Expression of CTLA-4 and CD86 Antigens and Epstein-Barr Virus Reactivation in Chronic Lymphocytic Leukemia-Any Link with Known Prognostic Factors?

Infection with Epstein-Barr virus (EBV) worsens the prognosis in chronic lymphocytic leukemia (CLL), but the underlying mechanisms are not yet established. We intended to assess whether EBV affects the course of CLL by the deregulation of the CTLA-4/CD86 signaling pathway. We used polymerase chain reaction to measure the load of EBV DNA in the blood of 110 newly diagnosed patients with CLL. The expression of CTLA-4 and CD86 antigen on lymphocytes was assessed with flow cytometry. Additionally, CTLA-4 and CD86 serum concentrations were measured through enzyme-linked immunosorbent assays. Fifty-four percent of the patients had detectable EBV DNA [EBV(+)]. In EBV(+) patients the CTLA-4 and CD86 serum concentrations and their expressions on investigated cell populations were significantly higher than in EBV(-) patients. EBV load correlated positively with unfavorable prognostic markers of CLL and the expression of CTLA-4 on CD3+ lymphocytes (r = 0.5339; p = 0.027) and CD86 on CD19+ cells (r = 0.6950; p < 0.001). During a median follow-up period of 32 months EBV(+) patients were more likely to require treatment or have lymphocyte doubling (p < 0.001). Among EBV(+) but not EBV(-) patients, increased expressions of CTLA-4 lymphocytes were associated with elevated risks of progression. We propose that EBV coinfection may worsen prognosis in CLL patients, partly due to EBV-induced up-regulation of CTLA-4 expression.

PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis.

Alterations to the programmed cell death protein-1 (PD-1) pathway were previously shown to be involved in a poorer prognosis for patients with proliferative glomerulonephritis (PGN). Here, we investigated the association between several infectious agents and the expression of PD-1 and its ligand (PD-L1) on T and B lymphocytes in patients with PGN and nonproliferative glomerulonephritis (NPGN). A cohort of 45 newly-diagnosed patients (23 with PGN and 22 with NPGN) and 20 healthy volunteers was enrolled. The percentage of peripheral blood mononuclear cells expressing PD-1 and PD-L1 antigens was determined by flow cytometry. We found PD-1 and PD-L1 expression on T and B lymphocytes was higher in PGN patients than in NPGN patients and controls. We also found that reactivation of the Epstein-Barr virus (EBV) correlated with the expression of PD-1/PD-L1 antigens in patients with PGN. Further receiver operating characteristic analysis indicated that PD-1 expression could distinguish EBV-positive PGN patients from those with NPGN or healthy controls. The use of PD-1 expression as a non-invasive marker of PGN should be further investigated.

Programmed cell death 1 expression and Epstein-Barr virus infection in chronic lymphocytic leukaemia: a prospective cohort study.

PURPOSE: Infection with Epstein-Bar virus (EBV) is associated with an unfavourable prognosis in chronic lymphocytic leukaemia (CLL), but the underlying mechanisms remain unknown. We aimed to establish whether EBV worsens the course of CLL by up-regulating the programmed cell death 1 expression. PATIENTS AND METHODS: Using polymerase chain reaction, we measured EBV DNA in the blood of 110 newly diagnosed, treatment-naïve patients with CLL. We used flow cytometry to measure the expression of programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand (PD-L1) on CD4+, CD8+, and CD19+ cells. Additionally, PD-1 and PD-L1 serum concentrations were measured using enzyme-linked immunosorbent assays. We related the expressions of PD-1 and PD-L1 to EBV DNA load and clinical outcomes. RESULTS: Fifty-nine (54%) patients had detectable EBV DNA [EBV(+)], and these patients had more advanced disease at baseline than the rest. PD-1 and PD-L1 serum concentrations and their expressions on all cell populations were higher in EBV(+) than EBV(-) patients. EBV load correlated positively with unfavourable clinical markers of CLL and the expression of PD-1 and PD-L1 on CD4+ and CD8+ cells (rho =0.42-0.75; p<0.001). EBV(+) patients had increased risks of treatment initiation and lymphocyte doubling during a median follow-up period of 32 months (p<0.001). Among EBV(+), but not EBV(-), patients, higher expressions of PD-1 and PD-L1 on CD4+ and CD8+ cells were associated with higher risks of treatment initiation and lymphocyte doubling (p≤0.020). CONCLUSION: EBV-induced up-regulation of PD-1-PD-L1 expression is associated with worse outcomes in CLL.

Does the Epstein-Barr Virus Play a Role in the Pathogenesis of Graves' Disease?

Graves' disease (GD) it the most common chronic organ-specific thyroid disorder without a fully recognized etiology. The pathogenesis of the disease accounts for an interaction between genetic, environmental, and immunological factors. The most important environmental factors include viral and bacterial infections. The Epstein-Barr virus (EBV) is one of the most common latent human viruses. Literature has suggested its role in the development of certain allergic and autoimmune diseases. EBV also exhibits oncogenic properties. The aim of the study was to analyze and compare the presence of EBV DNA in peripheral blood mononuclear cells (PBMCs) in patients with newly recognized GD and to find a correlation between EBV infection and the clinical picture of GD. The study included 39 untreated patients with newly diagnosed GD and a control group of 20 healthy volunteers who were gender and age matched. EBV DNA was detected with reverse transcription polymerase chain reaction (RT PCR) assay. The studies showed a significantly higher incidence of EBV copies in PBMCs among GD patients compared to the control group. Whereas, no significant correlations were found between the incidence of EBV copies and the evaluated clinical parameters. Our results suggest a probable role of EBV in GD development. EBV infection does not affect the clinical picture of Graves' disease.