Regulatory B Cells and Their Cytokine Profile in HCV-Related Hepatocellular Carcinoma: Association with Regulatory T Cells and Disease Progression.

Helal F Hetta,Mohamed A El-Mokhtar,Wael A Abbas,Amira A Kamel,Heba A Osman,Mohamed A Mekky,Haidi K Ramadan,Mohamed O Abdel-Malek,Asmaa M Zahran,Nahed A Mohamed,Muhammad Abbas El-Masry,Najat Marraiki,Gopala Koneru,Engy A Shafik,Gaber El-Saber Batiha,Amany Magdy Beshbishy

doi:10.3390/vaccines8030380

Abstract

Although regulatory B cells (Bregs) have been proven to play a suppressive role in autoimmune diseases, infections and different tumors, little is known regarding hepatocellular carcinoma (HCC), especially in hepatitis C-related settings. Herein, we analyzed the frequency of circulating Bregs, serum levels of IL-10, IL-35 and B-cell activating factor (BAFF) and investigated their association with regulatory T cells (Tregs) and disease progression in HCV-related HCC. For comparative purposes, four groups were enrolled; chronic HCV (CHC group, n = 35), HCV-related liver cirrhosis (HCV-LC group, n = 35), HCV-related HCC (HCV-HCC group, n = 60) and an apparently healthy control (Control-group, n = 20). HCC diagnosis and staging were in concordance with the Barcelona Clinic Liver Cancer (BCLC) staging system. Analysis of the percentage of Breg cells and peripheral lymphocyte subsets (Treg) was performed by flow cytometry. Serum cytokine levels of IL-10, IL-35 and B-cell activating factor (BAFF) were measured by ELISA. The frequency of Bregs was significantly higher in the HCV-HCC group compared to the other groups and controls. A significant increase was noted in late-HCC versus those in the early stages. The frequency of Bregs was positively correlated with Tregs, serum IL-10, IL-35 and BAFF. In conclusion, Peripheral Bregs were positively correlated with the frequency of Tregs, IL-10, IL-35 and BAFF, and may be associated with HCV-related HCC progression.

Highlights

Hepatocellular carcinoma (HCC) the fourth most common cause of cancer-related death worldwide;>80% of hepatocellular carcinoma (HCC) cases occur in low-resource and middle-resource countries, in Eastern Asia and sub-Saharan Africa, where medical and social care resources are often constrained [1]
The HCV- LC group were divided according to Child–Pugh score as follows: 15 (43%) patients were class A, 13 (37%) class B, and 7 (20%)
Many theories have tried to postulate the potential role of immune cells, especially that of immune-regulatory cells, such as IL-10+ Bregs and Tregs, that have been proven to play a pivotal role in immune down-regulation [35,36]

Summary

Introduction

Hepatocellular carcinoma (HCC) the fourth most common cause of cancer-related death worldwide;. >80% of HCC cases occur in low-resource and middle-resource countries, in Eastern Asia and sub-Saharan Africa, where medical and social care resources are often constrained [1]. One of the common risk factors for HCC is chronic hepatitis B and chronic hepatitis C (CHC) infection [2,3,4]. In areas with a high endemicity of HCV, like in Egypt, a rising trend of HCC will be expected [5,6,7]. There is a balance between immune effector cells and immunosuppressive cells to regulate the tumor microenvironment. It has been reported that there is a significant contribution of immune regulatory cells, including regulatory T cells (Tregs), to tumor progression [8,9,10]. There is evidence that B cells play a role in modulating the immune response to tumors and lymphoid malignancies [11]

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