Regulatory Role of B Cells and Its Subsets in Hepatitis E Virus Infection

Antibodies as well as memory B cells are the potential correlates of a protective immune response against hepatitis E virus (HEV) infection. Literature on the role of B regulatory cells (Bregs) in acute viral infections is limited. We have evaluated the role of IL-10 expressing Bregs in HEV infection. A total of 108 acute hepatitis E patients, 55 hepatitis E recovered individuals and 128 HEV naive healthy controls were enrolled. The percentages of peripheral CD19(+), immature CD19(+)CD24(hi)CD38(hi), mature CD19(+)CD24(int)CD38(int) and memory CD19(+)CD24(hi)CD38(-) B cells were analyzed by flowcytometry. Intracellular cytokine staining for IL-10 and TGF-beta, HEV-rORF2p specific T cell response (IFN-gamma expression) pre/post IL-10/IL-10R blocking and CD19(+)IL-10(+) B cells-depletion based assays were carried out to assess the functionality of Bregs. The percentage of HEV-rORF2p specific immature B cell phenotype was significantly higher in acute hepatitis E patients compared to hepatitis E recovered individuals and controls. Significantly higher IL-10 expression on B and HEV-rORF2p stimulated immature B cells of acute hepatitis E patients compared to controls indicated that Bregs are functional and HEV-rORF2p specific. Enhanced IFN-gamma expression on CD8(+) T cells upon IL-10/IL-10R blocking and also post CD19(+)IL-10(+) B cells depletion suggested that CD3(+)CD8(+)IFN-gamma(+) T cells corroborate the regulatory potential of Bregs via IL-10 dependent mechanism. We have identified HEV specific functional, immature CD19(+)CD24(hi)CD38(hi) B cells having IL-10 mediated regulatory activities and a potential to modulate IFN-gamma mediated T cell response in Hepatitis E. The prognostic/pathogenic role of Bregs in recovery from severe hepatitis E needs evaluation.