PERIPHERAL BLOOD B-CELLS AND CXCR3+ EXPRESSION IN CHRONIC HEPATITIS C VIRUS INFECTION



Cite item

Full Text

Abstract

Abstract

Hepatitis C virus (HCV) infection remains a serious global healthcare challenge, often leading to chronic disease with complications such as liver cirrhosis, hepatocellular carcinoma, and extrahepatic manifestations. According to the World Health Organization (WHO), an estimated about 50 million people lived with chronic HCV infection in 2022, highlighting the ongoing need to understand the immune mechanisms driving disease progression. HCV may evade of immunosurveillance, so that disease progression is linked to specific immune response, whereas reactivation risk after antiviral therapy exists, which together account for a need to gain understanding of underlying immune mechanisms. HCV may infect lymphocytes primarily B cells serving as a virus reservoir and result in diverse systemic complications. The current study focused on analyzing peripheral blood CXCR3+ B cells at various differentiation stages in patients with chronic HCV infection to assess a potential link to clinical and laboratory markers of disease progression. Blood samples collected from 58 patients with chronic HCV infection and 27 healthy controls were examined. When analyzing flow cytometry data, we noted a significant B cell redistribution in HCV infection compared to control samples presented as a shift towards activated mature, resting memory and ‘double negative’ B cells characterized by increased expression of chemokine receptor CXCR3. Flow cytometry analysis revealed no significant difference in total B-cell (CD19+) but elevated memory B-cells (CD27+CD19+) (p=0.037). CXCR3 expression peaked on memory B-cells and increased across all B-cell subsets in HCV patients (p<0.001). Redistribution toward differentiated B cell subsets—double-negative (CD38–CD27–), resting memory (CD38–CD27+), and activated mature (CD38+CD27+) B-cells was observed, with elevated CXCR3+ percentage in the latter two subsets (p=0.017 and p=0.001, respectively). HCV viral load correlated positively with CD38+ B-cells and CXCR3+ naïve/activated mature subset counts but inversely with CD38+ B1/B2/memory cell levels. Genotype 1 and advanced fibrosis (F3/cirrhosis) were associated with reduced B2 cells and increased CXCR3+ B1/B2 subset levels. These findings suggest that chronic HCV infection drives B-cell differentiation and CXCR3-mediated recruitment to the liver, implicating CXCR3 in disease progression.

About the authors

Natalia Alexandrovna Arsentieva

Saint Petersburg Pasteur Institute, St. Petersburg, Russian Federation;
First St. Petersburg State I. Pavlov Medical University, St.Petersburg, Russian Federation

Email: arsentieva_n.a@bk.ru
ORCID iD: 0000-0003-2490-308X

PhD in Biological sciences, senior researcher Laboratory of Molecular Immunology, associate professor of department of Immunology

Россия

Dmitrii Sergeevich Elezov

Saint Petersburg Pasteur Institute, St. Petersburg, Russian Federation

Email: elezovds@yahoo.com

PhD in Medicine sciences, Junior Researcher Laboratory of Molecular Immunology

Россия, 197101, Russian Federation, St. Petersburg, Mira str. 14

Igor Vladimirovich Kudryavtsev

Institute of Experimental Medicine, St.Petersburg, Russian Federation;
First St. Petersburg State I. Pavlov Medical University, St.Petersburg, Russian Federation

Email: igorek1981@yandex.ru

PhD in Biological sciences, head of laboratory of cellular immunology, associate professor of department of Immunology

Россия, 197376, St. Petersburg, acad. Pavlov str., 12

Zoya Romanovna Korobova

Saint Petersburg Pasteur Institute, St. Petersburg, Russian Federation;
First St. Petersburg State I. Pavlov Medical University, St.Petersburg, Russian Federation

Email: zoia-korobova@yandex.ru

Junior Researcher, Laboratory of Molecular Immunology, Senior Laboratory Assistant, Department of Immunology

Россия, 197101, St. Petersburg, Mira str., 14; St. Petersburg

Areg Artemovich Totolian

Saint Petersburg Pasteur Institute, St. Petersburg, Russian Federation;
First St. Petersburg State I. Pavlov Medical University, St.Petersburg, Russian Federation

Author for correspondence.
Email: totolian@spbraaci.ru

Member, PhD, MD (Medicine), Professor, Director, Head of the Department of Immunology

