Abstract
Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) provides developmental and survival signals that mimic those of a B-cell receptor (BCR). Expression of LMP2A during B-cell development results in the ability of B cells to exit the bone marrow in the absence of a BCR and persist in the periphery, where they would normally undergo apoptosis. This study extends the current knowledge of LMP2A function by examining the growth properties of bone marrow B cells from TgE LMP2A mice. Despite the lack of pre-BCR expression, bone marrow B cells from TgE LMP2A mice proliferate and survive in low concentrations of interleukin 7, similar to wild-type cells. Constitutive phosphorylation of ERK/MAPK and PI3K/Akt in TgE LMP2A bone marrow B cells is also reminiscent of signalling through the pre-BCR, altogether demonstrating that LMP2A provides a pre-BCR-like signal to developing B cells.
Highlights
While Epstein Barr virus (EBV) infections are typically asymptomatic, disease in adolescents presents as infectious mononucleosis and immunocompromised patients are susceptible to lymphoproliferative disorders (Rickinson & Kieff, 2007, Thorley-Lawson, 2005, Thorley-Lawson & Gross, 2004)
EBV is associated with malignancies of lymphoid and epithelial origin, including Hodgkin’s Lymphoma, Burkitt’s Lymphoma and Nasopharyngeal Carcinoma (Rickinson & Kieff, 2007)
Rag2−/− cells proliferate in response to high concentrations of IL-7 (0.1 and 0.05 dilutions), whereas the cells are unable to proliferate in low concentrations of IL-7 (0.01–0.001 dilutions). Both TgE Latent membrane protein 2A (LMP2A) and wild type (WT) bone marrow B-cells proliferate in low concentrations of IL-7 at similar levels and have increased proliferation at all IL-7 concentrations compared with Rag2−/− cells
Summary
TgE LMP2A mice are unable to rearrange the heavy-chain genes necessary for expression of a pre-BCR or a BCR, they are able to transition to a CD43− stage, albeit less efficiently than a wild type B-cell (Caldwell et al, 2000, Caldwell et al, 1998). Forty percent of the bone marrow cells from wild type mice express a pre-BCR, in contrast to barely detectable levels in TgE LMP2A and Rag2−/− cells. B-cells from the bone marrow of Rag deficient mice are unable to rearrange their immunoglobulin genes, and do not express a pre-BCR on the cell surface and require high concentrations of IL-7 to survive and proliferate (Fleming & Paige, 2001, Fleming & Paige, 2002, Marshall et al, 1998).
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