Telbivudine on IgG-associated hypergammaglobulinemia and TGF-β1 hyperactivity in hepatitis B virus-related liver cirrhosis

Autoři: Cheng-Hsun Ho aff001;  Ting-Tsung Chang aff002;  Rong-Nan Chien aff004
Působiště autorů: Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung, Taiwan aff001;  Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan aff002;  Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan aff003;  Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225482


As debate rumbles on about whether anti-hepatitis B virus (HBV) nucleos(t)ide analogue treatments modulate host immune system during end-stage liver diseases, we studied effects of two potent anti-HBV agents, telbivudine or entecavir, on humoral immune activities including cytokine secretion, immunoglobulin production, and IgG-Fc agalactosylation, which is known to induce proinflammatory responses, in liver cirrhosis. Serum IgG-Fc N-glycan structures in patients with HBV-related liver cirrhosis, who had received either telbivudine treatment or entecavir treatment for at least 48 weeks were analyzed using liquid chromatography tandem-mass spectrometry. Levels of cytokines and each immunoglobulin isotype were measured using enzyme-linked immunosorbent assays. Results showed that 48 weeks of entecavir treatment caused HBV DNA loss, alanine aminotransferase normalization, and an amelioration of hypergammaglobulinemia in cirrhotic patients; however, telbivudine treatment, though possessing similar efficacies on HBV suppression and an improvement in liver inflammation to entecavir treatment, did not mitigate IgG-related hypergammaglobulinemia. Levels of IgG and transforming growth factor (TGF)-β1 in sera of the cirrhotic patients before and during treatment were positively correlated. In vitro assays revealed that telbivudine treatment induced TGF-β1 expression in human macrophagic cells. Moreover, recombinant TGF-β1 treatment stimulated cell proliferation and IgG overproduction in human IgG-producing B cell lines. Finally, we found that telbivudine treatment enhanced the proportion of serum IgG-Fc agalactosylation in cirrhotic patients, which was associated with enhanced levels of TGF-β1 and IgG. In conclusion, telbivudine therapy was associated with TGF-β1 hyperactivity, IgG-related hypergammaglobulinemia, and IgG-Fc agalactosylation in HBV-related liver cirrhosis.

Klíčová slova:

Aminotransferases – B cells – Cirrhosis – Cytokines – Hepatitis B virus – Liver diseases – TGF-beta signaling cascade – Hypergammaglobulinemia


1. Punnoose AR, Lynm C, Golub RM. JAMA patient page. Cirrhosis. JAMA. 2012;307(8):874. Epub 2012/02/24. 307/8/874 [pii] doi: 10.1001/jama.2012.82 22357839.

2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128. Epub 2012/12/19. S0140-6736(12)61728-0 [pii] doi: 10.1016/S0140-6736(12)61728-0 23245604.

3. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383(9930):1749–61. Epub 2014/02/01. S0140-6736(14)60121-5 [pii] doi: 10.1016/S0140-6736(14)60121-5 24480518.

4. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838–51. Epub 2008/03/11. S0140-6736(08)60383-9 [pii] doi: 10.1016/S0140-6736(08)60383-9 18328931; PubMed Central PMCID: PMC2271178.

5. Rizzetto M. Treatment of hepatitis B virus cirrhosis. Hepat Mon. 2012;12(5):309–11. doi: 10.5812/hepatmon.6113 22783340; PubMed Central PMCID: PMC3389354.

6. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 52(3):886–93. Epub 2010/08/05. doi: 10.1002/hep.23785 20683932.

7. Ho CH, Chien RN, Cheng PN, Liu JH, Liu CK, Su CS, et al. Aberrant serum immunoglobulin G glycosylation in chronic hepatitis B is associated with histological liver damage and reversible by antiviral therapy. J Infect Dis. 2015;211(1):115–24. doi: 10.1093/infdis/jiu388 25015948.

8. Ho CH, Chien RN, Cheng PN, Liu CK, Su CS, Wu IC, et al. Association of serum IgG N-glycome and transforming growth factor-beta1 with hepatitis B virus e antigen seroconversion during entecavir therapy. Antiviral Res. 111:121–8. Epub 2014/09/28. S0166-3542(14)00278-2 [pii] doi: 10.1016/j.antiviral.2014.09.011 25260899.

