Antibody Secreting Cells (ASC), are the source of pathogenic autoantibodies in Systemic Lupus Erythematosus (SLE). Despite ample evidence documenting profound abnormalities in the generation of ASC in SLE and their correlation with active disease, little is still known regarding their diversity, mechanisms of generation and regulatory programs. Our previous studies document great phenotypic, functional, and molecular heterogeneity in human ASC and have provided original insight into the contribution of different B cell precursors to the generation of pathogenic ASC. Specifically, we described a large contribution of activated naïve B cells to pathogenic ASC in severe SLE and COVID19 infection through extra-follicular differentiation. Initial single cell (SC), studies provide an initial atlas of blood and bone marrow SLE B cell and ASC and a roadmap to decipher the pathogenic and therapeutic implications of ASC diversity in human disease. In this Project we will test the over-arching hypothesis that in order to fulfill protective functions in primary and memory responses a healthy immune system has evolved specialized differentiation pathways that determine the intensity, kinetics and longevity of diverse ASC populations. Such precise regulation is subverted in SLE owing to intrinsic programs (epigenetic) and extrinsic cues (microenvironment), determined by tissue-specific factors for local and systemic responses (nephritis and BM , respectively). A central corollary is that the different ASC populations will be differentially sensitive to therapies targeting separate B cell precursor and their ASC progeny. These postulates will be addressed in a synergistic fashion with the other PPG projects and Core B through 3 Aims: 1) Heterogeneity, origin, and fate of SLE ASC; 2) Molecular Regulation of tissue-specific and systemic pathogenic ASC in SLE; and 3) Using B cell targeting therapies to probe the origin, longevity and function of human ASC. Our studies will greatly enhance our knowledge of human ASC biology and their dysregulation in SLE. The information gained will also improve our ability to design safer and more effective therapies for SLE and multiple antibody-mediated diseases and modulatory strategies to optimize protective vaccine responses.