Antibodies, which are produced following infection and vaccination, promote rapid pathogen clearance and, if made for extended periods of time, can provide protection following re-exposure to the same or related pathogens. However, antibodies can also be detrimental and, if directed against the wrong antigen or epitopes, can cause, rather than prevent, disease. Pathologic antibodies are most often observed in the setting of chronic inflammatory diseases such as autoimmunity, allergy and organ transplantation. Given the importance of antibodies in promoting both health and disease there is a need to better understand the development and maintenance of the antibody secreting cells (ASCs). ASCs are the terminally differentiated effector progeny of the mature naïve and memory B cell pools. While we have made great gains in our understanding of the signals and transcription factors that control ASC development from the parent naïve and memory B cells, we know remarkably little about the factors, both intrinsic and extrinsic, that control the lifespan of ASCs. In our preliminary studies we show that the capacity of particular B cell subsets to differentiate into ASCs with a long survival potential appeared to be hardwired and limited to the memory B cell compartment rather than the naïve B cell pool. We identified several discrete subsets of memory B cells and showed that these memory B cells differed in their transcriptional, epigenetic and metabolic programs and exhibited distinct functional capabilities. We identified a subset of memory B cells (referred to as effector memory B cells), that were more similar to ASCs in their metabolic potential and expression of epigenetic modifiers like the methylase EZH2 and NAD-dependent deacetylase SIRT1. We showed that effector memory B cells differentiated into ASCs more rapidly than other memory subsets. Moreover, the ASCs derived from the effector memory B cells were uniquely capable of surviving for weeks when cultured in a supportive microenvironment. Finally, we showed that ASC survival is highly dependent on new NAD metabolism and that drugs which block vitamin B3-directed NAD biosynthesis will ablate ASCs in autoimmune and chronically infected animals. The central hypothesis tested in the Specific Aims is that the effector memory B cells, which have undergone specific epigenetic and metabolic programming steps, are licensed to give rise to ASCs with superior survival potential. The immediate objectives of this proposal are to: (i) identify the transcriptional and epigenetic changes controlling Bmem differentiation into long-lived ASCs; (ii) determine the role for EZH2 and SIRT1 in ASC survival; and (iii) assess the role of NAD metabolism in the survival of long-lived ASCs. We believe that these studies are important as they will advance our fundamental knowledge of the factors that control ASC lifespan and may in the future lead to new therapeutic approaches to dampen ASC responses to control antibody m...