The overarching objective of the Emory Autoimmunity Center of Excellence (ACE) U19 is to decipher the molecular programs responsible for the aberrant B cell responses underpinning autoimmune diseases. A central tenet of the Emory ACE is that unraveling the heterogeneity of human autoimmune diseases and translating that knowledge into mechanistically based treatments requires an integrated collaboration between physician-scientists, basic scientists, and expert clinicians with access to large populations of well-characterized autoimmune patients. Our fundamental goals are: (1) to understand B cell dysregulation in SLE using single cell interrogation of their molecular roadmaps, and (2) to assemble a scientific and technological platform that engages other ACE U19 and UM1 Centers through the Collaborative Project to perform similar studies in other immune cells and autoimmune disorders. These goals will be realized through a highly integrated collaboration between the three components of the Scientific Program supported by an Administrative Core. In the Principal Project, Dr. Sanz will ascertain the heterogeneity of effector B cells, their regulatory programs, and their differential utilization according to disease endotypes, and investigate the diversity and regulation of SLE memory cells. Specifically, his group will analyze germinal center dependent and independent memory and the role of antigenic persistence in the regulation of autoimmune and protective memory. In the Collaborative Project, Dr. Boss will investigate the epigenetic regulation of B cells and other immune cells in SLE and other human autoimmune diseases as part of the Collaborative Agenda that will be developed within the new ACE centers. Finally, in the Pilot Project, Dr. Scharer will pursue the functional characterization of SLE B cell differentiation using high-throughput loss-of-function and gain-of- function CRISPR screens. The Emory ACE also proposes to continue to manage the ACE Funds Management Core and to establish a centralized ACE Biorepository Core to coordinate the collection, storage, and management of samples from the Emory ACE and ACE Clinical Projects and their allocation for use in mechanistic studies. Collectively, the work proposed should contribute greatly to the charter mission and goals of the Autoimmunity Centers of Excellence Network.