Antibody secreting cells (ASC) are responsible for both protective and pathogenic responses through the function of populations endowed with different function and longevity. Hence, major unmet need in human health and disease is a deep understanding of the processes that underlie ASC generation from different B cell precursors through separate differentiation pathways; the metabolic, transcriptional and epigenetic programs that underpin these processes, thereby promoting the generation of diverse ASC populations of different longevity and function; and how these processes may be subverted in SLE leading to expansion of pathogenic autoreactive plasma cells. Proper ASC function and dysregulation respectively provide protection in vaccination and infection and mediate multiple diseases including SLE and other autoimmune conditions, allergic reactions and transplant rejection. Thus, understanding the processes that regulate differentiation and survival of protective ASC while avoiding the accumulation of pathogenic ones is essential for our ability to improve vaccination and treat multiple antibody- mediated diseases. Over the previous cycle, despite the severe disruption caused by the COVID-19 pandemic for over a year, our work has contributed major progress in these areas that provides the foundation for this renewal application. Combined, our work will address the following concepts: Theme 1 - ASC heterogeneity in human healthy and autoimmune responses; Theme 2 - Molecular and epigenetic regulation of PC development and survival; Theme 3 - Metabolic regulation of ASC differentiation, function and survival; Theme 4: Microenvironment regulation of ASC formation, survival and function. These goals will be accomplished by highly interactive investigators through the following Projects and cores: Project 1. Epigenetic and metabolic mechanisms governing commitment to the long-lived plasma cell pool (Lund, PI). Project 2. Epigenetic programming of plasma cell heterogeneity and metabolism. (Boss, PI) Project 3. Role of Cellular Senescence in long-lived plasma cell generation. (Lee, PI) Project 4. Heterogeneity. Regulation and Function of Antibody-Secreting Cells in SLE (Sanz, PI) Core A. Administrative Core (Sanz, PI) Core B. Epigenomics, Bioinformatics, and Genome Engineering (Scharer, PI)