Chemokine receptors and their ligands in peripheral blood of patients with chronic hepatitis C and aggravated comorbid background

The objective of this work which is the study of the immunopathogenesis of chronic hepatitis C (CHC) in patients with an unfavorable comorbid background is currently a topical area of research in connection with the search for the best tactics for managing and treating patients. The study involved 700 patients with CHC, observed in the period from 2013 to 2019 in Botkin hospital (St. Petersburg). Immunological features were studied in 79 patients with CHC. The concentrations of cytokines/chemokines: TNFα, IFNg, CCL20/MIP-3α, CXCL9/MIG, CXCL10/IP-10, CXCL11/ITAC in blood plasma were determined by multiplex analysis. In 61 patients, subpopulations of lymphocytes were determined: T-helpers, cytotoxic T-lymphocytes, B-lymphocytes, NK-cells, NKT-cells, and the expression of chemokine receptors CCR6 and CXCR3 on these cells by flow cytometry. The patients were divided into two groups with and without comorbidity, as well as non-infectious pathologies within the comorbidity group. Comorbidity was present in 63% of patients with CHC, among whom multimorbidity was found in 79.4%. The most frequent comorbidities were the following: diseases of the gastrointestinal tract and pancreas — 49% of cases; diseases of the circulatory system — 15.4%; and pathology of the endocrine system and metabolism — 13.9%. In the group of patients with comorbidity, the concentrations of the chemokines CXCL9/MIG and CCL20/MIP3-α were determined, which were 2 and 1.6 times higher than those in the group without comorbidity (p = 0.017). The suppression of the cells of the cytotoxic component of the immune system was more pronounced in the group of patients with aggravated comorbid background. Thus, the content of Th CCR6+, CTL, CTL CCR6+, NK CCR6+, NK CXCR3+, NKT CCR6+ and NK CXCR3+ in patients with comorbidities were 1.6; 2; 1.6; 1.8; 1.6; 2.7 and 1.7 times less than in the group without them. As a result of the study, more than half of the patients with CHC revealed the presence of various comorbid backgrounds. The cytokine profile showed high concentrations of CCL20/MIP-3α and CXCL9/MIG chemokines in the group of patients with comorbidity in comparison with patients without it, and the predominance of the CCL20/MIP-3α chemokine concentration in patients with endocrine pathology, including type 1 and type 2 diabetes. Also, a more pronounced suppression of the innate and adaptive cellular component of immunity with cytotoxic activity was revealed in patients with comorbidity.

1. Dzemova, A.A., Ganchenko R.A., Trifonova G.F., Esaulenko E.V. Hronicheskij gepatit S v Rossijskoj Federacii posle nachala programmy eliminacii HCV-infekcii. Gepatologiya i Gastroenterologiya. 2020; 4(2):165-170.

2. World Health Organization. 2018. [Электр. ресурс]. URL: https://www.who.int/gho/publications/world_health_statistics/2018/EN_WHS2018_TOC.pdf (дата обращения: 5.11.2021).

3. Heydtmann M., Adams D.H. Chemokines in the immunopathogenesis of hepatitis C infection // Hepatology. 2009. Vol.49. №2. P.676-688. DOI: https://doi.org/10.1002/hep.22763

4. Arsent'eva N.A., Semenov A.V., Lyubimova N.E., Basina V.V., Esaulenko E.V., Kozlov K.V., ZHdanov K.V., Totolyan A.A. Soderzhanie citokinov i hemokinov v plazme krovi bol'nyh hronicheskim virusnym gepatitom S. Rossijskij immunologicheskij zhurnal. 2015; 9(18): 83-92.

5. Belyakov N.A., Boeva E.V., Bushmanova A.D., Ogurcova S.V., Rassohin V.V., Svetlichnaya YU.S., Trifonova G.F., Esaulenko E.V., Azovceva O.V., Asadullaev M.R., Amozov A.M., Baryshkov K.V., Belkin I.V., Zagdyn Z.M., Kovelenov A.YU., Kozenkov D.S., Kurganova T.YU., Mel'nikova T.N., Pogan S.S., Popova E.S. i dr. Vichinfekciya i komorbidnye sostoyaniya v severo-zapadnom federal'nom okruge rossijskoj federacii v 2018 godu. Analiticheskij obzor / Sankt-Peterburg, 2019.

6. Larrubia J., Benito-Martínez S., Calvino M. et al. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection // World Journal of Gastroenterology. 2008. Vol.14(47). P.7149-7159. DOI: https://doi.org/10.3748/wjg.14.7149

7. Cooper C., Galanakis C., Donelle J. et al. HCV-infected individuals have higher prevalence of comorbidity and multimorbidity: a retrospective cohort study // Bmc Infectious Diseases. 2019. Vol.19. Article number: 712. DOI: https://doi.org/10.1186/s12879-019-4315-6

8. Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases // Journal of Hepatology. 2014. Vol.61(1). P.S69-S78. DOI: https://doi.org/10.1016/j.jhep.2014.08.003

9. Belyakov N.A., Boeva E.V., Bushmanova A.D., Ogurcova S.V., Rassohin V.V., Svetlichnaya YU.S., Trifonova G.F., Esaulenko E.V., Azovceva O.V., Asadullaev M.R., Amozov A.M., Baryshkov K.V., Belkin I.V., Zagdyn Z.M., Kovelenov A.YU., Kozenkov D.S., Kurganova T.YU., Mel'nikova T.N., Pogan S.S., Popova E.S. i dr. Vichinfekciya i komorbidnye sostoyaniya v severo-zapadnom federal'nom okruge rossijskoj federacii v 2018 godu. Analiticheskij obzor / Sankt-Peterburg, 2019.

