Introduction

The term Rh refers not only to a specific red blood cell (RBC) antigen but also to a complex blood group system that is currently composed of nearly 50 different antigenic specificities. Although the Rh antibodies were among the first to be described, scientists have spent years unraveling the complexities of the Rh system and its mode of inheritance, the genetic control of the Rh system, and the biochemical structure of the Rh antigens.

History of the Rh System

Before 1939, the only significant blood group antigens recognized were those of the ABO system. Transfusion medicine was thus based on matching ABO groups. Despite ABO matching, blood transfusions continued to result in morbidity and mortality. As the 1930s ended, two significant discoveries were made that would further the safety of blood transfusion and eventually result in defining the most extensive blood group system known. It began when Levine and Stetson1 described a hemolytic transfusion reaction in an obstetrical patient. After delivery of a stillborn infant, a woman required transfusions. Her husband, who had the same ABO type, was selected as her donor. After transfusion, the recipient demonstrated the classic symptoms of an acute hemolytic transfusion reaction. Subsequently, an antibody was isolated from the mothers serum that reacted both at 37_C and at 20_C with the fathers RBCs. It was postulated that the fetus and the father possessed a common factor that the mother lacked. While the mother carried the fetus, she was exposed to this factor and subsequently built an antibody that reacted against the transfused RBCs from the father, which resulted in the hemolytic transfusion reaction. A year later, Landsteiner and Wiener2 reported on an antibody made by guinea pigs and rabbits when they were transfused with rhesus monkey RBCs. This antibody, which agglutinated 85 percent of human RBCs, was named Rh. Another investigation by Levine and coworkers3 demonstrated that the agglutinin that had caused the hemolytic transfusion reaction and the antibody described by Landsteiner and Wiener appeared to define the same blood group. Many years later it was recognized that the two antibodies were different. However, the name Rh was retained for the human-produced antibody, and the anti-rhesus antibody formed by the animals was renamed anti-LW in honor of those first reporting it (Landsteiner and Wiener). Further research resulted in defining Rh as a primary cause of hemolytic disease of the newborn (HDN, also called erythroblastosis fetalis) and a significant cause of hemolytic transfusion reactions. Continued investigation47 showed additional blood group factors associated with the original agglutinin. By the mid-1940s, five antigens made up the Rh system. Today the Rh blood group system is made up of nearly 50 different specificities.

Nomenclatures of the Rh System

The terminologies used to describe the Rh system are derived from four sets of investigators. Two of the terminologies are based on the postulated genetic mechanisms of the Rh system. The third terminology describes only the presence or

absence of a given antigen. The fourth is the result of the combined efforts of the International Society of Blood Transfusion (ISBT) Working Party on Terminology for Red Cell Surface Antigens. The genetic pathways are described in detail after the discussion of the nomenclatures, although reference to the former may be included here.

Fisher-Race: The DCE Terminology

In the early 1940s, Fisher and Race8 were investigating the antigens found on human RBCs, including the newly defined Rh antigen. They postulated that the antigens of the system were produced by three closely linked sets of alleles (Fig. 71). Each gene was responsible for producing a product (or antigen) on the RBC surface. Each antigen and corresponding gene were given the same letter designation (when referring to the gene, the letter is italicized). Fisher and Race named the antigens of the system D, d, C, c, and E and e. Now it is known that d represents the absence of D antigen. The phenotype (blood type observed during testing) of a given RBC is defined by the presence of D, C, c, E, and e expression. The gene frequency for each Rh antigen is given in Table 71, and the Rh haplotype (the complement of genes inherited from either parent) frequencies are given in Table 72. Notice how the frequencies vary with race. According to the Fisher-Race proposal, each person inherits a set of Rh genes from each parent (i.e., one D or d, one C or c, and one E or e) (see Fig. 71). Because Rh genes are codominant, each inherited gene expresses its corresponding antigen on the RBC. The combination of maternal and paternal haplotypes determines ones genotype (the Rh genes inherited from each parent) and dictates ones phenotype (the antigens expressed on the RBC that can be detected serologically). An individuals Rh phenotype is reported as DCE rather than CDE because Fisher postulated that the C/c locus lies between D/d and E/e loci. This information is based on frequencies of the various gene combinations. It is essential to remember that d does not represent an antigen but simply represents the absence of the D antigen. C, c, E, and e represent actual antigens recognized by specific antibodies. For many students, the Fisher-Race nomenclature represents the easiest way to think about the five major Rh system antigens, but it has shortcomings in that many of the newer Rh antigens are not assigned name