Alessandra Pernis

The long-term goals of my laboratory are to delineate the molecular pathways responsible for lymphocyte dysfunction in autoimmune diseases such as Systemic Lupus Erythematosus and Rheumatoid Arthritis (RA). Our work initially focused on IRF4, a transcription factor that it is absolutely required for the production of IL17 and IL-21, two cytokines that have been implicated in the pathogenesis of multiple autoimmune disorders including SLE and RA. IRF4 also plays a fundamental role in B cell activation and differentiation. During studies aimed at isolating proteins interacting with IRF4, we cloned a novel protein termed Def6. We have found that Def6 exerts an important immunoregulatory role in vivo as demonstrated by the finding that Def6-deficient mice can, in the presence of additional genetic manipulations, develop either lupus or RA. At a molecular level, we have found that autoimmunity in these mice is due to dysregulated IRF function and aberrant regulation of Rho GTPase-ROCK mediated pathways. Notably we have recently shown that disease in these mice is critically dependent on Age-associated B cells (ABCs) and exhibits a sex-bias enabling us to harness this model to investigate the molecular mechanisms that control the well-known sex differences that accompany the development of autoimmunity in humans.