THE ROLE OF PLASMODIUM FALCIPARUM MALARIA IN ENDEMIC BURKITT'S LYMPHOMA PATHOGENESIS.
Basu Kong, Raka-Larissa.
Endemic Burkitt's lymphoma (eBL) is the most common pediatric cancer in sub-Saharan
Africa. BL is a B cell germinal center (GC)-derived lymphoma that is characterized by a
reciprocal chromosomal translocation involving the c-myc gene and an immunoglobulin (Ig)
locus, resulting in the constitutive activation of the c-myc proto-oncogene. This
translocation occurs via the action of the ... read moreenzyme activation-induced cytidine deaminase
(AID). The etiology of eBL has been linked to Plasmodium (P.) falciparum malaria and
Epstein-Barr virus (EBV) co-infection. While there has been much progress in explaining
the mechanisms linking EBV to lymphoma development, the role of P.falciparum malaria in
the genesis of eBL is only beginning to be understood. It is known that malaria caused
by P.falciparum infections has profound effects on the B cell compartment and is
immunosuppressive, resulting in an increased viral burden of Epstein-Barr virus (EBV).
This results in higher numbers of B cells latently infected with EBV that transit the
germinal center. Recently, our laboratory demonstrated that P.falciparum is capable of
deregulating AID expression in B cells, and this at least in part is triggered by the
malarial byproduct hemozoin. Our hypothesis is that P.falciparum heightens AID activity
in the GC. This increases the risk of a c-myc translocation occurring in a GC cell
latently infected with EBV, which prevents the cell from undergoing apoptosis, and
thereby able to tolerate this translocation. This thesis examines the impact of
P.falciparum malaria on AID expression and activity in human B cell sub-populations.
Levels of AID-induced somatic mutation were compared in c-myc of ex vivo human tonsil B
cell subsets from a region of holoendemic malaria compared to control cells. No
significant parallel was found between higher AID expression and mutation frequencies in
tonsil B cell subsets from the malaria-endemic compared to non-malaria regions. In vitro
studies however yielded novel findings. P.falciparum is capable of upregulating AID
expression and class switch recombination activity in tonsil B cells, as determined by
the measurement of IgG1 switch circle transcript levels. In addition, the
P.falciparum-specific antigen, PfEMP1 was found to be required for optimal AID induction
and the data also suggest its action is via the B cell receptor (BCR). Specific B-cell
subsets were probed and the impact of P.falciparum on AID activity was found to be
specific to the GC and memory B cell compartments. Altogether, these studies shed more
light on the induction of AID by P.falciparum and its contribution to eBL pathogenesis.
This work for the first time correlates augmented AID expression induced specifically by
P.falciparum with increased enzymatic activity in the site of the eBL lesion and
therefore an increased risk for c-myc/Ig
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Genetics.
Advisor: David Thorley-Lawson.
Committee: Erik Selsing, Philip Hinds, and John Coffin.
Keywords: Genetics, and Immunology.read less
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