Россия, 14, Mira str., St. Petersburg, 197101; St. Petersburg

References

  1. Арсентьева Н.А., Кудрявцев И.В., Елезов Д.С., Семенов А.В., Басина В.В., Эсауленко Е.В., Тотолян Арег А. Экспрессия хемокинового рецептора СХСR3 на субпопуляциях В-лимфоцитов периферической крови больных хроническим вирусным гепатитом // Медицинская иммунология. 2013. Т. 15, No 5. С. 471-476. Arsentyeva N.A., Kudryavtsev I.V., Elezov D.S., Semenov A.V., Basina V.V., Esaulenko E.V., Totolyan A.A. Expression of chemokine receptor CXCR3 on subpopulations of peripheral blood B-lymphocytes in patients with chronic viral hepatitis. Medical Immunology (Russia), 2013, vol. 15, no. 5, pp. 471-476. (In Russ.). https://doi.org/10.15789/1563-0625-2013-5-471-476
  2. Хайдуков С.В., Байдун Л.А., Зурочка А.В., Тотолян Арег А. Стандартизованная технология «Исследование субпопуляционного состава лимфоцитов периферической крови с применением проточных цитофлюориметров-анализаторов» (Проект) // Медицинская иммунология. 2012. Т. 14, No 3. С. 255-268. Khaydukov S.V., Baydun L.A., Zurochka A.V., Totolian Areg A. Standardized technology «Research of lymphocytes subpopulation composition in peripheral blood using flow cytometry analyzers» (Draft). Medical Immunology (Russia), 2012, vol. 14, no. 3, pp. 255-268. (In Russ.). https://doi.org/10.15789/1563-0625-2012-3-255-268
  3. Butera D., Marukian S., Iwamaye A. E., Hembrador E., Chambers T. J., Di Bisceglie A. M., Charles E. D., Talal A. H., Jacobson I. M., Rice C. M., Dustin L. B. Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C. Blood, 2005, vol. 106, no. 4, pp. 1175–1182. https://doi.org/10.1182/blood-2005-01-0126
  4. Curbishley S.M., Eksteen B., Gladue R.P., Lalor P., Adams D.H. CXCR3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am. J. Pathol., 2005, vol. 167, pp. 887-899. doi: 10.1016/S0002-9440(10)62060-3
  5. Fecteau J. F., Roy A., Néron S. Peripheral blood CD27+ IgG+ B cell B-cells rapidly proliferate and differentiate into immunoglobulin-secreting cells after exposure to low CD154 interaction. Immunology, 2009, vol. 128, no. 1, pp. 353-365. https://doi.org/10.1111/j.1365-2567.2008.02976.x
  6. Ferrari S. M., Fallahi P., Ruffilli I., Elia G., Ragusa F., Paparo S. R., Patrizio A., Mazzi V., Colaci M., Giuggioli D., Ferri C., & Antonelli A. Immunomodulation of CXCL10 Secretion by Hepatitis C Virus: Could CXCL10 Be a Prognostic Marker of Chronic Hepatitis C? Journal of immunology research, 2019, 5878960. https://doi.org/10.1155/2019/5878960
  7. Ferri C., Antonelli A., Mascia M. T., Sebastiani M., Fallahi P., Ferrari D., Giunti M., Pileri S. A., Zignego A. L. B-cells and mixed cryoglobulinemia. Autoimmunity reviews, 2007, vol. 7, no. 2, pp. 114–120. https://doi.org/10.1016/j.autrev.2007.02.019
  8. Hanley P., Sutter J.A., Goodman N.G., Du, Y., Sekiguchi D.R., Meng W., Rickels M.R., Naji A., Prak E.T.L. Circulating B cellB-cells in type 1 diabetics exhibit fewer maturation-associated phenotypes. Clin. Immunol., 2017, vol. 183, pp.336–343. https://doi.org/10.1016/j.clim.2017.09.021
  9. Ito M., Masumi A., Mochida K., Kukihara H., Moriishi K., Matsuura Y., Yamaguchi K., Mizuochi T. Peripheral B-cells may serve as a reservoir for persistent hepatitis C virus infection. J. Innate Immun., 2010, vol. 2, pp. 607–617. doi: 10.1159/000317690
  10. Kotb A., Ismail S., Kimito I., Mohamed W., Salman A., Mohammed A. A. Increased CD5+ B-cells are associated with autoimmune phenomena in lepromatous leprosy patients. Journal of infection and public health, 2019, vol. 12, no. 5, pp. 656–659. https://doi.org/10.1016/j.jiph.2019.03.001
  11. Kudryavtsev I.V., Arsentieva N.A., Batsunov O.K., Korobova Z.R., Khamitova I.V., Isakov D.V., Kuznetsova R.N., Rubinstein A.A., Stanevich O.V., Lebedeva A.A., Vorobyov E.A., Vorobyova S.V., Kulikov A.N., Sharapova M.A., Pevtcov D.E., Totolian A.A. Alterations in B Cell and Follicular T-Helper Cell Subsets in Patients with Acute COVID-19 and COVID-19 Convalescents. Curr Issues Mol Biol., 2021, vol. 44, no. 1, pp. 194-205. doi: 10.3390/cimb44010014
