SLE is the prototypical systemic autoimmune disease with high production of autoantibodies and dramatic abnormalities in B cell homeostasis including enhanced activation and increased numbers of Antibody Secreting Plasmablasts (PB). However, the molecular regulome of abnormal SLE B cell activation and differentiation into effector cells and the nature of the autoantigens that trigger these processes are not understood. The central goal of the Emory Autoimmunity Center of Excellence is to understand the interplay between these determinants of pathogenic B cell behavior in SLE (Principal Project) and other autoimmune diseases (Collaborative Project). During the current funding cycle, the Emory ACE U19 has delineated the cellular complexity of the human B cell compartment and defined novel singular populations of activated naïve cells and effector B cells. We have demonstrated the contribution of this effector pathway to active disease and gained insight into the extrinsic factors and internal molecular programs underlying its dysregulation in SLE. Importantly, we have found that even the resting naïve cells at the apex of this pathogenic cascade are epigenetically poised for activation and ASC differentiation. In all, the combined evidence suggests that SLE B cells undergo stimulation at early, pre-naïve developmental stages and remain epigenetically imprinted for activation after returning to a resting state. This Principal Project will test this model through a comprehensive investigation of the molecular programs and antigenic reactivity of the aforementioned B cell subsets and PB. Our goals will be accomplished through the following aims: Aim 1. Molecular programming of B cell development in SLE; Aim 2. Molecular programs and antigenic triggers of B cell tolerance breakdown in SLE; Aim 3. Epigenetic regulation of newly generated effector B cells during acute lupus flares. In addition to providing new fundamental insights into the pathogenesis of SLE, we expect to identify new therapeutic targets and a theoretical framework for the rational application of new therapies to individual patients and specific phases of the disease. Moreover, we will generate powerful candidate biomarkers with the potential to predict disease activity and outcome; determine reversal of disease programs post-B cell depletion; predict disease development in high-risk subjects; and segment different types of disease including B cell-independent SLE.