IMPLICATION OF SERUM IL-17 LEVELS IN CHRONIC HEPATITIS B PATIENTS

Abstract

Objective: Natural course and clinical outcomes of chronic hepatitis B virus (HBV) infection is closely releated to immun responses of host and viral factors. Studies have suggested that there is strongly correlation between the level of IL-17 and especially of advanced liver damages associated with HBV. Role of IL-17 on natural course of chronic hepatitis B disease is yet to be fully clarified. This study aimed to evaluate the correlation between serum IL-17 levels with histological, virological, serological and biochemical data of chronic hepatitis B patients. Material and Method: Simultaneous liver biopsy and blood samples were obtained from 88 with chronic HBV enfection. Ishak modified histological activity index system was used for histological evaluation.The patients were divided into three groups taking into account by scoring as none/mild (F0-1), moderate / severe (F2-4) and cirrhosis (F5-6) according to the stages of fibrosis (F). It was analyzed using enzyme-linked immunosorbent assay (ELISA) to IL-17 levels in serum samples. Results: A total of 88 CHB patients were evaluated, with an average age of 41.77±13.39, 43 male and 45 female. Fibrosis stage of 64 (72.7%) of the patients included in the study was determined as F2-4. There were no statistically significant correlation between serum IL-17 levels with histological, virological, serological and biochemical data of patients. Conclusion: These data indicate that the immunopathological role of IL-17 on HBV-related especially low and moderate liver injuries are limited.

Keywords

• Hepatitis B virus
• Chronic hepatitis B
• Fibrosis stage
• Interleukin-17

KRONİK HEPATİT B HASTALARINDA SERUM IL-17 DÜZEYLERİNİN DEĞERLENDİRİLMESİ

Abstract

Amaç: Kronik Hepatit B virüs (HBV) enfeksiyonunun doğal seyri ve klinik sonuçları enfekte bireyin immün yanıtları ve viral faktörler ile yakından ilişkilidir. Serum IL-17 düzeyleri ile HBV ilişkili özellikle şiddetli karaciğer hasarları arasında güçlü bir korelasyon olduğu öne sürülmektedir. Buna karşın IL-17’nin kronik hepatit B hastalığın doğal seyri üzerindeki rolü ise henüz net olarak tanımlanmamıştır. Bu çalışmada kronik hepatit B hastalarının (KHB) histolojik, virolojik, serolojik ve biyokimyasal verileri ile serum IL- 17 düzeyleri arasındaki ilişkinin değerlendirilmesi amaçlanmıştır. Gereç ve Yöntem: Kronik HBV enfeksiyonlu 88 hastadan eş zamanlı karaciğer biyopsi ve kan örnekleri elde edildi. Histolojik değerlendirme için Ishak modifiye histolojik aktivite indeksi sistemi kullanıldı. Hastalar fibrozis (F) evrelerine göre yok/hafif (F0- 1), orta/şiddetli (F2-4) ve siroz (F5-6) şeklinde skorlanarak üçer gruba ayrıldı. Serum IL-17 düzeyleri enzim bağlı immunosorbent assay (ELISA) yöntemi kullanılarak analiz edildi. Bulgular: Yaş ortalaması 41,77±13,39, 43’ü erkek 45’i kadın toplam 88 KHB hastası değerlendirildi. Çalışmaya dahil edilen hastaların 64’nün (%72,7) fibrozis evresi F2-4 olarak belirlendi. Serum IL-17 düzeyleri ile hastaların histolojik, virolojik, serolojik ve biyokimyasal verileri arasında istatistiksel olarak anlamlı bir korelasyon saptanmadı. Sonuç: Bu veriler IL-17’nin HBV ilişkili özellikle düşük ve orta düzeylerdeki karaciğer hasarları üzerindeki immünopatolojik rolünün sınırlı olduğuna işaret etmektedir.

