CD47 and the control of immune hemolysis

Oldenborg and colleagues (page 3500) provide convincing evidence for the role of CD47 in modulating immune hemolysis in NOD mice, which are naturally prone to the development of mild autoimmune hemolysis. Previously, these investigators have shown that CD47-SIRPα signaling inhibits macrophage activation and phagocytosis of opsonized red blood cells (RBCs). Interestingly, CD47^−/− NOD mice develop lethal autoimmune hemolysis, which is attributed in part to markedly increased clearance of CD47-deficient RBCs and higher levels of surface-bound RBC autoantibodies. Importantly, the NOD genetic background is a prerequisite for autoimmune hemolysis since lethal hemolysis was not observed in CD47^−/− nonautoimmune-prone mice, for example, the C57BL6 mice. Thus, CD47-mediated signaling, or the lack thereof, does not initiate but rather influences the severity and progression of autoimmune hemolysis. Which factors contribute to the severity of hemolysis in patients with autoimmune hemolytic anemia has been much debated. Many previous studies have focused on quantitative and qualitative aspects of RBC autoantibodies. For example, the IgG isotype of the RBC autoantibody correlates with macrophage clearance. But IgG RBC autoantibodies of various “pathogenic” isotypes also can be found in individuals without immune hemolysis. Similarly, the quantity or specificity of the RBC autoantibody by themselves does not predict severity and course of hemolysis in patients. More recently, IgG Fc receptors with inhibitory functions, reminiscent of the SIRPα receptor, have attracted much interest. These types of receptors likely play a significant role in controlling both the generation of RBC autoantibodies, as well as the rate of RBC clearance. Advances in the therapy of autoimmune hemolytic anemia, currently limited for the most part to corticosteroids, splenectomy, and transfusion, are needed. It will be exciting to see whether targeting the CD47/SIRPα receptor pair will prove to be a feasible approach for attenuating pathologic RBC autoimmune responses and their sequelae.