Rh Blood Group System

        The Rh (not Rhesus) system is the second most important blood group system in transfusion medicine because antigen-positive RBCs frequently immunize antigen-negative individuals through transfusion and pregnancy.

       Inheritance of Rh antigens is determined by a complex of two closely linked genes: one encodes the protein carrying D antigen (RhD); the other encodes the protein carrying C or c and E or e antigens (RhCE). RBCs from Rh-positive people have both RhD and RhCE, whereas Rh-negative RBCs have only RHCE. In the Rh system, eight common antigen combinations or haplotypes are possible: Dce (R₀, Rh₀), DCe (R₁, Rh₁), DcE (R_2, Rh₂), DCE (R_Z, Rh_z), ce (r, rh), Ce (r', hr'), cE (r″, hr″), and CE (ry, rh″). The letter "d" is commonly used to designate the lack of D, but there is no d antigen or anti-d.

         Several nomenclatures can be used to describe Rh genes and antigens. The Fisher-Race nomenclature, which uses CDE terminology, is more commonly used for antigens; the Wiener nomenclature, which uses Rh designations, is favored for haplotypes and gene complexes; and the Rosenfield and Rubinstein nomenclature, which uses numerical designations, was introduced to allow analyses without bias.²⁵

      The Rh blood group system has 48 antigens (ABO has four). By far the most important and immunogenic antigen is D (Rh₀ in Weiner terminology, referring to Weiner's discovery that a Rhesus monkey injected with human RBCs would produce antibody that agglutinated 85% of white New Yorkers). For most clinical purposes, testing individuals for the D antigen and classifying them as D+ (or Rh-positive), or D– or (Rh-negative) is sufficient. Approximately 85 percent of the Caucasian population is Rh-positive, and 15 percent is Rh-negative. Most Rh-negative recipients produce anti-D if they receive Rh-positive blood. Anti-D can cause hemolysis in adults following an Rh-mismatched transfusion and in the newborn (HDN) if antibodies were raised in the mother from a prior transfusion or pregnancy. The risk of anti-D sensitization by transfusion is eliminated by matching. The risk of anti-D sensitization in pregnancy is minimized by passive immunization of mothers at risk against D. Thus donors and recipients are routinely typed and matched for D.

The antigens C, c, E, and e are less immunogenic and become important in patient care only after the corresponding antibody develops or when the basic Rh haplotype must be determined. The remaining 40+ antigens are other Rh protein epitopes whose corresponding antibodies are seldom encountered. Some are encoded by variant Rh alleles and appear as antithetical antigens to C, c, E, or e or as related "extra" antigens. Others are referred to as compound antigens or cis gene products. For example, the protein produced by the gene ce encodes c, e, and f (or ce) antigen. Other compound specificities include Ce (rhⁱ), cE, CE, V (ce^s), and Ce^s. Still other Rh antigens are related to the complex "mosaic" nature of D and e antigens. If immunized, individuals who lack a part of D or e and make antibody to the portion they lack can present with a challenging serologic picture. For example, the D+ person who lacks part of the D epitope and makes an antibody to the missing portion appears to make alloanti-D because normal D+ RBCs carry all D epitopes.

       Some, but not all, individuals who lack part of the D antigen (partial D) have weak expression of D on their red cells that is detected only by antiglobulin test. Having a C gene in transposition to a D gene (e.g., Dce/Ce or DCe/Ce genotypes) also can weaken expression of D in some individuals. A third type of weak D expression results from inheriting a D gene that encodes all epitopes of D, but in less than normal quantity.

DNA analyses have revealed the molecular basis underlying antigens and phenotypes in the Rh blood group system. A list of the alleles that have been described to date is available at http://www.aecom.yu.edu. Rh blood group orthologs are present in nonhuman primates and other species on the evolutionary tree.²⁷ Rh functions as a CO₂ or perhaps an ammonium transporter.