9. Zhou H, Ma H, Wei W, Ji D, Song X, Sun J, et al. B4GALT family mediates the multidrug resistance of human leukemia cells by regulating the hedgehog pathway and the expression of p-glycoprotein and multidrug resistance-associated protein 1. Cell Death Dis. 2013;4:e654. Epub 2013/06/08. cddis2013186 [pii] doi: 10.1038/cddis.2013.186 23744354; PubMed Central PMCID: PMC3698553.

10. Gotte M, Spillmann D, Yip GW, Versteeg E, Echtermeyer FG, van Kuppevelt TH, et al. Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (beta4GalT-7) deficient form of Ehlers-Danlos syndrome. Hum Mol Genet. 2008;17(7):996–1009. Epub 2007/12/26. ddm372 [pii] doi: 10.1093/hmg/ddm372 18158310.

11. Liang J, Jiang MJ, Deng X, Xiao Zhou X. Efficacy and Safety of Telbivudine Compared to Entecavir Among HBeAg+ Chronic Hepatitis B Patients: a Meta-Analysis Study. Hepat Mon. 13(6):e7862. Epub 2013/09/14. doi: 10.5812/hepatmon.7862 24032045; PubMed Central PMCID: PMC3759781.

12. Wang N, Hu HD, Sun H, Feng Q, Hu P, Liu Q, et al. Comparison of the forty-eight week efficacy between telbivudine and entecavir in HBeAg-positive Asian patients with chronic hepatitis B: A meta-analysis. Turk J Gastroenterol. 24(3):230–40. Epub 2013/11/15. doi: 10.4318/tjg.2013.0680 24226716.

13. Tsai MC, Lee CM, Chiu KW, Hung CH, Tung WC, Chen CH, et al. A comparison of telbivudine and entecavir for chronic hepatitis B in real-world clinical practice. J Antimicrob Chemother. 67(3):696–9. Epub 2011/12/17. dkr495 [pii] doi: 10.1093/jac/dkr495 22174039.

14. Kim HR, Yim HJ, Kang S, Suh SJ, Kim SY, Hyun JJ, et al. Efficacy of telbivudine compared with entecavir in hepatitis B virus-related cirrhosis: 2 year follow-up data. Liver Int. 2015;35(3):860–9. doi: 10.1111/liv.12605 24905912.

15. Wu ZG, Yan WM, Guo W, Chen T, Zou Y, Wang HW, et al. Telbivudine preserves T-helper 1 cytokine production and downregulates programmed death ligand 1 in a mouse model of viral hepatitis. J Viral Hepat. 2010;17 Suppl 1:24–33. doi: 10.1111/j.1365-2893.2010.01268.x 20586931.

16. Wang GQ, Ding YP, Dong YH. Telbivudine treatment is associated with high hepatitis B e antigen seroconversion and immune modulatory effects in chronic hepatitis B patients. J Viral Hepat. 2013;20 Suppl 1:9–17. doi: 10.1111/jvh.12059 23458520.

17. Dooley S, ten Dijke P. TGF-beta in progression of liver disease. Cell Tissue Res. 2012;347(1):245–56. Epub 2011/10/19. doi: 10.1007/s00441-011-1246-y 22006249; PubMed Central PMCID: PMC3250614.

18. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18. Epub 2005/02/04. doi: 10.1172/JCI24282 15690074; PubMed Central PMCID: PMC546435.

19. Kirmaz C, Terzioglu E, Topalak O, Bayrak P, Yilmaz O, Ersoz G, et al. Serum tumor growth factor-beta 1 levels in patients with cirrhosis, chronic hepatitis B and chronic hepatitis C. European Cytokine Network. 2004;15(2):112–6. ISI:000222961700004. 15319169

20. Rath S, Devey ME. IgG subclass composition of antibodies to HBsAg in circulating immune complexes from patients with hepatitis B virus infections. Clin Exp Immunol. 1988;72(1):164–7. Epub 1988/04/01. 3396217; PubMed Central PMCID: PMC1541492.

21. Shen H, Zhang M, Kaita K, Minuk GY, Rempel J, Gong Y. Expression of Fc fragment receptors of immunoglobulin G (Fc gammaRs) in rat hepatic stellate cells. Dig Dis Sci. 2005;50(1):181–7. Epub 2005/02/17. 15712658.

