Abstract
BackgroundEpstein-Barr virus (EBV)-related malignancies harbour distinct serological responses to EBV antigens. We hypothesized that EBV serological patterns can be useful to identify different stages of chronic lymphocytic leukemia.MethodsInformation on 150 cases with chronic lymphocytic leukemia and 157 frequency-matched (by age, sex and region) population-based controls from a Spanish multicentre case-control study was obtained. EBV immunoglobulin G serostatus was evaluated through a peptide-based ELISA and further by immunoblot analysis to EBV early antigens (EA), nuclear antigen (EBNA1), VCA-p18, VCA-p40 and Zebra. Two independent individuals categorized the serological patterns of the western blot analysis. Patients with very high response and diversity in EBV-specific polypeptides, in particular with clear responses to EA-associated proteins, were categorized as having an abnormal reactive pattern (ab_EBV). Adjusted odds ratios (OR) and 95% confidence interval (CI) were estimated using logistic regression models.ResultsAlmost all subjects were EBV-IgG positive (>95% of cases and controls) whereas ab_EBV patterns were detected in 23% of cases (N = 34) and 11% of controls (N = 17; OR: 2.44, 95% CI, 1.29 to 4.62; P = 0.006), particularly in intermediate/high risk patients. Although based on small numbers, the association was modified by smoking with a gradual reduction of ab_EBV-related OR for all Rai stages from never smokers to current smokers.ConclusionsHighly distinct EBV antibody diversity patterns revealed by immunoblot analysis were detected in cases compared to controls, detectable at very early stages of the disease and particularly among non smokers. This study provides further evidence of an abnormal immunological response against EBV in patients with chronic lymphocytic leukemia.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-9378-10-5) contains supplementary material, which is available to authorized users.
Highlights
The gamma-herpes Epstein-Barr virus (EBV) infects and persists in human B-cells by exploiting the B-cells environment to maintain its life cycle and by avoiding the host’s immune surveillance with limited expression of viral proteins [1]
Healthy EBV carriers display anti-EBV antibodies to only a limited number of EBV proteins, including Esptein-Barr nuclear antigen 1 (EBNA1), viral capsid antigen (VCA)-p18, VCA-p40 (BdRF1) and Zebra (BZLF1) whereas a small proportion of healthy carriers with subclinical virus reactivation produces antibodies to early antigen (EA) [1]
High anti-VCA and anti-early antigen-diffuse (EAd) titers have been observed in EBV related malignancies such as Hodgkin lymphoma and nasopharyngeal carcinoma [2] but the role of EBV in chronic lymphocytic leukemia (CLL) remains unclear [3,4,5,6]
Summary
The gamma-herpes Epstein-Barr virus (EBV) infects and persists in human B-cells by exploiting the B-cells environment to maintain its life cycle and by avoiding the host’s immune surveillance with limited expression of viral proteins [1]. High anti-VCA and anti-early antigen-diffuse (EAd) titers have been observed in EBV related malignancies such as Hodgkin lymphoma and nasopharyngeal carcinoma [2] but the role of EBV in chronic lymphocytic leukemia (CLL) remains unclear [3,4,5,6]. Using data from the European case-control study EpiLymph, de Sanjose et al found that CLL patients were 3 times more likely to have an aberrant EBV antibody pattern (ab_EBV), mainly reflected by excessively high EA response, than controls, while no association with other lymphoma subtypes was observed [5]. De Roos et al examined the prospective antibody response to anti-VCA, EBNA1, EAd using multiplex technology and EBV DNA load samples collected before diagnosis in 142 CLL/ prolymphocytic leukemia patients and their matched controls [4]. We hypothesized that EBV serological patterns can be useful to identify different stages of chronic lymphocytic leukemia
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