Inhibition of Germinal Centre Apoptotic Programmes by Epstein-Barr Virus
Figure 2
EBV infection impacts on cell death and survival pathways in GC B cells. Interconnected signalling pathways regulate the apoptosis of GC B cells. Proapoptotic signals via B cell receptors and the canonical Smad pathway activated by the TGF-β receptor control the elimination of unwanted B cells by inducing intrinsic apoptosis. Intrinsic apoptosis is dependent on the activation of the proapoptotic BCL-2 family members BAX and BAK, permeabilisation of the mitochondrial membrane (ΔΨm) and release of proapoptotic factors resulting in the activation of the initiator caspase, caspase 9. An extrinsic apoptotic pathway occurs via the death receptor FAS. FAS stimulation results in the formation of the death-inducing signalling complex (DISC) comprised of FAS, the Fas-associated death domain (FADD), and pro-caspase 8. GC B cells, however, have a preformed DISC whose activation is inhibited by binding of the protein cFLIP. The cells are, therefore, dependent on continuous survival signals via CD40 for maintenance of cFLIP levels. CD40 signalling (along with other signals through BLyS (BAFF) and the BCR not shown on this diagram) also induces BCL-2 family members such as BFL-1 and BCL-XL which promote cell survival by inhibiting the intrinsic apoptosis pathway. EBV gene products target multiple points in the apoptosis pathways (shown in red). *In vitro studies of cell lines report the LMP-1-dependent upregulation of BCL-2, however, LMP-1 and BCL-2 expression levels do not correlate in primary tissue.
