Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease generated by abnormal B cell function that induces pathogenic autoantibodies. Our lab has previously defined multiple B cell abnormalities in SLE including the recent definition of an extrafollicular (EF) pathway responsible for the generation of pathogenic DN2 effector B cells and the characterization of their epigenetic programs. During the initial 4 years of this ACE cycle, we demonstrated that EF reactions are enhanced in severe black SLE patients by hyper-responsiveness to TLR7 stimulation. Notably, we also showed that naïve-derived EF pathogenic autoimmune responses are also strongly induced in patients with severe COVID-19 infections. Other studies from our ACE center have identified additional complexity in the diversity of human effector and memory B cells and their contribution to different immune responses and SLE pathogenesis and suggested the contributions of B cell endotypes to distinct autoreactive and protective B cell responses in SLE. However, the diversity of effector and memory B cell populations; their segregation into disease endotypes; their molecular regulation; and their contributions to disease pathogenesis remain to be understood. In this Principal Project, we will address these knowledge gaps through two specific Aims. In Aim 1, we will characterize the diversity and molecular regulatory programs of effector B cells in SLE using multi-spectral flow cytometry (MSFCM) and single cell multi-omics (SCMO). Studies will be performed with total B cells as well as antigen- specific B cells in blood, lymph nodes and Lupus kidneys. In Aim 2, we will study the diversity of memory B cells in SLE and their derivation through germinal center dependent and independent pathways and their regulatory programs using blood and lymph nodes. Combined with the Collaborative and Pilot Project, our studies will contribute original insight into the diversity and regulation of B cells in SLE, shed light into critical pathogenic processes, and identify cellular and molecular diagnostic candidates and new targets for precision therapies. In sum, this Project will enhance our ability to recognize SLE clusters with separate pathogenic mechanisms and responses to therapy in SLE in general, and more particularly in the underserved Black SLE population. .