A Comparative Study of B-Cell Homeostasis and Epstein-Barr Virus Reactivation in Cidldren from areas Experiencing Divergent Plasmodium, Falciparumexposure and Endemic Burkitt's Lymphoma Patients

Abstract

Endemic Burkitt's lymphoma (BL) is a pediatric B-cell malignancy.associated with a lot of mortality. Although studies have implicated Plasmodium falciparum and Epstein Barr VIT,uS(EBV).infections iIlBL pathogenesis.their role in the pathogenesis of this disease is '.' still not well understood. In addition, there is a paucity of data on B-cell or EBV reactivation and hematological parameters in BL patients. This study was, therefore, designed to answer some of these questions. This study involved a longitudinal cohort study of infants from geographically proximate regions with divergent malaria exposure, ,that is; Chulaimbo (malaria endemic region) and Mosoriot '(sporadic malaria transmission). In addition, this study involved a case-control study involving BL patients and age and gender-matched controls. Flow cytometric analysis of B::.cellswas performed on freshly isolated peripheralbloodmoD.om.lclearcells (PBMCs), EBV viral loads were ' quantified by quantitative polymerase chain reaction assay (Q-PCR); serological analysis was carried out by Luminex and ELISA assays" while hematological indices were measured by Coulter counter. Pair-wise comparisons were done using t-tests or Manri- Whitney U test while multiple comparisons were done using repeated measures analysis ,of variance or Kruskal- Wallis tests as appropriate. The results showed significantly higher CD19+ B-cells inChulaimborelative to Mosoriot infants at 12, 18 and 24 months '"(p=0.002, p=O.05 and p~O~05, respectively). However, the frequency of IgD+CD27+ memory B-cells were significantly higher in Mosoriot, relative to Chulaimbo at 12, 18 and 24 months (p=0.0214, p=0.0024 and p=O.0071, respectively). Flow cytometric analysis of peripheral blood of BL patients and controls showed significantly higher, frequencies of B-cell receptor deficient B-cells (p=0.0038) and lower frequencies of CD19+IgD+CD27+ memory Bvcells (p<O.OOOI) in BL patients relative to controls. Luminex assay and Q-PCR results revealed significantly increased anti-Zta (p=0.0017), VCA IgG levels (p<0.0001) and plasma EBV viral load (p<O.OOOI) in BL patients , relative to the controls. Hematological analysis revealed that severe anemia and elevated plasma viral load were adverse prognostic risk factors for overall survival (Hazard Ratio [HR]; 4.01, 95% CI; 1.15-13.90,p==0.0288 and HR; 4.98, 95%Cl; 1.59-15.60,p=0.0058, respectively). Taken together, these data indicate, that early exposure to P. falciparum malaria perturb B-cells homeostasis and EBV reactivation thus predisposing children from malaria endemic regions to develop BL. Both elevated antibodies to Zta and plasma EBV viral load are relevant biomarkers for BL disease prognosis. In addition, both severe anemia and elevated EBV viral load are associated with poor outcomes in BL patients.