Abstract
Background
T helper (Th) 17 cells participate in the pathogenesis of liver diseases but their exact role in acute-on-chronic hepatitis B liver failure (ACHBLF) still remains obscure.
Aims
This present study was aimed to characterize the circulating Th17 cells and to analyze their association with disease progression in ACHBLF.
Methods
This retrospective study consisted of 40 ACHBLF patients, 40 chronic hepatitis B (CHB) patients and 20 healthy controls. The frequency of peripheral Th17 cells and IL-17 mRNA level in peripheral blood mononuclear cells (PBMCs) were estimated by flow cytometry and relative quantitative real-time polymerase chain reaction.
Results
We found that the frequency of peripheral Th17 cells, as well as the level of IL-17 mRNA in PBMCs, was significantly increased in ACHBLF patients compared with CHB patients and healthy controls. In ACHBLF patients, the frequency of Th17 cells was positively correlated with serum total bilirubin (r = 0.392, P = 0.012) and model for end-stage liver disease scores (r = 0.383, P = 0.015), but negatively correlated with prothrombin activity (r = −0.317, P = 0.046). The same trend was observed as for relative expression of IL-17. Furthermore, the frequency of Th17 cells and IL-17 mRNA level were significantly elevated in non-survivors compared with survivors in ACHBLF patients.
Conclusions
These results suggested that Th17 cells as well as IL-17 might be related with disease severity and prognosis in ACHBLF patients.
Similar content being viewed by others
References
Lok AS. The maze of treatments for hepatitis B. N Engl J Med. 2005;352:2743–2746.
Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int. 2009;3:269–282.
Liu CL, Fan ST, Lo CM, et al. Live-donor liver transplantation for acute-on-chronic hepatitis B liver failure. Transplantation. 2003;76:1174–1179.
Apostolidis SA, Crispin JC, Tsokos GC. IL-17-producing T cells in lupus nephritis. Lupus. 2011;20:120–124.
Korn T, Oukka M, Kuchroo V, Bettelli E. Th17 cells: effector T cells with inflammatory properties. Semin Immunol. 2007;19:362–371.
Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing gamma delta T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31:321–330.
Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–1132.
Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology. 2010;51:81–91.
Wu W, Li J, Chen F, Zhu H, Peng G, Chen Z. Circulating Th17 cells frequency is associated with the disease progression in HBV infected patients. J Gastroenterol Hepatol. 2010;25:750–757.
Ge J, Wang K, Meng QH, Qi ZX, Meng FL, Fan YC. Implication of Th17 and Th1 cells in patients with chronic active hepatitis B. J Clin Immunol. 2010;30:60–67.
Yasumi Y, Takikawa Y, Endo R, Suzuki K. Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatol Res. 2007;37:248–254.
Ye Y, Xie X, Yu J, et al. Involvement of Th17 and Th1 effector responses in patients with Hepatitis B. J Clin Immunol. 2010;30:546–555.
Anderson SJ, Coleclough C. Regulation of CD4 and CD8 expression on mouse T cells. Active removal from the cell surface by two mechanisms. J Immunol. 1993;151:5123–5134.
Picker LJ, Singh MK, Zdraveski Z, et al. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood. 1995;86:1408–1419.
Chang YH, Yu CW, Lai LC, et al. Up-regulation of interleukin-17 expression by human papillomavirus type 16 E6 in nonsmall cell lung cancer. Cancer. 2010;116:4800–4809.
Bambha K, Kim WR, Kremers WK, et al. Predicting survival among patients listed for liver transplantation: an assessment of serial MELD measurements. Am J Transplant. 2004;4:1798–1804.
Mills KH. Induction, function and regulation of IL-17-producing T cells. Eur J Immunol. 2008;38:2636–2649.
Crispin JC, Oukka M, Bayliss G, et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008;181:8761–8766.
Glader P, Smith ME, Malmhall C, et al. Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin. Eur Respir J. 2010;36:1155–1164.
