The role of linked recognition and B cell precursor frequency in alloimmunization to transfused RBCs

Despite multiple alloantigenic differences in every allotransfusion, only 3-6% of transfusion recipients develop a detectable alloantibody even with multiple transfusions. Moreover, patients typically become alloimmunized only to some of the alloantigens to which they are exposed. In recent decades, precursor frequency of antigen-specific T and B cells has been demonstrated to be a key determinant of adaptive immunity. Given the small differences between donor and recipient alloantigens (typically a single amino acid), precursor frequencies for T and B cells are predicted to be extremely low for a given alloantigen. In this review, it is argued based upon existing evidence in the literature and new data presented herein that linked recognition occurs with red blood cell (RBC) alloantigens resulting in a dramatically increased precursor frequency for CD4⁺ T cell help with no increase in B cell precursor frequency. The hypothesis is forwarded that B cell precursor frequency is a limiting factor in RBC alloimmunization.