Project Summary/Abstract Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which autoantibodies to ubiquitous nuclear antigens cause inflammation and tissue damage in multiple organs. The treatment of SLE has improved considerably over the past 30 years, but these advances have relied on existing medications with insufficient efficacy and significant toxicities. Although several new therapeutics are now available, the new drugs are still only modestly effective. It is imperative, therefore, that advances in immunologic knowledge be applied to improve the treatment and quality of life of SLE patients by maintaining them in a remission state. Both B cell activation and myeloid cell activation can drive SLE onset and flare, leading to our focus on these two immune subsets and the period prior to flare in this proposal. Our Autoimmunity Center of Excellence proposal is centered on the hypothesis that an improved understanding of the mechanisms that regulate disease specific immune states that are perturbed during active disease or disease flare will form the basis for appropriate patient stratification and selection for clinical trials and will provide insights into new therapeutic targets. Autoantibody production is central to the pathogenesis of SLE but many questions remain about the origins of the plasma cells that produce them. It is clear that autoantibody production can precede disease onset by many years, and that flares of SLE are often associated with a new wave of plasma cell proliferation. The Principal Project (Dr. Betty Diamond) will address what B cell pathways are associated with the tolerance state during disease quiescence compared with active disease and healthy controls and whether B cell selection, activation or differentiation to plasmablasts are affected during active disease and remission. A crucial tool is a new fluorescent nuclear antigen preparation, developed by the Diamond group that can be used to identify and isolate autoreactive B cells that represent only a small fraction of the total B cell population. One B cell subset of particular interest in SLE is the non-classical ABC (age-associated B cell) subset that expands and produces autoantibodies and cytokines in response to innate stimuli and can activate T cells through antigen presenting functions. The Pilot Project (Dr. Sun Jung Kim) will address how ABCs take up and present antigen and what metabolic state is needed for their T cell activating function. This may suggest strategies to modulate their state to treat active disease or prevent flares. Activated monocytes are found in the blood of patients with SLE flares. The Collaborative Project (Dr. Anne Davidson) will study disease specific monocyte cell states by sampling blood and urine and define those cell states that are present in active disease or increase in frequency prior to disease flares. Our proposal is bolstered by close scientific interactions among the three lead investigator...