Keywords

• Hepatitis B virüs
• Kronik Hepatit B
• Fibrozis evre
• İnterlökin-17

References

1. 1. Global hepatitis report, 2017. Geneva: World Health Organization, 2017.
2. 2. Wu JF, Chang MH. Natural history of chronic hepatitis B virus infection from infancy to adult life-the mechanism of inflammation triggering and long-term impacts J Biomed Sci 2015;22:92. [CrossRef]
3. 3. Chisari FV, Isogawa M, Wieland SF Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 2010;58:258-66. [CrossRef]
4. 4. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut 2012;61(12):1754-64. [CrossRef]
5. 5. Balmasova IP, Yushchuk ND, Mynbaev OA, Alla NR, Malova ES, Shi Z. et.al. Immunopathogenesis of chronic hepatitis B. World J Gastroenterol 2014;20(39):14156-71. [CrossRef]
6. 6. Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010;7(8):425-36. [CrossRef]
7. 7. Jun J-I, Lau L-F. Resolution of organ fibrosis.J. Clin. Invest. 2018;28(1):97-107. [CrossRef] 8. Friedman SL. Liver fibrosis -- from bench to bedside. J Hepatol 2003;38(Suppl 1):38-53. [CrossRef]
8. 9. Veldhoen M. Interleukin 17 is a chief orchestrator of immunity. Nat Immunol 2017;18(6):612-21. [CrossRef]