10. Esaulenko E.V., Suhoruk A.A. Transplantaciya pecheni v detskom vozraste i u vzroslyh. Pediatr. 2015. T. 6. № 3. S. 98-103.

11. Novak K.E., Karev V.E., Dunaeva N.V., Esaulenko E.V. Harakteristika regeneratornoj sposobnosti pecheni(po ekspressii ki-67) u bol'nyh s neblagopriyatnymi iskhodami hronicheskih virusnyh gepatitov. Fundamental'nye issledovaniya. 2011. № 6. S. 138-143.

12. Novak K.E., Karev V.E., Dunaeva N.V., Esaulenko E.V. Postmortal'naya morfologicheskaya harakteristika pecheni bol'nyh hronicheskimi virusnymi gepatitami s klinicheskimi priznakami cirroza. Rossijskij medicinskij zhurnal. 2011. № 2. S. 8-11.

13. Labenz С., Huber Y., Kalliga E. et al. Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany // Alimentary Pharmacology & Therapeutics. 2018. Vol.48(10). P.1109-1116. DOI: https://doi.org/10.1111/apt.14976

14. Badawi A., Di Giuseppe G., Arora P. Cardiovascular disease risk in patients with hepatitis C infection: Results from two general population health surveys in Canada and the United States (20072017) // PLoS One. 2018. Vol.12. P.13(12). Article number: 0208839. DOI: https://doi.org/10.1371/journal.pone.0208839

15. McPherson S., Gosrani S., Hogg S. et al.Increased cardiovascular risk and reduced quality of life are highly prevalent among individuals with hepatitis C // BMJ Open Gastroenterology. 2020. Vol.7(1). Article number: 000470. DOI: https://doi.org/10.1136/bmjgast-2020-000470

16. Kuna L., Jakab J., Smolic R. et al. HCV Extrahepatic Manifestations // Journal of Clinical and Translational Hepatology. 2019. Vol. 7(2). P.172-182. DOI: https://doi.org/10.14218/JCTH.2018.00049

17. Yan F., Chen A., Hao F. et al. Hepatitis C virus may infect extrahepatic tissues in patients with hepatitis C // World Journal Gastroenterology. 2000. Vol.6(6). P.805-811. DOI: https://doi.org/10.3748/wjg.v6.i6.805

18. Sayed-Ahmed L., Kotb N., El-Serogy H. et al. TNF-alpha and CXCL-10 correlation with insulin resistance in patients with chronic hepatitis C virus infection // Egyptian Journal of Immunology. 2010. Vol. 17(1). P.101-111.

19. Hung C-H., Lee C-M., Lu S-N. Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications // Expert Review of Anti-infective Therapy. 2011. Vol.9(5). P.525-533. DOI: https://doi.org/10.1586/eri.11.33

20. Liu C., Feng X., Li Q. et al. TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis // Cytokine. 2016. Vol.86. P.100-109. DOI: https://doi.org/10.1016/j.cyto.2016.06.028

21. Gonnella D. Type 1 diabetes and MIG // Clinical Therapeutics. 2019. Vol. 170(6). P.е465-е471. DOI: https://doi.org/10.7417/CT.2019.2177

22. Antonelli А., Ferrari S., Corrado A. et al. CXCR3, CXCL10 and type 1 diabetes // Cytokine & Growth Factor Reviews. 2014. Vol.25(1). P. 57-65. DOI: https://doi.org/10.1016/j.cytogfr.2014.01.006

23. Hung C-H., Lee C-M., Chen C-H. et al.Association of inflammatory and anti-inflammatory cytokines with insulin resistance in chronic hepatitis C // Liver International. 2009. Vol.29(7). P.1086-93. DOI: https://doi.org/10.1111/j.14783231.2009.01991

24. Corrado A. Ferrari S., Ferri C. et al. Type 1 diabetes and (CX-C motif) ligand (CXCL) 10 chemokine // Clinical Thera https://doi.org/peutics. 2014. Vol.165(2). P.181-185. DOI: https://doi.org/10.7471/CT.2014.1706

25. Ferrari S., Ruffilli I., Colaci M. et al. CXCL10 in psoriasis // Advances in Medical Sciences. 2015. Vol. 60(2). P.349-354. DOI: https://doi.org/10.1016/j.advms.2015.07.011

26. Antonelli A. Ferrari S., Giuggioli D. et al. Chemokine (C-XC motif) ligand (CXCL)10 in autoimmune diseases // Autoimmunity Reviews. 2014. Vol.13(3). P. 272-280. DOI: https://doi.org/10.1016/j.autrev.2013.10.010

27. McKinney E., Lee J., Jayne D. et al. T-cell exhaustion, costimulation and clinical outcome in autoimmunity and infection // Nature. 2015. Vol.30. P.523(7562). 612-6. DOI: https://doi.org/10.1038/nature14468