Pitcher C, Honing S, Fingerhut A, Bowers K, Marsh M. Cluster of differentiation antigen 4 (CD4) endocytosis and adaptor complex binding require activation of the CD4 endocytosis signal by serine phosphorylation. Mol Biol Cell. 1999;10:677–691.
Figueroa-Vega N, Alfonso-Perez M, Benedicto I, Sanchez-Madrid F, Gonzalez-Amaro R, Marazuela M. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2010;95:953–962.
Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60:1472–1483.
Zhang Z, Zou ZS, Fu JL, et al. Severe dendritic cell perturbation is actively involved in the pathogenesis of acute-on-chronic hepatitis B liver failure. J Hepatol. 2008;49:396–406.
Zou Y, Chen T, Han M, et al. Increased killing of liver NK cells by Fas/Fas ligand and NKG2D/NKG2D ligand contributes to hepatocyte necrosis in virus-induced liver failure. J Immunol. 2010;184:466–475.
Xu D, Fu J, Jin L, et al. Circulating and liver resident CD4 + CD25 + regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 2006;177:739–747.
Hu X, Ma S, Huang X, et al. Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease. J Viral Hepat. 2011;18:458–467.
Leifeld L, Cheng S, Ramakers J, et al. Imbalanced intrahepatic expression of interleukin 12, interferon gamma, and interleukin 10 in fulminant hepatitis B. Hepatology. 2002;36:1001–1008.
Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver Int. 2006;26:912–919.
Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis. 2007;27:339–350.
Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008;453:1051–1057.
Wang Q, Zheng Y, Huang Z, et al. Activated IL-23/IL-17 pathway closely correlates with increased Foxp3 expression in livers of chronic hepatitis B patients. BMC Immunol. 2011;12:25.
Hartel C, Bein G, Muller-Steinhardt M, Kluter H. Ex vivo induction of cytokine mRNA expression in human blood samples. J Immunol Methods. 2001;249:63–71.
Li J, Wu W, Peng G, et al. HBcAg induces interleukin-10 production, inhibiting HBcAg-specific Th17 responses in chronic hepatitis B patients. Immunol Cell Biol. 2010;88:834–841.
Said A, Williams J, Holden J, et al. Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease. J Hepatol. 2004;40:897–903.
Sun QF, Ding JG, Xu DZ, et al. Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model. J Viral Hepat. 2009;16:464–470.
Zheng MH, Shi KQ, Fan YC, et al. A model to determine 3-month mortality risk in patients with acute-on-chronic hepatitis B liver failure. Clin Gastroenterol Hepatol. 2011;9:351–356, e353.
Stauber RE, Wagner D, Stadlbauer V, et al. Evaluation of indocyanine green clearance and model for end-stage liver disease for estimation of short-term prognosis in decompensated cirrhosis. Liver Int. 2009;29:1516–1520.
Tanaka JS. “How big Is big enough?”: sample size and goodness of fit in structural equation models with latent variables. Child Dev. 1987;58:134–146.
Acknowledgments
This work was supported by grants from the Key Project of Chinese Ministry of Science and Technology (2008ZX10002-007), the Natural Science Foundation of Shandong Province (ZR2010HM070, ZR2010HQ040), the Independent Innovation Foundation of Shandong University (IIFSDU, 2010TS013), and the Foundation for Youth of Shandong Bureau of Public Health (2009QZ014).
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Li-yuan Wang, Qing-Hua Meng and Zhi-Qiang Zou contributed equally to this work and should be considered as co-first authors.
Rights and permissions
About this article
Cite this article
Wang, LY., Meng, QH., Zou, ZQ. et al. Increased Frequency of Circulating Th17 Cells in Acute-on-Chronic Hepatitis B Liver Failure. Dig Dis Sci 57, 667–674 (2012). https://doi.org/10.1007/s10620-011-1930-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-011-1930-5