Lower expression of CD81 B-cell receptor in lymphoproliferative diseases associated with hepatitis C virus infection

Abstract

Chronic hepatitis C virus (HCV) infection is frequently associated with type II mixed cryoglobulinaemia (MC), a benign lymphoproliferative disease (LPD). More recently, HCV has been implicated as a possible aetiologic factor of B-cell non-Hodgkin lymphoma (B-NHL). CD81, a B-cell surface receptor, has been proposed as a receptor for HCV binding and entry in circulating B cells. The stimulation of CD81 complex enables B cells to respond to lower concentrations of antigen and finally induces B-cell proliferation. We studied the phenotypic expression of CD81, CD19 and CD5 on circulating B cells in HCV patients LPD-positive or LPD-negative. Sixty-two patients were anti-HCV antibody positive. Among HCV positive patients, 44 were HCV RNA positive with an histologically proven chronic active hepatitis of whom 10 had a B-NHL, 14 an MC and 24 no extrahepatic manifestation. Eighteen patients were HCV RNA negative with evidence of resolved infection. A control group included 40 healthy subjects. Peripheral blood mononuclear cells (PBMC) were stained for surface expression of CD81, CD19 and CD5 using monoclonal antibodies, and were analyzed by flow cytometry. The percentage of PBMC expressing CD81, CD19 and CD5 receptors were compared between the groups by univariate analysis. Logistic regression model variables were then evaluated to correlate the presence of an LPD with HCV infection characteristics (i.e. age, gender, genotype, duration of infection, HCV RNA positivity, liver histological lesions), or phenotypic expression of CD81, CD19 and CD5 receptors on PBMC. HCV antibody-positive compared with HCV-negative subjects had a higher expression of CD19 receptor (23 +/- 13 vs 13 +/- 1%, P = 0.003). Among HCV RNA positive-patients, LPD+ compared with LPD- patients had a lower expression of CD81 (58 +/- 28 vs 82 +/- 18%, P = 0.001) and CD5 receptor (66 +/- 16 vs 74 +/- 13%, P = 0.04). In multivariate analysis, the expression of CD81 receptor was a negative (OR = 0.15, 95% CI = 0.04-0.64, P = 0.01) and CD19 receptor a positive (OR = 4.81, 95% CI =1.29-17.88, P = 0.02) predictive factor for an LPD. We found two negative predictive factors for HCV RNA positivity, i.e. age (OR = 0.23, 95% CI. = 0.08-0.62, P = 0.003) and the expression of CD81 receptor (OR = 0.34, 95% CI = 0.13-0.89, P = 0.02). In patients with a chronic active HCV infection, the presence of a lymphoproliferative disease, either MC or B-NHL, is associated with lower expression of CD81 and higher expression of CD19 receptor on peripheral B cells.