Since its description, the human leukocyte antigen (HLA) system has been intricately linked to transfusion. In 1952, Jean Dausset described for the first time an agglutination of white blood cells induced by the serum coming from a transfused subject. This fascinating observation led J. Dausset to understand that there are groups of white blood cells, just as there are groups of red blood cells [1]. This pioneering observation led to major scientific advances in transplantation and transfusion, as well as in anthropology, raising even philosophical questions about the uniqueness of each individual.

The alloimmune response is defined as an immune response directed against antigens from an individual of the same species. Given the wide diversity of HLA molecules, it is reasonable to expect that exposure to HLA alloantigens would often lead to the production of antibodies in the context of pregnancy, transfusion, or transplantation. However, the situation is more complex than theory postulates since pregnancy or transfusion events do not systematically lead to the production of alloantibodies 2, 3 and the specificity of antibodies depends on the clinical context (Table 1) 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Moreover, some natural anti-HLA antibodies have also been described in nonalloimmunized men, although the etiology is less well characterized 15, 16. This suggests that different factors influence the production of such alloantibodies in a patient following an immunization event. Alloimmunization against HLA-I molecules usually does not cause any symptoms. Nonetheless, it can eventually lead to major complications, such as engraftment failure or platelet transfusion refractoriness 17, 18.

Anti-HLA IgA, IgE, and IgM isotypes have been detected in patients, most of the time in concurrence with IgG 19, 20. IgG is considered as the most clinically relevant anti-HLA-I class, as it is most frequently associated with allograft rejection and resistance to platelet transfusion. IgG3 poses an increased risk of complement activation and antibody-mediated rejection compared to other IgG subclasses [21].

This highlights the medical importance of improving the detection and characterization of anti-HLA-I antibodies and of better understanding the factors that lead to their production.

In this review, we will focus on the anti-HLA immunization following transfusion. It is now well established that leukoreduction during blood product preparation was a substantial advancement to decrease immunization. Even though it drastically reduces a primary source of HLA-I and HLA-II antigens [22], alloimmunization continues to occur in the setting of a transfusion. This is a consequence of the HLA antigens expressed on the residual leukocytes (i.e. below 106 per cellular product, as stipulated by European legislation) on the platelet cell surface and on microvesicles [23].

We will compile here the knowledge of immune mechanisms associated with HLA class I immunization following platelet transfusion and identify key factors that should be considered for future management strategies to prevent such antibody production.