UTICAJ IMUNOLOŠKOG ODGOVORA NA RAZVOJ FIBROZE KOD HRONIČNIH BOLESTI JETRE RAZLIČITE ETIOLOGIJE – PREGLEDNI ČLANAK
Ključne reči:
hronični hepatitis C, nealkoholni steatohepatitis, inflamacija
Sažetak
Hronična bolest jetre (Chronic Liver Disease, engl, CLD) je postepena, kontinuirana inflamacija, destrukcija i regeneracija hepatocita trajanja dužeg od šest meseci, čija progresija dovodi do fibroze, potom ciroze jetre a u najtežim slučajevima hepatocelularnog karcinoma (HCC).
Uloga imunološkog sistema u CLD je prepoznata pre nekoliko decenija, ali do danas nisu razjašnjeni svi imunološki mehanizmi oštećenja jetre, koji bi mogli biti značajni i kao potencijalne terapijske opcije. Citokini osovine interleukin (IL)-23/IL-17 su opisani kao ključni citokini uključeni u imunopatogenezu CLD. Brojne studije su opisivale uticaj osovine IL-23/IL-17 na razvoj fibroze jetre sa heterogenim rezultatima. Ovi rezultati su uglavnom opisivali patofiziologiju, ali su se bavili i potencijalnim imunoterapijskim opcijama. Najkontradiktorniji rezultati objavljeni u aktuelnim studijama koje se bave ovom temom odnose se na hronični hepatitis C (HHC) i nealkoholni steatohepatitis (NASH).
Još uvek je nejasno da li postoje varijacije u koncentraciji proinflamatornih citokina na lokalnom i sistemskom nivou u HHC koje potencijalno mogu usmeravati imunoterapeutske strategije kod ovih pacijenata. Sa druge strane, u NASH-u zapaljenje je jedan od ključnih pokretača progresije bolesti i razvoja fibroze. Regulacija upale je kontroverzna, u zavisnosti od više intrahepatičnih i ekstrahepatičnih faktora, te do sada nisu jasno otkriveni mehanizmi imunopatogeneze ni kod ove hronične bolesti jetre.
Potrebna su dalja istraživanja koja bi jasno sugerisala da li bi neki od imunopatogenetski značajnih mehanizama kod hroničnih bolesti jetre mogao biti potencijalni prognostički i imunoterapijski faktor.
Ključne reči: hronični hepatitis C, nealkoholni steatohepatitis, inflamacija
Reference
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3. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology. 2003 Mar;37(3):493-503.
4. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397-411.
5. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35.
6. Buob S, Johnston AN, Webster CR. Portal hypertension: pathophysiology, diagnosis, and treatment. J Vet Intern Med. 2011 Mar-Apr;25(2):169-86. doi: 10.1111/j.1939-1676.2011.00691.x. PMID: 21382073.
7. Cheemerla, S.; Balakrishnan, M. Global Epidemiology of Chronic Liver Disease. Clin. Liver Dis. 2021, 17, 365–370.
8. Moon, A.M.; Singal, A.G.; Tapper, E.B. Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clin. Gastroenterol. Hepatol. 2020, 18, 2650–2666.
9. CDC National Vital Statistics Reports. July 2021. Available online: https://www.cdc.gov/nchs/nvss/leading-causes-of-death. htm (accessed on 26 July 2021).
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18. Peters, M.; Vierling, J.; Gershwin, E.M.; Milich, D.; Chisari, F.V.; Hoofnagle, J.H.M.D. Immunology and the liver. Hepatology 1991, 13, 977–994.
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21. Cătană, C.S.; Berindan Neagoe, I.; Cozma, V.; Magda¸s, C.; Tăbăran, F.; Dumitra¸scu, D.L. Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease. World J. Gastroenterol. 2015, 21, 5823–5830.
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23. Bankir, M.; Acik, D.Y. IL-17 and IL-23 levels in patients with early-stage chronic lymphocytic leukemia. North. Clin. Istanb. 2020, 8, 24–30.
