Proposed model of heme pathways in SCD B cells and response to allogeneic transfusion. Upon engagement with RBC alloantigens, activated naïve B cells from nonresponder SCD patients do not differentiate into plasma cells because of heme-mediated downregulation of DOCK8 and HO-1–mediated signaling. In responder SCD patients, these heme pathways are impaired, enabling plasma cell differentiation to proceed. The combination of heme and the heme-binding molecule quinine causes induction of very high levels of HO-1 and suppression of plasma cell differentiation in both responder and nonresponder SCD patients. Ag, antigen.