In addition to red blood cells (RBCs), a recipient of an RBC transfusion is exposed to donor plasma, white blood cells, and platelets; the potential contribution of these elements to RBC alloimmunization remains unclear. formation. Triggers for alloimmunization in pregnancy are not well-understood beyond the presence of a fetal/maternal bleed. Studies using animal models of pregnancy-induced RBC alloimmunization may provide insight in this regard. A better understanding of alloimmunization triggers and signatures of responders and nonresponders is needed for prevention strategies to be optimized. A common goal of such strategies is usually increased transfusion security and improved pregnancy outcomes. Learning Objectives To consider the role of RBC antigen characteristics and blood processing in RBC alloimmunization To understand the role of recipient genetics and environmental influences in RBC alloimmunization Tnfrsf1b Introduction Red blood cell (RBC) alloimmunization, or the formation of antibodies against nonCself-antigens on RBCs, may occur after exposure through transfusion or pregnancy. These antibodies may be clinically significant in both settings, leading to delayed hemolytic or serologic transfusion reactions or hemolytic disease of the fetus and newborn (HDFN). As shown in Table 1, the number of alloimmunized transfused patients1 is likely higher than CHMFL-ABL-121 the 1% to 3% generally quoted, taking into consideration the frequent occurrence CHMFL-ABL-121 of RBC antibody evanescence. Complications from RBC alloantibodies are a leading cause of transfusion-associated death,2 although the true morbidity/mortality burden from RBC alloimmunization is likely higher than that appreciated from the Food and Drug AdministrationCreported statistics alone.3,4 Table 1. Alloimmunization rates reported in various patient populations and disease says* shares CHMFL-ABL-121 orthology with KEL and shares orthology with Fy. This is not just a theoretical concern; it has been exhibited that peripheral blood mononuclear cells from humans never before exposed to RBCs have evidence of T-cell reactivity upon activation with overlapping KEL peptides.25 Similarly, animal studies using a model antigen have shown that exposure to sequences contained in a virus are able to prime a recipient to robustly respond to a transfusion of RBCs containing the shared epitope.40 Of note, an RBC antibody screen completed in a clinical blood bank after computer virus exposure but before RBC exposure would never detect this prior T-cell priming. Exposure to RBC antigens during pregnancy or delivery Although this manuscript is usually primarily focused on potential triggers of RBC alloimmunization during transfusion, a brief conversation of triggers during pregnancy and delivery is usually warranted. All pregnant women are exposed to fetal RBCs during pregnancy and around the time of delivery. The vast majority of women do not become alloimmunized after this exposure, although a subset do. The immunogenicity of the RBC antigen appears to be one crucial factor in whether a woman will become alloimmunized, with the majority of clinically significant HDFN cases being due to antibodies against antigens in the Rh, K, Fy, Jk, and MNS families. ABO incompatibility between mother and fetus plays a protective role against RBC alloimmunization, presumably because of maternal isohemagglutinins rapidly clearing fetal RBCs from your maternal blood circulation. In addition to fetal/maternal bleeds, 1 other trigger of RBC alloimmunization in pregnancy is usually intrauterine transfusion.41 These transfusions are typically given to women in the late second or third trimesters of pregnancy if their fetus shows indicators of anemia or hydrops. Given that HDFN is usually most often secondary to maternal alloimmunization, the pregnant women being transfused have already confirmed themselves to be responders to RBC antigens. Thus, that at least 25% of these women form additional RBC antibodies in response to intrauterine transfusions is not entirely amazing. These women are not only at risk of forming additional RBC alloantibodies, but also of forming HLA alloantibodies. Reviewed in a past issue of the ASH Education Book,42 a better understanding of the mechanism of action of RhIg may facilitate an understanding of the way in which fetal RBCs expressing the RhD antigen stimulate anti-RhD formation in women. Further, a better understanding of the mechanism of action of RhIg may facilitate the production of a standardized RhIg-like product that is not dependent on immunizing RhD-negative male volunteers with RhD-positive RBCs. In-depth mechanistic studies are logistically hard to total in humans; an RhD transgenic mouse has recently been generated and may provide the answers to some of these questions. Studies of strategies to prevent alloantibody formation through pregnancy in other animal models may provide additional insight. Conclusions There are numerous potential triggers of RBC alloimmunization in.