24. Kolls, J.K.; Lindén, A. Interleukin-17 family members and inflammation. Immunity 2004, 21, 467–476.
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31. Bălănescu, P.; Lădaru, A.; Voiosu, T.; Nicolau, A.; Ene, M.; Bălănescu, E. Th17 and IL-17 immunity in chronic hepatitis C infection. Rom. J. Intern. Med. 2012, 50, 13–18.
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34. Paquissi, F.C. Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front. Immunol. 2017, 8, 1195.
35. de Souza-Cruz, S.; Victória, M.B.; Tarragô, A.M.; da Costa, A.G.; Pimentel, J.P.; Pires, E.F.; Araújo, L.d.P.; Coelho-dos-Reis, J.G.; Gomes, M.d.S.; Amaral, L.R.; et al. Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: A proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10. BMC Microbiol. 2016, 16, 3.
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38. Aboushousha, T.; Emad, M.; Rizk, G.; Ragab, K.; Hammam, O.; Fouad, R.; Helal, N.S. IL-4, IL-17 and CD163 Immunoexpression and IL-6 Gene Polymorphism in Chronic Hepatitis C Patients and Associated Hepatocellular Carcinoma. Asian Pac. J. Cancer Prev. 2021, 22, 1105–1113.
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40. Gomes, A.L.; Teijeiro, A.; Burén, S.; Tummala, K.S.; Yilmaz, M.; Waisman, A.; Theurillat, J.P.; Perna, C.; Djouder, N. Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma. Cancer Cell 2016, 30, 161–175.
41. 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, 273–278.
42. Macek Jilkova, Z.; Afzal, S.; Marche, H.; Decaens, T.; Sturm, N.; Jouvin-Marche, E.; Huard, B.; Marche, P.N. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17(+) neutrophils. Liver Int. 2016, 36, 1116–1124.
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2. Poynard T, Mathurin P, Lai CL, Guyader D, Poupon R, Tainturier MH, Myers RP, Muntenau M, Ratziu V, Manns M, Vogel A, Capron F, Chedid A, Bedossa P. PANFIBROSIS Group. A comparison of fibrosis progression in chronic liver diseases. J Hepatol. 2003 Mar;38(3):257-65.
3. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology. 2003 Mar;37(3):493-503.
4. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397-411.
5. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35.
6. Buob S, Johnston AN, Webster CR. Portal hypertension: pathophysiology, diagnosis, and treatment. J Vet Intern Med. 2011 Mar-Apr;25(2):169-86. doi: 10.1111/j.1939-1676.2011.00691.x. PMID: 21382073.
7. Cheemerla, S.; Balakrishnan, M. Global Epidemiology of Chronic Liver Disease. Clin. Liver Dis. 2021, 17, 365–370.
8. Moon, A.M.; Singal, A.G.; Tapper, E.B. Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clin. Gastroenterol. Hepatol. 2020, 18, 2650–2666.
9. CDC National Vital Statistics Reports. July 2021. Available online: https://www.cdc.gov/nchs/nvss/leading-causes-of-death. htm (accessed on 26 July 2021).
10. Eslam, M.; Sanyal, A.J.; George, J.; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020, 158, 1999–2014.e1.
11. Dixon, J.B.; Bhathal, P.S.; O’Brien, P.E. Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001, 121, 91–100.
12. Younossi, Z.M.; Golabi, P.; Paik, J.M.; Henry, A.; Van Dongen, C.; Henry, L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology 2023, 77, 1335–1347.
13. Rinella, M.E.; Neuschwander-Tetri, B.A.; Siddiqui, M.S.; Abdelmalek, M.F.; Caldwell, S.; Barb, D.; Kleiner, D.E.; Loomba, R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023, 77, 1797–1835.
