The interferon regulatory factor 5 (IRF5) systemic lupus erythematosus (SLE) risk loci is considered one of the most strongly and consistently associated SLE loci identified. It has been detected using both candidate gene and genome-wide association studies. Haplotypes are associated with increased, decreased, or neutral levels of risk for SLE and have been shown to associate with functional changes in IRF5-mediated signaling, including increased expression and elevated IFNα activity. The majority of studies, however, were performed in peripheral blood mononuclear cells and thus little is known of the function of IRF5 in specific human immune cell populations. We are interested in understanding the role of IRF5 in human B cells since previous studies in mice implicated a role for IRF5 in effector B-cell development and function and murine models of lupus lacking the Irf5 gene showed reduced ANA, glomerulonephritis and pathogenic autoantibody production. Unfortunately, many of these studies were complicated by the finding of a secondary mutation in the Dock2 gene amongst Irf5-/- mice. Recent findings from our laboratory indicate that IRF5 is constitutively localized to the nucleus of human SLE memory B cells and that activation of healthy donor B cells results in IRF5 nuclear localization, suggesting a functional role for IRF5 in human B cells.