ROLE OF CYTOSOLIC DNA SENSING PATHWAYS IN LUPUS AND REGULATION OF IMMUNE TOLERANCE

Abstract

Systemic Lupus Erythematoses (SLE) is characterized by the loss of tolerance to nuclear self-antigens leading to the production of anti-nuclear ANAs and chronic inflammation. The underlying causes for loss of tolerance and the chronic production of pro-inflammatory cytokines including type I IFNs remain unclear. We have previously demonstrated that sensing of cytosolic DNA produced as a result of DNA damage in tumor cells contributes to the break of tolerance and type I IFN production. In silico analysis of a murine SLE susceptibility locus implicated in the break of tolerance indicates the presence of unusually long DNA sequences that have been implicated in replication-associated damage. We hypothesized that the presence of such sequences may lead to the accumulation of cytosolic DNA and the activation of DNA sensing pathways. I found that cytosolic DNA accumulates in immune cells of Sle1 mice before the onset of the disease and is sensed by cytosolic nucleic acid sensors with the activation of downstream pathways.