Rh and LW blood group antigens

History and nomenclature The Rh system is second only to the ABO system in importance in transfusion medicine because Rh antigens, especially D, are highly immunogenic and cause hemolytic disease of the fetus and newborn (HDFN) and hemolytic transfusion reactions (HTRs). HDFN was first described by a French midwife in 1609 in a set of twins, one of whom was hydropic and stillborn, whereas the other was jaundiced and died of kernicterus. That a wide range of observed clinical scenarios involving red cell hemolysis were related—from severely hydropic stillborn fetuses to infants with mild or significant levels of jaundice and kernicterus—was not realized until 1932. The cause of red cell hemolysis remained elusive until 1939, when Levine and Stetson described a woman who delivered a stillborn fetus and also suffered a severe hemolytic reaction when transfused with blood from her husband. Levine and Stetson correctly surmised that the mother had been immunized by a fetal red cell antigen inherited from the father and suggested that the cause of the erythroblastosis fetalis was maternal antibody in the fetal circulation. They did not give the target blood group antigen a name. Meanwhile Landsteiner and Wiener, in an effort to discover new blood groups, injected rabbits and guinea pigs with rhesus monkey red cells. The antiserum they obtained agglutinated not only rhesus monkey red cells but also the red cells of 85% of White subjects, whom they called “Rh positive”; the remaining 15% of individuals studied were termed “Rh negative.” The “anti-Rhesus” serum seemed to be reacting similarly to the maternal antibody in serologic testing, hence the blood group system responsible for HDFN came to be known as “Rh.” The anti-Rhesus serum, in actual fact, was detecting the LW antigen (subsequently named for Landsteiner andWiener), which is present in greater amounts on D-positive than on D-negative red cells. Years of debate followed concerning whether the human antibodies and the Rhesus antibodies were detecting the same antigen and extended long after serologic profiles suggested they were reacting with different structures. Landsteiner and Wiener never accepted the LW terminology, because doing so would imply that they had not discovered the cause of HDFN. It was soon obvious that Rh was not a simple, single-antigen system. In 1941, Fisher named the C and c antigens (A and B had been used for ABO), and used the next letters of the alphabet, D and E, to define antigens recognized by additional antibodies. In 1945, the e antigen was identified. It is important for transfusion medicine specialists to appreciate that the often confusing nomenclature used to describe Rh antigens results from the difference in opinion that existed concerning the number of genes that were involved in their expression. The Fisher– Race nomenclature suggested that three closely linked genes (C/c, E/e, and D) were responsible, whereas the Wiener nomenclature (Rh-Hr) was based on his belief that a single gene encoded one “agglutinogen” that carried several blood group factors. Even though neither theory was correct (there are two genes—RHD and RHCE—correctly proposed by Tippett), for written communication the Fisher–Race designation (DCE) for haplotypes is preferred, and for spoken communication a modified version ofWiener’s nomenclature is preferred (Table 14.1). The “R” indicates thatD is present, anduse of a lowercase “r” (or “little r”) indicates that it is not. The C or c and E or e Rh antigens carried with D are represented by subscripts: 1 for Ce (R1), 2 for cE (R2), 0 for ce (R0), and Z for CE (Rz). The CcEe antigens present without D are represented by superscript symbols: “prime” for Ce (r ́), “double-prime” for cE (r ́ ́), and “y” for CE (r). The “R” versus “r” terminology allows one to convey the commonRh antigens present on one chromosomal haplotype in a single term (a phenotype). The major Rh antigens are D, C, c, E, and e, but the Rh blood group system is one of the most complex because of the number of additional antigens that have been reported (Table 14.2). These additional antigens include compound antigens in cis (e.g., f [ce], Ce, and CE), low-incidence antigens arising from partial-D hybrid proteins (e.g., D, Go, and Evans), and antigens arising from various point mutations in the RhCE protein (e.g., C, C, and VS). Table 14.2 also includes the numeric designations for Rh antigens. With a few exceptions (RH17 and RH29), the numeric designations are not widely used in the clinical laboratory.