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.

Characterization of the light chain-restricted clonal B cells in peripheral blood of HCV-positive patients

“…The association between HCV-related immune disorders and the increase of CD5? B cells remains controversial [17][18][19][20]. In the present study, no significant differences were found in the frequencies of CD5?…”

“…While some authors reported increase of CD5? B cells in the patients with HCV or HCV-related cryoglobulinemia [17,18], others reported a lower expression of CD5 in patients with HCV-related lymphoproliferative disease [19], and others reported that no correlation was found between the increase of CD5? B cells and the presence of cryoprecipitate or rheumatoid factor (RF) in patients with HCV [20].…”

Monoclonal B cell lymphocytosis in hepatitis C virus infected individuals

“…This heterogeneity may help to explain the discrepancies present in the literature regarding the phenotype of B cells clones in HCV infected individuals (4,(24)(25)(26)(27)(28). Accordingly, also a sizeable fraction of CD5 À MBL do exist in HCV infected patients.…”

“…Some studies showed that in the course of HCV infection, B cell clones were mainly CD5 þ (4,24), although this has not been confirmed by others (25,26). CD5 À B cells have been reported to produce monoclonal IgM in MC (13,27,28).…”

Hepatitis C virus and risk of non‐Hodgkin lymphoma in British Columbia, Canada

“…The stimulation of the CD81 complex enables B-cells to respond to lower concentrations of antigen and facilitates B-cell proliferation. 26 Finally, the t(14; 18) translocation has been shown to be present in a significant percentage of peripheral blood lymphocytes in HCV infected individuals, particularly with MC. 27 This translocation is responsible for BCL-2 activation, which extends B-cell survival by inhibiting apoptosis.…”