Abstract
Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology and several cytokines have been implicated in its pathogenesis and onset. Our objective was to determine the profile of pro and anti-inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-23, IFN-γ, TNF-α, IL-10 in autoimmune hepatitis and their association with HLA gene polymorphisms. Serum cytokine levels were determined in 50 autoimmune hepatitis patients and one hundred fifty controls using chemiluminescence and ELISA techniques and HLA genotyping performed by PCR SSP. The levels of IL-6 (12 pg/mL vs. 5.5 pg/mL, p = 0.017), IL-8 (24.1 pg/mL vs. 7.8 pg/mL, p = 0.006), and TNF-α (61.1 pg/mL vs. <4.00 pg/mL, p = 0.002) were significantly higher in AIH patients in pretreatment phase compared to levels after remission and in controls. HLA*DRB15 was significantly associated with higher levels of IL-8. IL-6, IL-8, and TNF-α may be biomarkers of AIH activity. HLA gene expression may play a role in higher cytokine production and could allow an earlier diagnosis and better management of the disease.
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References
Manns MP, Vogel A. Autoimmune hepatitis, from mechanisms to therapy. Hepatology 2006; 43: 132–44.
Lohse AW, Mieli-Vergani G. Autoimmune hepatitis. J Hepatol 2011; 55: 171–82.
Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51: 2193–213.
Kogan J, Safadi R, Ashur Y, Shouval D, Ilan Y. Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients. J Clin Gastroenterol 2002; 35: 75.
Werner M, Prytz H, Ohlsson B, Almer S, Björnsson E, Bergquist A. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand J Gastroenterol 2008; 43: 1232–40.
Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD41 T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 1995; 16: 34–8.
Czaja AJ. Current concepts in autoimmune hepatitis. Ann hepatol 2005; 4(1):6.
Czaja AJ. Autoimmune hepatitis: Evolving concepts and treatment strategies. Dig Dis Sci 1995; 40: 435.
Nishioji K, Okanoue T, Itoh Y, et al. Increase of chemokine interferon-inducible protein-10 (IP-10) in the serum of patients with autoimmune liver diseases and increase of its mRNA expression in hepatocytes. Clin Exp Immunol 2001; 123: 271–9.
Czaja AL, Sievers C, Zein NN. Nature and behavior of serum cytokines in Type 1 autoimmune hepatitis. Dig Dis Sci 2000; 45: 1028.
Coffman RL. Origins of the T(H)1-T(H)2 model: a personal perspective. Nat Immunol 2006; 7: 539.
Lohr HF, Schaak JF, Gerken G, Fleischer B, Dienes H-P, Meyer zum Buschenfelde K-H. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver Int 1994; 14: 161.
Al-Wabel A, Al-Janadi M, Raziuddin S. Cytokine profile of viral and autoimmune chronic active hepatitis. J Allergy Clin Immunol 1993; 92: 902.
Kammoun-Krichen M, Bougacha-Elleuch N, Makni K, Rebai M, Peraldi-Roux S, Rebai A. Association analysis of interleukin gene polymorphisms in autoimmune thyroid diseases in the Tunisian population. Eur Cytokine Netw 2007; 18(4):196.
Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev 1996; 9: 532–62.
Czaja AJ, Manns MP. The validity and importance of subtypes of autoimmune hepatitis: a point of view. Am J Gastroenterol 1995; 90: 1206.
Marrakchi R, Moussa A, Ouerhani S, et al. Rouissi Interleukin 10, Promoter region polymorphisms in inflammatory bowel disease in Tunisian population. Inflamm Res 2009; 58(3):155–60.
Miyazaki A, Hanafusa T, Itoh N, et al. Demonstration of interleukin-1 beta on perifollicular endothelial cells in the thyroid glands of patients with Graves’disease. J Clin Endocrinol Metab 1989; 69: 738.
Zouidi F, Stayoussef M, Bouzid D, Fourati H, Abida O, João C. Association of BANK1 and cytokine gene polymorphisms with type 1 diabetes in Tunisia. Gene 2014; 536(2):296–301.
Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K. Cytokine profile in Behçet’s disease patients. Relationship with disease activity. Scand J Rheumatol 2009; 31(4):205–10.
Lagha A, Zidi S, Stayoussef M, Gazouani E, Kochkar R, Ochbati S. Interleukin-1β, Interleukin1-Ra, Interleukin-10, and tumor necrosis factor-α polymorphisms in Tunisian patients with rheumatoid arthritis. Pathol Biol 2015; 63: 179–84.
Eddleston AL, Donaldson PT, Hegarty JE, Reed BD. Immunological aspects of liver disease. Gut 1991; 32: 540–6.
Landi A, Weismuller TJ, Lankisch TO, et al. Differential serum levels of eosinophilic eotaxins in primary sclerosing cholangitis, primary biliary cirrhosis and autoimmune hepatitis. J Interferon Cytokine Res 2014; 34: 204.
Chaouali M, Azaiez MB, Tezeghdenti A, et al. Association of TNF-α-308 polymorphism with susceptibility to autoimmune hepatitis in Tunisians. Biochem Genet 2018; 56: 650.
Chaouali M, Carvalho A, Tezeghdenti A, et al. Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population. Genes Dis 2017; 30: 256.
Chaouali M, Fernandes V, Ghazouani E, Pereira L, Kochkar R. Association of STAT4, TGFβ1, SH2B3 and PTPN22 polymorphisms with autoimmune hepatitis. Exp Mol Pathol 2018; 3: 279.
Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterol 1992; 103: 264–74.
Maggiore G, De Benedetti F, Massa M, Pignatti P, Martini A. Circulating levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in children with autoimmune hepatitis. J Pediatr Gastroenterol Nutr 1995; 20: 23–7.
Kishimoto T. The biology of interleukin-6. Blood 1989; 74: 1.
Chaouali M, Kochkar R, Messadi A, et al. Distribution of HLA-DRB1/DQB1 alleles and DRB1-DQB1 haplotypes among Tunisian patients with autoimmune hepatitis. Egypt J Hum Med Genet 2017; 18: 335.
Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, Donaldson PT. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 1999; 30: 851.
Czaja AJ, Cookson S, Constantini PK, Clare M. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterol 1999; 117: 645.
Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med 2011; 43: 503–11.
Zhao L, Tang Y, You Z, et al. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One 2011; 6(4):e18909.
Kamijo A, Yoshizawa K, Joshita S, Yoneda S, Umemura T, Ichijo T. Cytokine profiles affecting the pathogenesis of autoimmune hepatitis in Japanese patients. Hepatol Res 2011; 41: 350.
Acknowledgements
We thank all patients for their contribution to the study. We are indebted to Dr J Kharat, professor at the Gastroenterology Department of Habib Thameur Hospital and Dr K El Jeri, professor at the Gastroenterology of Charles Nicolle hospital, for their help and contribution. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Chaouali, M., Azaiez, M.B., Tezeghdenti, A. et al. High levels of proinflammatory cytokines IL-6, IL-8, TNF-A, IL-23, and IFN-γ in Tunisian patients with type 1 autoimmune hepatitis. Eur Cytokine Netw 31, 94–103 (2020). https://doi.org/10.1684/ecn.2020.0450
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DOI: https://doi.org/10.1684/ecn.2020.0450