Transfusion-induced autoantibodies and differential immunogenicity of blood group antigens: a novel hypothesis

Blood bank serology has identified hundreds of red blood cell (RBC) antigens contained within numerous blood group systems. Although most blood group antigens are defined by amino acid polymorphisms in the extracellular domain of membrane proteins, it is also possible that additional nonexofacial polymorphisms (NEPs) may exist within cytoplasmic or transmembrane domains. To assess this possibility, we analyzed several blood group molecules by searching the SNPper database for nonsynonymous single-nucleotide polymorphisms. We report the identification of a number of NEPs in the Kell, Kidd, and Duffy molecules. Because the identified NEPs are not exposed on the surface of intact RBCs and are, thus, not accessible to recipient antibodies, they would neither be detected by blood bank serology in vitro, nor would they be recognized targets in hemolytic transfusion reactions in vivo. The presentation of peptides containing NEPs by recipient MHC Class II molecules, however, would nevertheless produce helper T-cell epitopes. In addition to identifying NEPs in human blood group molecules, we explore a novel hypothesis that the presence of NEPs contributes to the immunogenicity of blood group antigens. We further hypothesize that NEPs provide a mechanism by which transfusion can lead to anti-RBC autoantibodies, which are known to occur in humans after transfusion. The scientific basis, existing evidence, approaches to testing, and predicted biology of this hypothesis are presented.