The Rh blood group system in review: A new face for the next decade

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h is the most well-recognized blood group system after ABO, probably because of the dramatic presentation of a fetus suffering hemolytic disease of the newborn (HDN) following maternal alloimmunization to the D antigen. Even individuals not associated with medicine have heard of the “Rh factor” and are aware that it has some importance in pregnancy. The earliest recorded description of the syndrome dates to the 1600s from a French midwife who attended the delivery of a set of twins, one of which was hydropic and the other was jaundiced and died of kernicterus. The agent responsible for the wide range of fetal symptoms, from mild jaundice to fetal demise, remained obscure until 1941. Levine and colleagues observed that the delivery of a stillborn fetus and the adverse reaction in the mother to a blood transfusion from the father were related and were the result of an immune reaction to a paternal antigen. Serologists’ relationship with the offending blood group system began when it was confused with a Rhesus monkey red blood cell (RBC) protein, now termed LW, and much argument and debate ensued over who should receive credit for its discovery. Becoming aware of the antigen, however, was only the beginning of the story. This blood group system would become notorious for its complexity, with numerous antigens and multiple nomenclatures defining it. Several seminal events characterized the history of the Rh system. One of the most important was the observation that ABO mismatch between a mother and the fetus had a partial protective effect against immunization R to D. This suggested the rationale for the development of Rh immune globulin (RhIG). Although immunoglobulin M (IgM) antibodies did not provide protection, immunoglobulin G (IgG) anti-D was effective. By the early 1960s, a mere 20 years after the discovery of Rh incompatibility, an effective treatment was available. Despite their clinical importance, the extremely hydrophobic nature of the Rh proteins made biochemical studies difficult, and the proteins were not successfully isolated until the late 1980s. This led to the cloning of the genes in the 1990s and to major advances in our understanding of the Rh system. The molecular bases of most Rh antigens have been determined, and the RH gene structure explains why this system is so polymorphic. Specifically, the conventional Rh antigens are encoded by two genes, RHD and RHCE, but numerous gene conversion events between them create hybrid genes. The resulting novel hybrid proteins containing regions of RhD joined to RhCE, or the converse, generate the myriad of different Rh antigens. The goal of this review is to highlight the insights gained since the cloning of the genes, describe applications for RH molecular testing to clinical practice, introduce other members of the Rh family of proteins that are present in other tissues, and focus on the next piece of the Rh puzzle, that is, efforts to determine the structure and function of the Rh family of proteins.