Rh Factor and Rh System

Abstract

Rh factor refers to the D antigen on the erythrocyte membrane, the first antigen identified as belonging to the human Rh blood group system. It is so named because of anti-Rh, an antibody made in rabbits when injected with rhesus monkey blood. Over seven decades of studies have unveiled a complex, polymorphic system containing five common antigens (D, C, c, E, and e) and numerous allelic variants at the level of populations. The five antigens reside on different Rh polypeptides encoded by RHD and RHCE genes in tandem on chromosome 1p34-36.2. Rh factor is most potent in eliciting alloimmune reaction and its incompatible state, Rh positive (D+) versus Rh negative (D–), is a major cause of hemolytic disease of fetuses and newborns. The expression of Rh polypeptides at cell surface entails a genetic as well as a physical interaction with the homolog, Rh-associated glycoprotein (RhAG). The two proteins appear to mediate a macromolecular assembly in the plasma membrane dubbed ‘Rh membrane complex’. Inactivation of either the RH or RHAG locus by rare mutations results in the Rh deficiency syndrome, a genetic disorder that exhibits a varying degree of anemia, stomatocytosis, and membrane abnormalities. Rh factor is the founding member of the Rh protein family that has apparently arisen from a recent gene duplication event during primate evolution. Rh polypeptides and RhAG have, in parallel, undergone fast evolution in mammals with respect to their epithelial RhBG and RhCG homologs. The selective pressure underlying this acceleration is obscure, but could be related to the adaptive changes involving immunological and morphological processes during erythrocyte evolution. The biological role, the physicochemical mechanism, and the substrate specificity of Rh proteins with regard to CO2 or ammonia transport remain to be established.