Anti-Granulocyte Antibodies in Transfusion Medicine

Granulocyte antibodies, in contrast to antibodies recognizing red blood cells and platelets, have been widely neglected in transfusion medicine for several decades, although their clinical relevance is well-described. Autoimmune neutropenia of infancy and neonatal alloimmune neutropenia are probably the most well-known granulocyte antibody-induced disorders. The facts that antibody-induced neutropenias are rare disorders with a favorable prognosis and that sophisticated, labor-intensive in-house techniques are required for granulocyte antibody detection may both have contributed to this negligence. When transfusion-related acute lung injury (TRALI) was delineated as the leading cause of transfusion-associated mortality and, subsequently, granulocytes were identified as key players in TRALI, granulocyte antibodies received progressively higher attention. It took only a short period of time to unravel that transfusion of granulocyte antibodies can lead to activation of the transfusion recipient’s own granulocytes with subsequent breakdown of the pulmonary endothelial barrier and lung edema. Clinical and regulatory pressure has prompted the identification of new target antigens on granulocytes, the development of better diagnostic approaches for antibody identification, and drastic changes in blood component production in order to reduce the risk of TRALI. There were two major fields of controversy in this rather straight-forward process. First, there are two groups of antibodies associated with TRALI: 1) granulocyte antibodies in sensu strictu, i.e., those which recognize human neutrophil antigens (HNA); and 2) human leukocyte antigen (HLA) antibodies which can bind to granulocytes, but also to other cells. These observations led to a debate on whether granulocytes are primary target cells or, at least in some cases, “auxiliary” cells in TRALI. Evidence from animal studies supports the idea that HLA class I antibodies may bind to endothelial cells and recruit granulocytes to the vessel wall, where they get activated; and that HLA class II antibodies, since their target antigen is not expressed on quiescent granulocytes, may bind to monocytes which then activate granulocytes. Recent data on HNA antibodies which cause TRALI by direct binding to pulmonary endothelium in the absence of granulocytes have added to the complexity, as has the observation from prospective clinical trials that HLA class I antibodies are of less relevance than previously anticipated. Today, there is consensus that different antibodies can cause TRALI by different pathways which do partially overlap. Second, the presence of granulocyte antibodies in blood components as the only causative factor for TRALI appeared partially doubtful: a minority of components produced from the same donor and transfused to different recipients led to TRALI. These doubts were further substantiated by the fact that in some TRALI cases, no antibodies whatsoever could be identified. Other substances often referred to as biological response modifiers (BMR) were demonstrated causative for TRALI, but only in animals pre-exposed to priming agents. This observation was crucial in understanding that not only factors present in a blood component (antibody or BMR) need to be considered, but also factors present in the recipient; this led to the “two-hit model” or “threshold model” of TRALI. Nowadays, there is consensus that antibody-mediated TRALI and non-antibody-mediated TRALI exist, with the latter one posing new challenges for transfusion medicine. This overview will start from pre-TRALI knowledge of granulocyte antibodies, consider antibody-mediated TRALI in detail, and will finally return to non-TRALI disorders in the light of relevant new findings in the field.