Pathogenesis of cell death in lupus bone marrow (BA12P.112)

Abstract

Abstract Pristane-treated mice develop lupus mediated by TLR7-driven production of IFNα (autoantibodies, nephritis) and TNFα (anemia). Anemia is IFN-independent, is caused by TNFα produced by bone marrow (BM) neutrophils, and is associated with a striking accumulation of dead BM niche cells and erythroid precursors in the BM. TNFα and dead cells also were found in BM from anemic SLE patients. The dead cells may drive TNFα/IFNα production by releasing TLR7 ligands. Fas-deficient (B6/lpr) mice were completely refractory to induction of pristane-lupus implicating cell death in its pathogenesis. Interestingly, accumulation of dead cells was abolished in BM from B6 TNFα-/- mice, suggesting that they were killed by TNFα. Signaling through both Fas and the TNF receptor I can activate caspase-3 and processing of the BCL-2 family member BID, which is involved in a mitochondrial amplification loop for Fas-mediated apoptosis. However, pristane injection in BID-/- mice induced TNFα and IFNα production as well as autoantibody production comparable to wild type B6 mice. We conclude that the requirement for Fas signaling in pristane-lupus involves the death of “Type I” cells, which undergo Fas-mediated apoptosis without a requirement for truncated BID and its crosstalk with the mitochondrial cell death pathway.