  12. Luning Prak E.T., Ross J., Sutter J., Sullivan K.E. Age-related trends in pediatric B-cell subsets. Pediatr. Dev. Pathol., 2011, vol. 14, no. 1, pp. 45-52. doi: 10.2350/10-01-0785-OA
  13. Mizuochi T., Ito M., Saito K., Kasai M., Kunimura T., Morohoshi T., Momose H., Hamaguchi I., Takai K., Iino S., Suzuki M., Mochida S., Ikebuchi K., Yamaguchi K. Possible recruitment of peripheral blood CXCR3+CD27+CD19+ B cells to the liver of chronic hepatitis C patients. J. Interferon Cytokine Res., 2010, vol. 30, no. 4, pp. 243-252 doi: 10.1089/jir.2009.0047
  14. Mizuochi T., Ito M., Takai K., Yamaguchi K. Peripheral blood memory B cellB-cells are resistant to apoptosis in chronic hepatitis C patients. Virus. Res., 2011, vol. 155, no 1, pp. 349-351. doi: 10.1016/j.virusres.2010.09.017
  15. Reyes-Avilés E., Kostadinova L., Rusterholtz A., Cruz-Lebrón A., Falck-Ytter Y., Anthony D.D. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy. PloS one, 2015, vol. 10, no. 12, e0144629. https://doi.org/10.1371/journal.pone.0144629
  16. Rosa D., Saletti G., De Gregorio E., Zorat F., Comar C., D’Oro U., Nuti S., Houghton M., Barnaba V., Pozzato G., Abrignani S. Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 51, pp. 18544-1854. doi: 10.1073/pnas.0509402102
  17. Rubinstein A., Kudryavtsev I., Arsentieva N., Korobova Z. R., Isakov D., Totolian A. A. CXCR3-Expressing T Cells in Infections and Autoimmunity. Frontiers in bioscience (Landmark edition), 2024, vol. 29, no. 8, 301. https://doi.org/10.31083/j.fbl2908301
  18. Santer D.M., Hockman D., Landy A., Tyrrell D.L., Houghton M. Enhanced activation of memory, but not naïve, B cells in chronic hepatitis C virus-infected patients with cryoglobulinemia and advanced liver fibrosis. PloS one, 2013, vol. 8, no. 6, e68308. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695964
  19. Shetty S., Bruns T., Weston C.J., Stamataki Z., Oo Y.H., Long H.M., Reynolds G.M., Pratt G., Moss P., Jalkanen S., Hubscher S.J., Lalor P.F., Adams D.H. Recruitment mechanisms of primary and malignant B cells to the human liver. Hepathology, 2012, vol. 56, pp. 1521-1531. doi: 10.1002/hep.25790
  20. Tasleem S., Sood G. K. Hepatitis C Associated B-cell Non-Hodgkin Lymphoma: Clinical Features and the Role of Antiviral Therapy. Journal of clinical and translational hepatology, 2015, vol. 3, no. 2, pp. 134–139. https://doi.org/10.14218/JCTH.2015.00011
  21. Visco C., Finotto S. Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment. World journal of gastroenterology, 2014, vol. 20, no. 32, pp. 11054–11061. https://doi.org/10.3748/wjg.v20.i32.11054
  22. Weerakkody Y., Bell D., Rezaee A. METAVIR score. Reference article, Radiopaedia.org (Accessed on 14 Mar 2025) https://doi.org/10.53347/rID-51855
  23. World Health Organization 2024. Global Hepatitis Report 2024. Geneva: World Health Organization. 2024. P. 19. https://www.who.int/publications/i/item/9789240091672
  24. Zignego A. L., Giannini C., Ferri C. Hepatitis C virus-related lymphoproliferative disorders: an overview. World journal of gastroenterology, 2007, vol. 13, no. 17, pp. 2467–2478. https://doi.org/10.3748/wjg.v13.i17.2467
  25. Zuckerman E. Expansion of CD5+ B-cell overexpressing CD81 in HCV infection: towards better understanding the link between HCV infection, B-cell activation and lymphoproliferation. J. Hepatol., 2003, vol. 38, no 5, pp. 674-676. doi: 10.1016/S0168-8278(03)00122-3

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) Арсентьева Н.А., Elezov D.S., Kudryavtsev I.V., Korobova Z.R., Totolian A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies