Immunoregulatory networks in sickle cell alloimmunization

Red blood cell (RBC) transfusions are critical for treatment and prevention of complications of sickle cell disease (SCD), and most SCD patients will receive 1 or more transfusions by age 20. However, SCD alloimmunization remains a serious complication of transfusions that can lead to life-threatening acute and delayed transfusion reactions. Alloimmunization rates are higher in SCD patients most likely due to RBC antigenic differences between largely white donors vs mainly African-American recipients and frequency of transfusions. However, it remains unclear why some but not all SCD patients develop alloantibodies. Cellular immune responses that differ between alloimmunized and nonalloimmunized SCD patients are beginning to be characterized. Altered CD4⁺ T helper cell responses, known to control immunoglobulin G production, have been identified in alloimmunized SCD patients, including abnormalities in regulatory T cells, as well as helper type 1 (T_H1), T_H17, and follicular helper T cells. Furthermore, heightened innate immune cell responses to cell free heme with cell polarization toward proinflammatory T cell profiles were recently reported in SCD antibody responders, suggesting that the ongoing hemolytic state in SCD may impair the ability of innate immune cells in these already alloimmunized patients to counter alloimmunization. Identification of molecular pathways in key cellular components that differ between alloimmunized and nonalloimmunized SCD patients is likely to lead to identification of biomarkers of alloimmunization and future design of targeted therapies to prevent or even dampen alloantibody responses in these highly susceptible patients.