22. Dispenzieri A, Gertz MA, Therneau TM, Kyle RA. Retrospective cohort study of 148 patients with polyclonal gammopathy. Mayo Clin Proc. 2001;76(5):476–87. Epub 2001/05/19. S0025-6196(11)62913-3 [pii] doi: 10.4065/76.5.476 11357794.

23. Feizi T. Immunoglobulins in chronic liver disease. Gut. 1968;9(2):193–8. doi: 10.1136/gut.9.2.193 4172757; PubMed Central PMCID: PMC1552579.

24. Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis. 2001;33(1):41–8. Epub 2001/04/17. doi: 10.1016/s1590-8658(01)80134-1 11303974.

25. Stobo JD. Cirrhosis and hypergammaglobulinemia. Dig Dis Sci. 1979;24(10):737–40. Epub 1979/10/01. doi: 10.1007/bf01317204 573678.

26. Tanaka S, Okamoto Y, Yamazaki M, Mitani N, Nakqjima Y, Fukui H. Significance of hyperglobulinemia in severe chronic liver diseases—with special reference to the correlation between serum globulin/IgG level and ICG clearance. Hepatogastroenterology. 2007;54(80):2301–5. Epub 2008/02/13. 18265652.

27. Fallatah HI, Akbar HO. Elevated serum immunoglobulin G levels in patients with chronic liver disease in comparison to patients with autoimmune hepatitis. Libyan J Med. 2010;5. Epub 2010/01/01. doi: 10.3402/ljm.v5i0.4857 21483590; PubMed Central PMCID: PMC3071169.

28. Kekow J, Hobusch G, Gross WL. Predominance of the IgG1 subclass in the hypergammaglobulinemia observed in pre-AIDS and AIDS. Cancer Detect Prev. 1988;12(1–6):211–6. 3180125.

29. Lebman DA, Lee FD, Coffman RL. Mechanism for transforming growth factor beta and IL-2 enhancement of IgA expression in lipopolysaccharide-stimulated B cell cultures. J Immunol. 1990;144(3):952–9. Epub 1990/02/01. 2295822.

30. Kim PH, Kagnoff MF. Transforming growth factor beta 1 increases IgA isotype switching at the clonal level. J Immunol. 1990;145(11):3773–8. Epub 1990/12/01. 2246513.

31. van Vlasselaer P, Punnonen J, de Vries JE. Transforming growth factor-beta directs IgA switching in human B cells. J Immunol. 1992;148(7):2062–7. Epub 1992/04/01. 1347548.

32. Coffman RL, Lebman DA, Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989;170(3):1039–44. Epub 1989/09/01. PubMed Central PMCID: PMC2189449. doi: 10.1084/jem.170.3.1039 2788703

33. Defrance T, Vanbervliet B, Briere F, Durand I, Rousset F, Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med. 1992;175(3):671–82. Epub 1992/03/01. doi: 10.1084/jem.175.3.671 1371300; PubMed Central PMCID: PMC2119142.

34. Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10(4):429–34. doi: 10.1038/nm1006 15152612.

35. Klein A, Carre Y, Louvet A, Michalski JC, Morelle W. Immunoglobulins are the major glycoproteins involved in the modifications of total serum N-glycome in cirrhotic patients. Proteomics Clin Appl. 2010;4(4):379–93. doi: 10.1002/prca.200900133 21137058.

36. Furukawa K, Matsuta K, Takeuchi F, Kosuge E, Miyamoto T, Kobata A. Kinetic study of a galactosyltransferase in the B cells of patients with rheumatoid arthritis. Int Immunol. 1990;2(1):105–12. Epub 1990/01/01. doi: 10.1093/intimm/2.1.105 2128462.

37. Keusch J, Lydyard PM, Berger EG, Delves PJ. B lymphocyte galactosyltransferase protein levels in normal individuals and in patients with rheumatoid arthritis. Glycoconj J. 1998;15(11):1093–7. Epub 1999/07/01. doi: 10.1023/a:1006957711557 10386894.

38. Keusch J, Lydyard PM, Isenberg DA, Delves PJ. beta 1,4-Galactosyltransferase activity in B cells detected using a simple ELISA-based assay. Glycobiology. 1995;5(4):365–700. Epub 1995/06/01. doi: 10.1093/glycob/5.4.365 7579790.

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