Epstein-Barr virus persistence: implications for the pathogenesis of endemic Burkitt's and immunosuppression-related B-cell lymphoma
germinal center model (GCM) of Epstein-Barr virus (EBV) persistence proposes that EBV
infects and drives naïve B cells through the GC to become resting memory B cells
where the virus persists quiescently in a non-pathogenic state for the lifetime of the
host. Yet, EBV causes several cancers. First, we asked how simultaneous infection with
Plasmodium falciparum malaria and EBV ... read morecauses the GC B cell-derived endemic Burkitt's
lymphoma (eBL), which is the most common childhood cancer in malaria-endemic areas of
Africa. eBL is associated with EBV and malaria infections, and accumulated evidence
indicates that eBL arises when deregulated expression of activation-induced cytidine
deaminase (AID) causes a c-Myc/Ig translocation that in turn activates the c-Myc
oncogene in an EBV-infected GC B cell. Previously, we showed that in humans, Plasmodium
falciparum malaria causes deregulated expression of AID mRNA in GC B cells, increases
the level of GC B cells and dramatically increases the frequency of EBV-infected GC B
cells. Here, with the aid of ex vivo tonsillar B cell stimulation assays, we demonstrate
that Plasmodium falciparum strongly stimulates AID mRNA and protein, due in part to
hemozoin, the metabolic by-product of hemoglobin digestion by the parasite. We conclude
that Plasmodium falciparum causes deregulated expression/activity of AID in GC B cells
concomitant with an increase in the level of EBV-infected GC B cells. This increases:
the risk of the c-Myc/Ig translocation in EBV-infected GC B cells that can tolerate the
translocation, and the incidence of eBL. In a second study, we searched for the in vivo
precursors of immunosuppression-related/immunoblastic B-cell lymphoma (IL) which occurs
in immunosuppressed transplant and HIV patients. IL resembles in vitro EBV- infected B
cells driven by EBV to become indefinitely proliferating lymphoblastoid cell lines
(LCLs). Using comparative human tonsillar B cell analysis, we demonstrate that
EBV-infected marginal zone (MZ) B cells which are GC-independent, are the closest in
vivo correlates of LCLs/ILs and hence the plausible in vivo precursors of IL in humans.
Taken together, these studies show that there are two pathways of EBV persistence in
humans: 1. the GCM and 2. the GC-independent MZ model, and these result in two types of
lymphoma: eBL and IL, respectively. EBV-associated malignancies are the consequence of
immune-dysregulation that allows EBV-infected cells at specific stages of B cell
differentiation to escape immune-surveillance, survive and engender
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Immunology.
Advisor: David Thorley-Lawson.
Committee: Joan Mecsas, Honorine Ward, and Thereza Imanishi-Kari.
Keyword: Immunology.read less