14. Kountouras, J.; Kazakos, E.; Kyrailidi, F.; Polyzos, S.A.; Zavos, C.; Arapoglou, S.; Boziki, M.; Mouratidou, M.C.; TzitiridouChatzopoulou, M.; Chatzopoulos, D.; et al. Innate immunity and nonalcoholic fatty liver disease. Ann. Gastroenterol. 2023, 36, 244–256.
15. Yuan, L.; Hanlon, C.L.; Terrault, N.; Alqahtani, S.; Tamim, H.; Lai, M.; Saberi, B. Portrait of Regional Trends in Liver Transplantation for Nonalcoholic Steatohepatitis in the United States. Am. J. Gastroenterol. 2022, 117, 433–444.
16. Sebastiani, G.; Gkouvatsos, K.; Pantopoulos, K. Chronic hepatitis C and liver fibrosis. World J. Gastroenterol. 2014, 20, 11033–11053.
17. Sherlock, S. The immunology of liver disease. Am. J. Med. 1970, 49, 693–706.
18. Peters, M.; Vierling, J.; Gershwin, E.M.; Milich, D.; Chisari, F.V.; Hoofnagle, J.H.M.D. Immunology and the liver. Hepatology 1991, 13, 977–994.
19. Meng, P.; Zhao, S.; Niu, X.; Fu, N.; Su, S.; Wang, R.; Zhang, Y.; Qiao, L.; Nan, Y. Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses. Int. J. Mol. Sci. 2016, 17, 1070, Erratum in Int. J. Mol. Sci. 2016, 17, 1070.
20. Li, H.; Tsokos, G.C. IL-23/IL-17 Axis in Inflammatory Rheumatic Diseases. Clin. Rev. Allergy Immunol. 2021, 60, 31–45.
21. Cătană, C.S.; Berindan Neagoe, I.; Cozma, V.; Magda¸s, C.; Tăbăran, F.; Dumitra¸scu, D.L. Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease. World J. Gastroenterol. 2015, 21, 5823–5830.
22. Menter, A.; Krueger, G.G.; Paek, S.Y.; Kivelevitch, D.; Adamopoulos, I.E.; Langley, R.G. Interleukin-17 and Interleukin-23: A Narrative Review of Mechanisms of Action in Psoriasis and Associated Comorbidities. Dermatol. Ther. 2021, 11, 385–400.
23. Bankir, M.; Acik, D.Y. IL-17 and IL-23 levels in patients with early-stage chronic lymphocytic leukemia. North. Clin. Istanb. 2020, 8, 24–30.
24. Kolls, J.K.; Lindén, A. Interleukin-17 family members and inflammation. Immunity 2004, 21, 467–476.
25. Iwakura, Y.; Ishigame, H. The IL-23/IL-17 axis in inflammation. J. Clin. Investig. 2006, 116, 1218–1222.
26. Heredia, J.E.; Sorenson, C.; Flanagan, S.; Nunez, V.; Jones, C.; Martzall, A.; Leong, L.; Martinez, A.P.; Scherl, A.; Brightbill, H.D.; et al. IL-23 signaling is not an important driver of liver inflammation and fibrosis in murine non-alcoholic steatohepatitis models. PLoS ONE 2022, 17, e0274582.
27. Yan, S.; Wang, L.; Liu, N.; Wang, Y.; Chu, Y. Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis. Immunol. Cell Biol. 2012, 90, 421–428.
28. He, Y.; Hwang, S.; Ahmed, Y.A.; Feng, D.; Li, N.; Ribeiro, M.; Lafdil, F.; Kisseleva, T.; Szabo, G.; Gao, B. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol. Immunol. 2021, 18, 18–37.
29. Krassenburg, L.A.P.; Maan, R.; Ramji, A.; Manns, M.P.; Cornberg, M.; Wedemeyer, H.; de Knegt, R.J.; Hansen, B.E.; Janssen, H.L.A.; de Man, R.A.; et al. Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity. J. Hepatol. 2021, 74, 1053–1063.
