Abstract
IntroductionEndemic Burkitt's lymphoma (eBL) is associated with Epstein–Barr virus and repeated malaria infections. A defining feature of eBL is the translocation of the c‐myc oncogene to the control of the immunoglobulin promoter. Activation‐induced cytidine deaminase (AID) has been shown to be critical for this translocation. Malaria infection induces AID in germinal center B cells, but whether malaria infection more broadly affects AID activation in extrafollicular B cells is unknown.MethodsWe either stimulated purified B cells from AID‐green fluorescence protein (GFP) reporter mice or infected AID‐GFP mice with Plasmodium chabaudi, AID fluorescence was monitored in B cell subsets by flow cytometry.ResultsIn vitro analysis of B cells from these mice revealed that CpG (a Toll‐like receptor 9 ligand) was a potent inducer of AID in both mature and immature B cell subsets. Infection of AID‐GFP mice with Plasmodium chabaudi demonstrated that AID expression occurs in transitional and marginal zone B cells during acute malaria infection. Transitional B cells were also capable of differentiating into antibody secreting cells when stimulated in vitro with CpG when isolated from a P. chabaudi‐infected mouse.ConclusionsThese data suggest that P. chabaudi is capable of inducing AID expression in B cell subsets that do not participate in the germinal center reaction, suggesting an alternative role for malaria in the etiology of eBL.
Highlights
Endemic Burkitt’s lymphoma is associated with Epstein–Barr virus and repeated malaria infections
In vitro studies of human immature B cells have shown that CpG stimulation through TLR9 signaling is capable of inducing Activation-induced cytidine deaminase (AID) activity [10]
The phenotype of the immature B cells following treatment with both anti-IgM and CpG included both type 1 (T1) and IgMþ CD23þ transitional type 2 (T2) B cells (Fig. 1). These data demonstrate that CpG has the ability to induce AID expression in vitro in both mature and T1 B cells, and that anti-IgM treatment in conjunction with CpG is capable of leading to persistence of AID expressing T2 B cells
Summary
Endemic Burkitt’s lymphoma (eBL) is associated with Epstein–Barr virus and repeated malaria infections. Activation-induced cytidine deaminase (AID) has been shown to be critical for this translocation. Malaria infection induces AID in germinal center B cells, but whether malaria infection more broadly affects AID activation in extrafollicular B cells is unknown. Antigen receptor editing and isotype switching are found uniquely in B cells and require the activity of activationinduced cytidine deaminase (AID). The activity of AID has been implicated in several B cell lymphomas including endemic Burkitt’s lymphoma (eBL). The activity of AID is necessary to induce c-myc translocations commonly seen in certain B cell lymphomas and the over-activity of AID is sufficient to lead to malignancy in mice [2, 3]. The role of Plasmodium as a broadly acting B cell stimulator on immature B cell populations has not been studied in depth and may represent an additional pathway to lymphomagenesis
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