9. 10. Ma WT, Yao XT, Peng Q, Chen DK. The protective and pathogenic roles of IL-17 in viral infections: friend or foe? Open Biol 2019;9(7):190109. [CrossRef]
10. 11. Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, et al. IL- 17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol 2013;191(4):1835-44. [CrossRef]
11. 12. Griffin GK, Newton G, Tarrio ML, Bu D, Maganto-Garcia E, Azcutia V, et al. IL-17 and TNF-α sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol 2012;188(12):6287-99. [CrossRef]
12. 13. Fabre T, Kared H, Friedman SL, Shoukry NH. IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner. J Immunol 2014;193(8):3925- 33. [CrossRef]
13. 14. Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012;143(3):765-76. [CrossRef]
14. 15. Du WJ, Zhen JH, Zeng ZQ, Zheng ZM, Xu Y, Qin LY, et al. Expression of interleukin-17 associated with disease progression and liver fibrosis with hepatitis B virus infection: IL-17 in HBV infection. Diagn Pathol 2013;8:40. [CrossRef]
15. 15. Vittal R, Fan L, Greenspan DS, Mickler EA, Gopalakrishnan B, Gu H, et al. IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis. Am J Physiol Lung Cell Mol Physiol 2013;304(6):401-14. [CrossRef]
16. 16. Zhang JY, Zhang Z, Lin F, Zou ZS, Xu RN, Jin L, et al. Interleukin-17- producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology 2010;51(1):81-91. [CrossRef]
17. 17. Sun HQ, Zhang JY, Zhang H, Zou ZS, Wang FS, Jia JH. Increased Th17 cells contribute to disease progression in patients with HBV-associated liver cirrhosis. J Viral Hepat 2012;19(6):396-403. [CrossRef]
18. 18. Yang B, Wang Y, Zhao C, Yan W, Che H, Shen C, Zhao M. Increased Th17 cells and interleukin-17 contribute to immune activation and disease aggravation in patients with chronic hepatitis B virus infection. Immunol Lett 2013;149(1- 2):41-9. [CrossRef]
19. 19. Feng H, Yin J, Han Y-P, Zhou X-Y, Chen S, Yang L, et al. Sustained changes of Treg and Th17 cells during interferon-α therapy in patients with chronic hepatitis B. Viral Immunol 2015;28(8):412-17. [CrossRef]
20. 20. Hao C, Wang J, Kang W, Xie Y, Zhou Y, Ma L, et al. Kinetics of Th17 cytokines during telbivudine therapy in patients with chronic hepatitis B. Viral Immunol 2013;26(5):336-42. [CrossRef]
21. 21. Wang L-Y, Meng Q-H, Zou Z-Q, Fan Y-C, Han J, Qi Z-X, et al. Increased frequency of circulating Th17 cells in acute-onchronic hepatitis B liver failure. Dig Dis Sci 2012;57(3):667- 74. [CrossRef]
22. 22. Wang L, Chen S, Xu K. IL-17 expression is correlated with hepatitis B related liver diseases and fibrosis. Int J Mol Med 2011;27(3):385-92. [CrossRef]
23. 23. Chang Q, Wang Y-K, Zhao Q, Wang C-Z, Hu Y-Z, Wu B-Y. Th17 cells are increased with severity of liver inflammation in patients with chronic hepatitis C. J Gastroenterol Hepatol 2012;27(2):273-8. [CrossRef]
24. 24. Zhang GL, Zhang T, Zhao QY, Xie C, Lin CS, Gao ZL. Increased IL-17-producing CD8(+) T cell frequency predicts short-term mortality in patients with hepatitis B virusrelated acute-on-chronic liver failure. Ther Clin Risk Manage 2018;14:2127-36. [CrossRef]
25. 25. Yang C, Cui F, Chen LM, Gong XY, Qin B. Correlation between Th17 and nTreg cell frequencies and the stages of progression in chronic hepatitis B. Mol Med Rep 2016;13(1): 853-59. [CrossRef]
26. 26. Cho HJ, Kim SS. Nam JS, Oh MJ, Kang DJ, Kim JK. et.al. Higher serum interleukin-17A levels as a potential biomarker for predicting early disease progression in patients with hepatitis B virus-associated advanced hepatocellular carcinoma treated with sorafenib. Cytokine 2017;95:118-25. [CrossRef]
27. 27. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection. J Hepatol 2017;67(2):370-98.
28. 28. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22(6):696-99. [CrossRef]
29. 29. Li T-Y, Yang Y, Zhou G, Tu Z-K. Immune suppression in chronic hepatitis B infection associated liver disease: A review. World J Gastroenterol 2019;25(27):3527-37. [CrossRef]
30. 30. Mohammad Kazemi Arababadi MK, Mohammad Zare Bidaki MZ, Kennedy D. IL-17A in hepatitis B infection: friend or foe? Arch Virol 2014;159(8):1883-8. [CrossRef]
31. 31. Paquissi FC. Immunity and Fibrogenesis: The Role of Th17/ IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front Immunol 2017;28:1195. [CrossRef]
32. 32. Yu X, Guo R, Ming D, Su M, Lin C, Deng Y, et al. Ratios of regulatory T cells/T-helper 17 cells and transforming growth factor-β1/interleukin-17 to be associated with the development of hepatitis B virus-associated liver cirrhosis. J Gastroenterol Hepatol 2014;29(5):1065-72. [CrossRef]
33. 33. Metanat M, Alijani E, Ansari-Moghaddam A, Bahrehmand F, Khalili M, Arbabi, Soheila N. et.al. The Relationship Between Serum IL-17 Level and Viral Load in Chronic Hepatitis B. Arch Clin Infect Dis 2019;14(3):e68172. [CrossRef]
34. 34. Wiegand S.B, Beggel B, Wranke A, Aliabadi E, Jaroszewicz J, Xu C-J. Soluble immune markers in the different phases of chronic hepatitis B virus infection.Sci Rep 2019;9(1):14118. [CrossRef]
35. 35. Shi M, Wei J, Dong J, Meng W, Ma J, Wang T, et al. Function of interleukin-17 and -35 in the blood of patients with hepatitis B-related liver cirrhosis. Mol Med Rep 2015;11(1):121-6. [CrossRef]
36. 36. El-Gazzar AA, El-Basuoni MA, Soliman MA, Zaghla HE, Allam MM. Interleukin-17-producing CD4+T cells in patients with chronic hepatitis B. Menoufia Medical Journal 2014;27(4):775-9. [CrossRef]
37. 37. 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(4):750-7. [CrossRef]
38. 38. Yang Y, Dai J, Yan M, Yue M, Wang X. h, Min X, Wang Y. y, Zhang W. Expression of interleukin-17 is associated with different immune phases in patients with chronic hepatitis B. European Journal of Inflammation 2018;16:1-7. [CrossRef]
39. 39. Wiegand SB, Beggel B, Wranke A, Aliabadi E, Jaroszewicz J, Xu C-J. Soluble immune markers in the different phases of chronic hepatitis B virus infection. Sci Rep 2019;9(1):14118. [CrossRef]
40. 40. Gehring A, Koh S, Chia A, et al. Licensing virus-specific T cells to secrete the neutrophil attracting chemokine CXCL-8 during hepatitis B virus infection. PloS One 2011;6:e23330. [CrossRef]
41. 41. Lan Y-T, Wang Z-L, Tian P, Gong X-N, Fan Y-C, Wang K. Treg/Th17 imbalance and its clinical significance in patients with hepatitis B associated liver cirrhosis Diagn Pathol 2019;14:114. [CrossRef]