30. Lee, U.E.; Friedman, S.L. Mechanisms of hepatic fibrogenesis. Best Pract. Res. Clin. Gastroenterol. 2011, 25, 195–206.
31. Bălănescu, P.; Lădaru, A.; Voiosu, T.; Nicolau, A.; Ene, M.; Bălănescu, E. Th17 and IL-17 immunity in chronic hepatitis C infection. Rom. J. Intern. Med. 2012, 50, 13–18.
32. Rios, D.A.; Casciato, P.C.; Caldirola, M.S.; Gaillard, M.I.; Giadans, C.; Ameigeiras, B.; De Matteo, E.N.; Preciado, M.V.; Valva, P. Chronic Hepatitis C Pathogenesis: Immune Response in the Liver Microenvironment and Peripheral Compartment. Front. Cell. Infect. Microbiol. 2021, 11, 712105.
33. Falleti, E.; Fabris, C.; Toniutto, P.; Fontanini, E.; Cussigh, A.; Bitetto, D.; Fumolo, E.; Fornasiere, E.; Bragagnini, W.; Pinato, D.J.; et al. Interleukin-6 polymorphisms and gender: Relationship with the occurrence of hepatocellular carcinoma in patients with end-stage liver disease. Oncology 2009, 77, 304–313.
34. Paquissi, F.C. Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front. Immunol. 2017, 8, 1195.
35. de Souza-Cruz, S.; Victória, M.B.; Tarragô, A.M.; da Costa, A.G.; Pimentel, J.P.; Pires, E.F.; Araújo, L.d.P.; Coelho-dos-Reis, J.G.; Gomes, M.d.S.; Amaral, L.R.; et al. Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: A proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10. BMC Microbiol. 2016, 16, 3.
36. El-Emshaty, H.M.; Nasif, W.A.; Mohamed, I.E. Serum Cytokine of IL-10 and IL-12 in Chronic Liver Disease: The Immune and Inflammatory Response. Dis. Markers 2015, 2015, 707254.
37. Owusu, D.O.; Phillips, R.; Owusu, M.; Sarfo, F.S.; Frempong, M. Increased levels of circulating IL-10 in persons recovered from hepatitis C virus (HCV) infection compared with persons with active HCV infection. BMC Res. Notes 2020, 13, 472.
38. Aboushousha, T.; Emad, M.; Rizk, G.; Ragab, K.; Hammam, O.; Fouad, R.; Helal, N.S. IL-4, IL-17 and CD163 Immunoexpression and IL-6 Gene Polymorphism in Chronic Hepatitis C Patients and Associated Hepatocellular Carcinoma. Asian Pac. J. Cancer Prev. 2021, 22, 1105–1113.
39. 53. Tan, Z.; Qian, X.; Jiang, R.; Liu, Q.; Wang, Y.; Chen, C.; Wang, X.; Ryffel, B.; Sun, B. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J. Immunol. 2013, 191, 1835–1844.
40. Gomes, A.L.; Teijeiro, A.; Burén, S.; Tummala, K.S.; Yilmaz, M.; Waisman, A.; Theurillat, J.P.; Perna, C.; Djouder, N. Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma. Cancer Cell 2016, 30, 161–175.
41. 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, 273–278.
42. Macek Jilkova, Z.; Afzal, S.; Marche, H.; Decaens, T.; Sturm, N.; Jouvin-Marche, E.; Huard, B.; Marche, P.N. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17(+) neutrophils. Liver Int. 2016, 36, 1116–1124.
43. Santiago, A.M.; da Silva Graça Amoras, E.; Queiroz, M.A.F.; da Silva Conde, S.R.S.; Cayres-Vallinoto, I.M.V.; Ishak, R.; Vallinoto, A.C.R. TNFA -308G>A and IL10 -1082A>G polymorphisms seem to be predictive biomarkers of chronic HCV infection. BMC Infect. Dis. 2021, 21, 1133.
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