Attacking the source: targeting plasma cell survival in lupus
In SLE, auto-antibody titres correlate with disease severity and responsiveness to therapy. Removing pathogenic plasma cells and thus reducing auto-reactive antibodies would have clinical benefit. We therefore propose the development of a novel strategy to target plasma cell survival, potentially restricted to those secreting pathogenic antibodies. Using Lyn-deficient mice, a well-characterized model of SLE, we have discovered that Lyn is a crucial negative regulator of plasma cell survival, controlling responsiveness to key survival factors. We propose to investigate this hyper-responsiveness, identifying the signaling pathways controlled by Lyn and thus the signaling molecules that control plasma cell survival. We will use our unique ability to recover plasma cells from inflamed tissues in Lyn mice to determine if they have unique survival characteristics and pathways. We will screen kinase inhibitors on pathogenic and total plasma cells to determine their sensitivity to such inhibition. Collectively this information will allow us to isolate the components of the survival pathways, using plasma cell lines we will make. Finally, our mouse results will be verified in plasmablasts from both controls and SLE patients. Thus we will identify therapeutic targets that will kill plasma cells in SLE.