David M. Rothstein, MD

The Rothstein lab is focused on immunoregulation mediated by the balance between regulatory (Bregs) and inflammatory/effector (Beff) B cells.  We identified TIM-1, a molecule key to Breg development and expression of a variety of anti-inflammatory and coinhibitory molecules utilized by Bregs to suppress immune responses.  Specific deletion of TIM-1 expression on B cells results in spontaneous autoimmunity.  We are now re-examining the role of plasma cells as regulatory B cells; identifying factors that control Breg expansion, examining localization of Breg function, and trying to determine whether Bregs arise stochastically or as a lineage.  In contrast, we have identified TIM-4 as a marker for iBeffs that strongly promote inflammation through expression of a host of inflammatory cytokines.  We are currently comparing the gene expression profiles and examining the epigenetic regulation of TIM-1 versus TIM-4+ B cells.  Thus, we are engaged in novel studies to expand our understanding of the biology of these potent immune regulators in murine autoimmune and allograft models.  We also perform translational studies examining the ratio of Bregs/Beff cells (through their relative expression of IL-10 vs. TNFalpha) in the peripheral blood of transplant patients. This ratio serves as an indicator of immunological reactivity and serves as an accurate early prognostic marker for renal allograft outcomes.  Ultimately, this biomarker may allow us to individualize immuosuppressive therapy in transplant patients.