Increased killer B cells in chronic HCV infection may lead to autoimmunity and increased viral load

• Published in: Clinical and experimental immunology Vol. 193; no. 2; pp. 183 - 193
• Main Authors: Eiza, N., Zuckerman, E., Carlebach, M., Rainis, T., Goldberg, Y., Vadasz, Z.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-08-2018; John Wiley and Sons Inc
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Antinuclear - blood; Antibodies, Blocking - pharmacology; Apoptosis; Autoimmunity; B cell; B-Lymphocytes, Regulatory - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD5 Antigens - metabolism; CD8 antigen; Cells, Cultured; Chronic infection; Cytokines; Cytotoxicity, Immunologic; Fas Ligand Protein - immunology; Fas Ligand Protein - metabolism; FasL protein; Female; Fluorescence; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatitis C, Chronic - immunology; Humans; Immune response; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Middle Aged; Monoclonal antibodies; Original; Rheumatoid factor; Standard error; Tumors; Viral Load; Viruses; autoimmunity; B cell; viral load
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13139

Summary
Regulatory B (Breg) cells are characterized by various membrane markers and the secretion of different inhibitory cytokines. A new subset of Breg cells was identified as CD5hi Fas‐ligand (FasL)hi. Their main reported role is to suppress anti‐viral and anti‐tumour immune responses, and, hence they have been dubbed ‘killer’ B cells. In this study, we aim to assess the role of these cells in chronic hepatitis C virus (HCV) infection, and determine if they contribute to the increased viral load and persistence of HCV and its related autoimmunity. (i) FasL expression on CD5hi B cells is increased significantly in HCV‐infected patients compared to healthy individuals [28·06 ± 6·71 mean fluorescence intensity (MFI) ± standard error of the mean (s.e.m.), median = 27·9 versus 10·87 ± 3·97 MFI ± s.e.m., median = 10·3, respectively, P <  0·0001]. (ii) Killer B cells from HCV patients increased autologous CD4+ T cell apoptosis compared to the apoptosis in healthy individuals [39·17% ± 7·18% mean ± standard deviation (s.d.), median = 39·6 versus 25·92 ± 8·65%, mean ± s.d., median = 24·1%, P <  0·0001, respectively]. A similar increase was observed in CD8+ T cell apoptosis (54·67 ± 15·49% mean ± s.d., median = 57·3 versus 21·07% ± 7·4%, mean ± s.d., median = 20%, P = 0·0006, respectively). (iii) By neutralizing FasL with monoclonal anti‐FasL antibodies, we have shown that the induction of apoptosis by killer B cells is FasL‐dependent. (iv) Increased expression of FasL on CD5hi B cells is correlated positively with an increased viral load and the presence of anti‐nuclear antibodies and rheumatoid factor in HCV. This is the first study in which killer B cells have been suggested to play a pathogenic role in HCV. They seem to be involved in HCV's ability to escape efficient immune responses.
In our study, we found Killer B cells, a subset of B regulatory cells (CD19+CD5hiFasLhi) to be increased in HCV patients when compared to healthy controls and in correlation with increased autoimmunity in these patients. The co‐culture of killer B cells with autologous CD4 or CD8 T cells increases the rate of T cells apoptosis, mainly in HCV patients, in a Fas‐FasL dependent mechanism.