PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of variable severity and course. The disease is characterized by a tendency for flares, in which symptoms get worse, followed by periods of quiescence (also termed remission) that can last for months or even years. While drivers of disease activity have been extensively studied in SLE, regulatory pathways activated during remission remain largely unknown. In preliminary studies, we identified soluble Izumo1 as a potential candidate involved in long-term remission in SLE. Izumo1 is the ligand for the Izumo1 receptor (Izumo1R), which is one of the most prominent genes induced by FoxP3, and has been shown to be essential for the maintenance of FoxP3-expressing T regulatory (Tregs) cells. Izumo1R is also induced in chronically activated conventional CD4+ T cells, where it has been proposed to be a marker of hypo-responsiveness and anergy. Our overarching hypothesis is that soluble levels of Izumo1 increase as a compensatory mechanism to activate regulatory pathways that attenuate inflammation in SLE. In this proposal, we will study a large prospective cohort of patients with SLE to provide clinical and functional evidence to support or discard this novel hypothesis. If this proposal is successful, it may identify the first biomarker and potential therapy linked to the induction of remission in SLE.