All Title Author
Keywords Abstract

The Possible Role of TLR2 in Chronic Hepatitis B Patients with Precore Mutation

DOI: 10.1155/2013/780319

Full-Text   Cite this paper   Add to My Lib


Recognition mechanisms of innate immune response help to improve immunotherapeutic strategies in HBeAg-negative chronic hepatitis B (CHB). Toll-like receptor 2 (TLR2) is an important component of innate immunity. In this study, the frequency of precore mutations of the hepatitis B virus (HBV) and serum TLR2 were evaluated in CHB patients. Fifty-one patients with chronic hepatitis B, negative for HBeAg and detectable HBV DNA, were examined for the presence of mutations in pre-core region of HBV genome by direct sequencing. Serum TLR2 was measured by enzyme-linked immunosorbent assay. Interactions of truncated HBeAg and TLR2 proteins were evaluated with molecular docking software. The G1896A pre-core mutation were detected in 29 (57%) which was significantly associated with higher concentration of serum TLR2 in comparison with patients without this mutation (4.8 2.9 versus 3.4 2.2?ng/mL, ). There was also a significant correlation between serum ALT and TLR-2 ( ; ). Docking results illustrated residues within the N-terminus of truncated HBeAg and TLR2, which might facilitate the interaction of these proteins. These findings showed the dominance of G1896A pre-core mutation of HBV variants in this community which was correlated with serum TLR2. Moreover TLR2 is critical for induction of inflammatory cytokines and therefore ALT elevation. 1. Introduction Hepatitis B virus (HBV) infection is an important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [1]. The transmission of HBV from infected mothers to neonates causes persistent infection [2]. Chronic infection of HBV is a global health problem. However, the prevalence and genotype distribution of HBV are different among the geographical areas [3]. The majority of chronic hepatitis B patients lose HBe antigen (HBeAg) and develop anti-HBe antibody, which is generally associated with a decrease in serum HBV DNA levels and a gradual accumulation of precore or core promoter mutations [4]. HBeAg-negative chronic hepatitis B is the predominant type of CHB in Mediterranean inhabitants [3]. Two types of precore and core promoter HBV mutations that reduce HBeAg formation are more frequent in regions where patients are predominantly infected with HBV genotype D [4, 5]. Infection with wild-type strains of HBV often induces mild symptoms and responds well to interferon alpha therapy, but patients infected with precore mutant variants may show clinical evidence of elevated or fluctuating ALT and HBV DNA [6]. The reason that precore negative mutants become predominant in some patients during


