Blood plasma сytokine levels in patients with chronic viral hepatitis B stage-dependent liver fibrosis

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Introduction. Hepatitis B is an infectious inflammatory liver disease resulting from hepatitis B virus infection. According to the WHO estimates, 254 million people with chronic hepatitis B (CHB) were recorded worldwide in 2022. CHB is accompanied by developing liver fibrosis, which leads to impaired liver function. The progression of liver fibrosis involves multilayered cellular interactions between hepatic stellate cells, resident macrophages, and specialized immune cells. this cell interplay is regulated by humoral factors, among which cytokines play a key role. Due to this, the analysis of peripheral blood cytokines in CHB patients allows assessment of immune process activity in the liver, fibrosis progression intensity, and therapeutic effectiveness. The aim of our work was to evaluate blood plasma cytokine spectrum in CHB patients related to liver fibrosis staging.

Materials and methods. The study included 53 patients diagnosed with chronic viral hepatitis B, subdivided into three groups based on liver fibrosis stage. Blood plasma samples were collected from all study subjects. Concentration for 42 cytokines was assessed by xMAP multiplexing technology. The results underwent statistical processing using nonparametric statistical methods.

Results. Compared to apparently healthy group, CHB patients showed: significantly elevated concentrations for IL-6, IL-27, CCL11/Eotaxin, CXCL9/MIG, CXCL-10/IP-10, M-CSF; significantly decreased levels for IL-2, IL-4, IL-12(p70), IL-13, IL-17A, IFN2α, sCD40L, CCL3/MIP-1α, CCL7/MCP-3, CXCL1/GROα, CXCL8/IL-8, CX3CL1/ Fractalkine, EGF, PDGF-AA, PDGF-AB/BB, VEGF-A. Based on different liver fibrosis stages, significant differences in cytokine levels were found between patient groups for: IL-6, IL-10, IL-12(p70), IL-27, sCD40L, CXCL9/MIG, CXCL-10/IP-10, M-CSF, PDGF-AA, PDGF-AB/BB. Correlation analysis revealed a positive relationship between liver fibrosis severity and levels for IL-6, IL-27, TNFα, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, and M-CSF, and a negative relationship between the severity of liver fibrosis and levels for IL-12(p70), IFN2α, sCD40L, CX3CL1/Fractalkine, EGF, PDGF-AA and PDGF-AB/BB. Thus, blood plasma cytokine spectrum in CHB patients was evaluated, identifying factors involved in CHB immunopathogenesis, including those playing a significant role for developing liver fibrosis.

作者简介

Oleg Batsunov

St. Petersburg Pasteur Institute; Pavlov First Saint Petersburg State Medical University

编辑信件的主要联系方式.
Email: batsunov@gmail.com

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

俄罗斯联邦, St. Petersburg

N. Arsentieva

St. Petersburg Pasteur Institute; Pavlov First Saint Petersburg State Medical University

Email: batsunov@gmail.com

PhD (Biology), Senior Researcher, Laboratory of Molecular Immunology, Associate Professor, Department of Immunology

俄罗斯联邦, St. Petersburg; St. Petersburg

N. Liubimova

St. Petersburg Pasteur Institute

Email: batsunov@gmail.com

Infectiologist, Department of Epidemiology

俄罗斯联邦, St. Petersburg

D. T. Duong

Pavlov First Saint Petersburg State Medical University

Email: batsunov@gmail.com

infectious disease doctor of the Department of epidemiology

俄罗斯联邦, St. Petersburg

V. Basina

St. Petersburg State Pediatric Medical University

Email: batsunov@gmail.com

PhD (Medicine), Assistant Professor, Department of Infectious Diseases Adults and Epidemiology

俄罗斯联邦, St. Petersburg

E. Esaulenko

St. Petersburg Pasteur Institute; St. Petersburg State Pediatric Medical University

Email: batsunov@gmail.com

DSc (Medicine), Professor, Head of the Viral Hepatitis Laboratory, Head of the Department of Infectious Diseases Adults and Epidemiology

俄罗斯联邦, St. Petersburg; St. Petersburg

A. Totolian

St. Petersburg Pasteur Institute; Pavlov First Saint Petersburg State Medical University

Email: batsunov@gmail.com

RAS Full Member, DSc (Medicine), Professor, Director, Head of the Department of Immunology

俄罗斯联邦, St. Petersburg; St. Petersburg

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2. Figure 1. Concentrations of cytokines: IL-1α, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IL-17-E/IL-25, IL-17F, IL-18, IL-27, IFN2α, IFNγ, TNFα, TNFβ, sCD40L in the blood plasma of patients with chronic hepatitis B with different stages of liver fibrosis: F0–1 (n = 28), F2–3 (n = 6), F4 (n = 19) Note. The green horizontal bar indicates the interquartile range (Q25–Q75) for conditionally healthy individuals (n = 32). The groups that demonstrated statistically significant differences compared to conditionally healthy individuals are highlighted in red. The Kruskal–Wallis test was used for intergroup comparisons.

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3. Figure 2. Concentrations of chemokines CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROα, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine in the blood plasma of patients with chronic hepatitis B with different stages of liver fibrosis: F0–1 (n = 28), F2–3 (n = 6), F4 (n = 19) Note. The green horizontal bar indicates the interquartile range (Q25–Q75) for conditionally healthy individuals (n = 32). The groups that demonstrated statistically significant differences compared to conditionally healthy individuals are highlighted in red. The Kruskal–Wallis test was used for intergroup comparisons.

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4. Figure 3. Concentrations of growth factors: EGF, FGF-2, Flt-3L, G-CSF, M-CSF, PDGF-AA, PDGF-AB/BB, TGFα, VEGF-A in the blood plasma of patients with chronic hepatitis B with different stages of liver fibrosis: F0–1 (n = 28), F2–3 (n = 6), F4 (n = 19) Note. The green horizontal bar indicates the interquartile range (Q25–Q75) for conditionally healthy individuals (n = 32). The groups that demonstrated statistically significant differences compared to conditionally healthy individuals are highlighted in red. The Kruskal–Wallis test was used for intergroup comparisons.

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