Systemic lupus erythematosus (SLE) is a devastating systemic autoimmune disease marked by the production of antinuclear autoantibodies whose etiology has both genetic and environmental components. We and others have shown that CD19, a positive regulator of B cell receptor (BCR) signaling, is ~20% decreased on peripheral blood (PB) naïve B cells in >95% of SLE patients (Pts). We have also identified an expanded subpopulation of IgG+ memory B cells in 25-35% of SLE Pts that display a 2-4 fold increase in CD19 expression (CD19hi). SLE Pts with an expanded CD19hi population (CD19hi Pts) have a unique pattern of autoantibody production and increased adverse clinical outcomes, particularly end stage renal disease and neurological complications. CD19hi B cells have an activated phenotype, and sequencing analysis shows they are somatically hypermutated and antigen selected. Our data indicate they are most likely in G1 phase of the cell cycle and are in the early stages of differentiation to plasma cells. CD19hi cells also have a ~3 fold increase in basal levels of phosphorylated Syk (pSyk) and ERK1/2 (pERK1/2), suggesting that they have been recently activated. Although CD19hi cells are refractory to further increases in pSyk or pERK1/2, they phosphorylate other intermediates similarly to healthy control B cells in response to BCR stimulation. CXCR3 expression is >14-fold elevated in CD19hi cells, and they chemotax effectively towards a CXCR3 ligand, suggesting they are homing to sites of inflammation. Importantly, CD19hi B cells are enriched for autoreactivity compared to CD19lo B cells from the same patient, and a 2-fold increase in this enrichment is associated with a 100-fold increase in the serum autoantibody titer, suggesting these cells are precursors to autoantibody producing plasma cells. Finally, CD19hi Pts are short-term or non-responders to rituximab treatment, indicating a need for a new therapy modality for these Pts. Taken together, these results suggest that dysregulation of CD19 on B cells plays a role in the etiology and pathogenesis of SLE, and that CD19hi cells represent an autoreactive memory B cell subset that plays an important role in the pathology of this disease.