Effects of genetic, epigenetic, and environmental factors on alloimmunization to transfused antigens: Current paradigms and future considerations

Transfused red blood cells, platelets, or coagulation factors have the capacity to induce alloantibodies, which once formed, can be a clinical barrier to future transfusion therapy and/or transplantation. Large observational studies over the last 50 years have characterized some of the general properties of transfusion induced alloimmunization, which appear to vary to a considerable extent from what is generally observed for human responses to other immunogens, such as microbial pathogens and vaccines. Transfused cells and factor only induce immune responses in the minority of recipients. There are data to suggest that differences in the unit may play a role. However, there are clearly differences in recipient biology, as once a recipient makes one antibody they are much more likely to make additional antibodies; indeed, recipients have been categorized as "responder" and "non-responder" by the field. Recent mechanistic studies have begun to define potential causes for such differences in alloimmunization from patient to patient, but much progress needs to be made to understand how, why, and in whom alloimmunization occurs. This review gives a general background on immunology in the context of transfusion, summarizes recent progress in the field, and discusses future directions for exploration. Particular attention is paid to the general concept that the human immune system is melded by the wide range of antigens encountered in our environment, and that the effects of such on the immune system may have a profound effect upon response to transfused cells.