A pilot study on some critical immune elements in HBV infection: evidence of Alpha-1 Antitrypsin as an immunological biomarker HBV and critical immune elements
Gastroenterology and Hepatology from Bed to Bench,
Aim: This study is an attempt to screen the key immune elements that participate during HBV infection and the related pathways that are modulated.
Background: The pathogenesis of Hepatitis B virus and the corresponding clinical manifestations in the host are primarily immune-mediated.
Methods: This study utilizes a PCR array to screen immune-related genes that are differentially expressed in the presence of the virus in HBV replicating HepG2.2.15 cells as compared to control HepG2 cells. The significantly up-regulated genes were subjected to bioinformatic analysis utilizing GSEA and STRING. Additionally, ELISA was used to corroborate the levels of Alpha 1 antitrypsin (AAT) from patients’ sera.
Results: The expressions of 31% of the studied genes were significantly up-regulated (> 2-fold, p<0.05) in HepG2.2.15 cells compared to controls, and this included the SERPINA1, FN1, IL1R2, LBP, LY96, LYZ and PROC genes. When they were clustered based on biological processes, signaling pathways, and disease progression, the genes related to biotic stimulus, complement-coagulation cascades, and fibrosis, respectively, showed the highest (p<0.05) enrichment. Analysis of patients’ sera by ELISA revealed that the serum AAT (SERPINA1) levels were significantly higher in asymptomatic carriers and in patients with chronic liver disease than in controls (p<0.05). Moreover, SERPINA1 levels were also positively correlated with the levels of serum ALT (r=0.4495, p<0.05) among HBV infected patients.
Conclusion: The current study highlights the key immune elements and pathways that are modulated during HBV infection and proposes the possible use of AAT as a non-invasive immunological biomarker to follow the progression of liver disease.
- HBV, Immune biomarker, Alpha 1 antitrypsin, immune pathways
How to Cite
1. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004;350: 1118-1129.
2. Davis GL, Dempster J, Meler JD, Orr DW, Walberg MW, Brown B. Hepatocellular carcinoma: management of an increasingly common problem. Proc (Bayl Univ Med Cent) 2008; 21(3): 266–280.
3. Chisari FV. Viruses, Immunity, and Cancer: Lessons from Hepatitis B. Am J Pathol. 2000; 156(4): 1117–1132.
4. Zhang E, Lu M. Toll-like receptor (TLR)-mediated innate immune responses in the control of hepatitis B virus (HBV) infection. Med Microbiol Immunol. 2015; 204: 11–20.
5. Ma Z, Zhang E, Yang D, Lu M. Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses. Cell Mol Immunol. 2015; 12(3): 273–282.
6. Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79(11):7269-72.
7. Sarkar N, Panigrahi R, Pal A, Biswas A, Singh SP,, Kar SK. Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-β in hepatocytes. J Viral Hepat. 2015;22(10):817-27.
8. Hui CK, Lau GK. Immune system and hepatitis B virus infection. J Clin Virol. 2005;34 Suppl 1:S44-8.
9. Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis. 2015;6:e1694.
10. Tan XF, Wu SS, Li SP, Chen Z, Chen F. Alpha-1 antitrypsin is a potential biomarker for hepatitis B. Virol J. 2011;8:274.
11. Wu S, Kanda T, Imazeki F, Nakamoto S, Shirasawa H, Yokosuka O. Nuclear receptor mRNA expression by HBV in human hepatoblastoma cell lines. Cancer Lett. 2011;312(1):33-42.
12. Jiang X, Kanda T, Wu S, Nakamura M, Miyamura T, Nakamoto S, Banerjee A, Yokosuka O. Regulation of microRNA by hepatitis B virus infection and their possible association with control of innate immunity. World J Gastroenterol. 2014;20(23):7197-206.
13. Topic A1, Ljujic M, Radojkovic D. Alpha-1-antitrypsin in pathogenesis of hepatocellular carcinoma. Hepat Mon. 2012 Oct;12(10 HCC):e7042. doi: 10.5812/hepatmon.7042. Epub 2012 Oct 30.
14. Shiraishi Y, Fujimoto A, Furuta M, Tanaka H, Chiba K, Boroevich KA. Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers. PLoS One. 2014;9(12):e114263.
