Rare B cells co-expressing two different antibodies (i.e., dual-reactive B cells) exist in mice and are present in humans. Our goal is to understand whether dual-reactive B cells represent a relevant B cell subset in SLE and can be distinguished from single-reactive B cells. Preliminary data demonstrate that lupus-prone mice generate dual-reactive immature and mature B cells more frequently than nonautoimmune mice. Moreover, dual-reactive B cells generate autoantibodies more frequently than single-reactive B cells and are highly enriched in the antigen-activated B cell subsets of autoimmune mice. The goals of this proposal are to better understand the nature and role of dual-reactive B cells in lupus. We propose to compare the gene expression profile of single and dual-reactive B cells in mice to find unique characteristics of dual-reactive B cells that might allow their detection and targeting. Moreover, we propose to determine whether the presence of dual-reactive B cells affects the development of murine lupus or whether these cells simply correlate with disease progression. Finally, we aim to measure the prevalence of dual-reactive B ceils in humans affected by SLE to determine whether the frequency of these cells correlate with human.