
    • 2
  • Johanna Hietala
    • 1
    • 2
  • Petra Anttila
    • 1
    • 2
  • Onni Niemelä
    • 1
    • 2
  1. 1.Medical Research Unit and Department of Laboratory MedicineSeinäjoki Central HospitalSeinajokiFinland
  2. 2.University of TampereTampereFinland

Personalised recommendations