15. Ding D, Lou X, Hua D, Yu W, Li L, Wang J. Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach. PLoS Genet. 2012;8(12):e1003065.
16. Dioguardi N, Dell'Oca M, Arosio E. A computer-assisted study of macrophage behavior in HBV and nAnB related infectious chronic active hepatitis. Ric Clin Lab. 1990;20(3):187-95.
17. Adamska I, Szaflarska-Szczepanik A, Chrobot A, Kulwas A, Czerwionka-Szaflarska M. Antithrombin III, protein C and protein S in children with chronic viral hepatitis B or C. Med Wieku Rozwoj. 2003;7(2):289-97.
18. Thomas MA, Yang L, Carter BJ, Klaper RD. Gene set enrichment analysis of microarray data from Pimephales promelas (Rafinesque), a non-mammalian model organism. BMC Genomics. 2011;12:66.
19. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-50.
20. Irizarry RA, Wang C, Zhou Y, Speed TP. Gene set enrichment analysis made simple. Stat Methods Med Res. 2009;18(6):565-75.
21. Mukherjee S, Karmakar S, Babu SS. TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braz J Infect Dis. 2016. pii: S1413-8670(15)00224-X.
22. Vanlandschoot P, Van Houtte F, Roobrouck A, Farhoudi A, Stelter F, Peterson DL. LPS-binding protein and CD14-dependent attachment of hepatitis B surface antigen to monocytes is determined by the phospholipid moiety of the particles. J Gen Virol. 2002;83:2279-89.
23. Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol. 2015;109:14.12.1-14.12.10.
24. Puro R, Schneider RJ. Tumor necrosis factor activates a conserved innate antiviral response to hepatitis B virus that destabilizes nucleocapsids and reduces nuclear viral DNA.J Virol. 2007;81(14):7351-62.
25. Karimi-Googheri M, Daneshvar H, Nosratabadi R, Zare-Bidaki M, Hassanshahi G, Ebrahim M.Important roles played by TGF-β in hepatitis B infection. J Med Virol. 2014;86(1):102-8.
26. Akcam FZ, Tigli A, Kaya O, Ciris M, Vural H.Cytokine levels and histopathology in chronic hepatitis B and chronic hepatitis C. J Interferon Cytokine Res. 2012;32(12):570-4.
27. Panigrahi R, Sarkar N, Biswas A, Pal A, Saha D, Singh SP. Association of TNF-α Promoter Polymorphism with HBV Associated Disease Outcome Among HBV Infected Patients from Orissa, Southern Part of East India. J Clin Exp Hepatol. 2014;4(3):202-8.
28. Ying Guo, Chunbao Zang, Yajun Li, Li Yuan, Qingjun Liu, Lingyan Zhang. Association Between TGF-β1 Polymorphisms and Hepatocellular Carcinoma Risk: A Meta-Analysis. Genet Test Mol Biomarkers. 2013; 17(11): 814–820.
29. Majano PL, García-Monzón C, López-Cabrera M, Lara-Pezzi E, Fernández-Ruiz E, García-Iglesias C, Borque MJ, Moreno-Otero R.Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. J Clin Invest. 1998;101(7):1343-52.
30. Qin X, Gao B.The complement system in liver diseases. Cell Mol Immunol. 2006;3(5):333-40.
31. Xu R, Lin F, He J, Jin L, Zhang JY, Fu J.Complement 5a stimulates hepatic stellate cells in vitro, and is increased in the plasma of patients with chronic hepatitis B. Immunology. 2013;138(3):228-34.
32. Tzeng HT, Tsai HF, Chyuan IT, Liao HJ, Chen CJ, Chen PJ, Hsu PN.Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model. PLoS One. 2014;9(7):e103008.
33. Chang ML, Liaw YF.Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol. 2014;61(6):1407-17.
34. Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency--a model for conformational diseases. N Engl J Med. 2002;346(1):45-53.
35. Lubrano V, Vergaro G, Maltinti M, Ghionzoli N, Emdin M, Papa A. α-1 Antitrypsin as a potential biomarker in chronic heart failure. J Cardiovasc Med (Hagerstown). 2020 Mar;21(3):209-215.
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