[1]  G. Montazeri, “Current treatment of chronic hepatitis B,” Archives of Iranian Medicine, vol. 9, no. 1, pp. 1–10, 2006.
[2]  P. Gerner, A. H?rning, S. Kathemann, K. Willuweit, and S. Wirth, “Growth abnormalities in children with chronic hepatitis B or C,” Advances in Virology, vol. 2012, Article ID 670316, 5 pages, 2012.
[3]  Y.-F. Liaw, M. R. Brunetto, and S. Hadziyannis, “The natural history of chronic HBV infection and geographical differences,” Antiviral Therapy, vol. 15, supplement 3, pp. 25–33, 2010.
[4]  H. Poustchi, A. Mohamadkhani, S. Bowden et al., “Clinical significance of precore and core promoter mutations in genotype D hepatitis B-related chronic liver disease,” Journal of Viral Hepatitis, vol. 15, no. 10, pp. 753–760, 2008.
[5]  S. M. Alavian, F. Fallahian, and K. B. Lankarani, “The changing epidemiology of viral hepatitis B in Iran,” Journal of Gastrointestinal and Liver Diseases, vol. 16, no. 4, pp. 403–406, 2007.
[6]  M. M. Mir-Nasseri, A. Mohammadkhani, H. Tavakkoli, E. Ansari, and H. Poustchi, “Incarceration is a major risk factor for blood-borne infection among intravenous drug users: incarceration and blood borne infection among intravenous drug users,” Hepatitis Monthly, vol. 11, no. 1, pp. 19–22, 2011.
[7]  A. Mohamadkhani, M. Sotoudeh, S. Bowden et al., “Downregulation of HLA class II molecules by G1896A pre-core mutation in chronic hepatitis B virus infection,” Viral Immunology, vol. 22, no. 5, pp. 295–300, 2009.
[8]  A. Mohamadkhani, A. Pourdadash, S. Tayebi, et al., “The potential role of APOBEC3G in limiting replication of hepatitis B virus,” Arab Journal of Gastroenterology, vol. 13, no. 4, pp. 170–173, 2012.
[9]  J.-Q. Lian, X.-Q. Wang, Y. Zhang, C.-X. Huang, and X.-F. Bai, “Correlation of circulating TLR2/4 expression with CD3+/4+/8+ T cells and treg cells in HBV-related liver cirrhosis,” Viral Immunology, vol. 22, no. 5, pp. 301–308, 2009.
[10]  P. Carotenuto, A. Artsen, A. D. Osterhaus, and O. Pontesilli, “Reciprocal changes of na?ve and effector/memory CD8+ T lymphocytes in chronic hepatitis B virus infection,” Viral Immunology, vol. 24, no. 1, pp. 27–33, 2011.
[11]  A. Mohamadkhani, F. Bastani, M. Sotoudeh, et al., “Influence of B cells in liver fibrosis associated with hepatitis B virus harboring basal core promoter mutations,” Journal of Medical Virology, vol. 84, no. 12, pp. 1889–1896, 2012.
[12]  M. Schnare, G. M. Barton, A. C. Holt, K. Takeda, S. Akira, and R. Medzhitov, “Toll-like receptors control activation of adaptive immune responses,” Nature Immunology, vol. 2, no. 10, pp. 947–950, 2001.
[13]  N. J. Gay and M. Gangloff, “Structure and function of toll receptors and their ligands,” Annual Review of Biochemistry, vol. 76, pp. 141–165, 2007.
[14]  E. E. Hamilton-Williams, A. Lang, D. Benke, G. M. Davey, K.-H. Wiesmüller, and C. Kurts, “Cutting edge: TLR ligands are not sufficient to break cross-tolerance to self-antigens,” Journal of Immunology, vol. 174, no. 3, pp. 1159–1163, 2005.
[15]  D. R. Milich, M. K. Chen, J. L. Hughes, and J. E. Jones, “The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence,” Journal of Immunology, vol. 160, no. 4, pp. 2013–2021, 1998.
[16]  M. Isogawa, M. D. Robek, Y. Furuichi, and F. V. Chisari, “Toll-like receptor signaling inhibits hepatitis B virus replication in vivo,” Journal of Virology, vol. 79, no. 11, pp. 7269–7272, 2005.
[17]  K. Visvanathan, N. A. Skinner, A. J. V. Thompson et al., “Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein,” Hepatology, vol. 45, no. 1, pp. 102–110, 2007.
[18]  M. K. Arababadi, A. A. Pourfathollah, A. Jafarzadeh, and G. Hassanshahi, “Serum levels of IL-10 and IL-17A in occult HBV-infected South-East Iranian patients,” Hepatitis Monthly, vol. 10, no. 1, pp. 31–35, 2010.
[19]  S. Tayebi and A. Mohamadkhani, “The TNF-α -308 promoter gene polymorphism and chronic HBV infection,” Hepatitis Research and Treatment, vol. 2012, Article ID 493219, 6 pages, 2012.
[20]  E. LeBouder, J. E. Rey-Nores, N. K. Rushmere et al., “Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk,” Journal of Immunology, vol. 171, no. 12, pp. 6680–6689, 2003.
[21]  A.-C. Raby, E. Le Bouder, C. Colmont et al., “Soluble TLR2 reduces inflammation without compromising bacterial clearance by disrupting TLR2 triggering,” Journal of Immunology, vol. 183, no. 1, pp. 506–517, 2009.
[22]  K. Ishaka, A. Baptistab, L. Bianchic, et al., “Histological grading and staging of chronic hepatitis,” Journal of Hepatology, vol. 22, no. 6, pp. 696–699, 1995.
[23]  R. B. Gan, M. J. Chu, L. P. Shen, S. W. Qian, and Z. P. Li, “The complete nucleotide sequence of the cloned DNA of hepatitis B virus subtype adr in pADR-1,” Scientia Sinica B, vol. 30, no. 5, pp. 507–521, 1987.
[24]  H. Kaur, A. Garg, and G. P. S. Raghava, “PEPstr: a de novo method for tertiary structure prediction of small bioactive peptides,” Protein and Peptide Letters, vol. 14, no. 7, pp. 626–631, 2007.
[25]  M. S. Jin, S. E. Kim, J. Y. Heo et al., “Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a Tri-Acylated lipopeptide,” Cell, vol. 130, no. 6, pp. 1071–1082, 2007.
[26]  N. Andrusier, R. Nussinov, and H. J. Wolfson, “FireDock: fast interaction refinement in molecular docking,” Proteins, vol. 69, no. 1, pp. 139–159, 2007.
[27]  D. Schneidman-Duhovny, Y. Inbar, R. Nussinov, and H. J. Wolfson, “PatchDock and SymmDock: servers for rigid and symmetric docking,” Nucleic Acids Research, vol. 33, supplement 2, pp. W363–W367, 2005.
[28]  C.-M. Chu, C.-T. Yeh, C.-S. Lee, I.-S. Sheen, and Y.-F. Liaw, “Precore stop mutant in HBeAg-positive patients with chronic hepatitis B: clinical characteristics and correlation with the course of HBeAg-to-anti-HBe seroconversion,” Journal of Clinical Microbiology, vol. 40, no. 1, pp. 16–21, 2002.
[29]  S. A. Taghavi, M. Tabibi, A. Eshraghian, H. Keyvani, and H. Eshraghian, “Prevalence and clinical significance of hepatitis B basal core promoter and precore gene mutations in southern iranian patients,” Hepatitis Monthly, vol. 10, no. 4, pp. 294–297, 2010.
[30]  H. P. Dienes, G. Gerken, B. Goergen, K. Heermann, W. Gerlich, and K. H. M. zum Buschenfelde, “Analysis of the precore DNA sequence and detection of precore antigen in liver specimens from patients with anti-hepatitis B e-positive chronic hepatitis,” Hepatology, vol. 21, no. 1, pp. 1–7, 1995.
[31]  C.-M. Chu and Y.-F. Liaw, “Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B,” Gastroenterology, vol. 133, no. 5, pp. 1458–1465, 2007.
[32]  C. P. Desmond, S. Gaudieri, I. R. James et al., “Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV)infection, and adaptation is greatest in HBV e antigen-negative disease,” Journal of Virology, vol. 86, no. 2, pp. 1181–1192, 2012.
[33]  R. Romieu-Mourez, M. Fran?ois, M.-N. Boivin, M. Bouchentouf, D. E. Spaner, and J. Galipeau, “Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype,” Journal of Immunology, vol. 182, no. 12, pp. 7963–7973, 2009.
[34]  T. Matsumura, T. Degawa, T. Takii et al., “TRAF6-NF-κB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes,” Immunology, vol. 109, no. 1, pp. 127–136, 2003.


comments powered by Disqus