As part of the numerous nomenclature and classification proposals of the Rh system antigens, in this paragraph the Fisher and Race nomenclature will be used, updated according to current genetic and biochemical knowledge. Historically, the Rh antigen (later identified with the D antigen) was described in 1939 by Levine in a woman whose infant was found to have HDFN, and she herself developed a hemolytic posttransfusion reaction after transfusion of red blood cells donated by her husband. The name Rh derives from the fact that in 1940, Landsteiner and Wiener described an antiserum obtained by immunizing guinea pigs with Macaques rhesus monkey red cells, capable of reacting with 85% of human red blood cell samples, and which behaved like the antisera obtained by women whose foetuses had suffered from MEN. Later, in the second half of the 1940s, four additional antigens named C, E, c and e were included in the Rh system, which currently consists of more than 50 antigens, thus becoming the much larger erythrocyte blood group system. Antigens of the Rh system begin to be represented on the surface of the red cells as early as the eighth gestational week, and are fully expressed in the term new-born. They are characteristic exclusively of red blood cells, not being expressed in other cells or tissues.

Genes: At present it is believed that the antigens of the Rh system (D, C/c, E/e) are encoded by two alleles called RHD and RHCE, located on chromosome 1 in two contiguous and closely linked loci. These alleles encode nonglycosylated polypeptides expressing Rh antigens. The RHD gene encodes a transmembrane protein expressing antigen specificity D, while a d antigen has never been described. In D-negative subjects of Caucasian origin the RHD gene is deleted, while in subjects of African or Asian origin the D-negative phenotype is frequently associated with an inactive or mutated RHD gene. The RHCE gene encodes a single nonglycosylated polypeptide, which expresses the certain antigenic C, c, E, and e (its alleles are RHCe, RHCE, RHcE, and RHce). From a biochemical point of view, both the RHD gene and the RHCE gene encode a transmembrane protein of 417 amino acid residues. Unlike what has been observed for other antigenic determinants of erythrocyte blood group systems, this polypeptide chain does not present glycosylation but bonds fatty acids. There is a high homology between the products of the different alleles of the RHCE gene. For example, the C and c antigens differ from each other only by four amino acids in positions 16, 60, 68 and 103. The presence of a proline or an alanine in position 226, on the other hand, differentiates the E allele from that e. Rh proteins (D and CE) are complexed with Rh-associated glycoprotein (RhAG), which has 37% homology with Rh polypeptides, and is encoded by the RHAG gene located on chromosome 6.

Rh phenotype and genotype: Commercial anti-D, anti-C, anti-E, anti-c and anti-e antisera are used for the determination of the Rh phenotype. The set of antigens detected on a subject’s red blood cells therefore constitutes its Rh phenotype. D-negative subjects lack the RHD gene that encodes the D antigen or have a nonfunctional RHD gene. Most of the D-negative subjects are homozygous for the RHce allele, which represents the gene encoding the antigens c and e. Less frequently they may have RHCe or RHcE alleles, which code for C and e or for c and E, respectively. The RHCE gene, which produces the C and E antigens, is very rare in D-negative individuals. The D genotype of D-positive persons cannot be determined with serological tests, as molecular biology techniques must be used.

In the Rh system, the interaction between genes (position effect) is well described. If the interaction occurs between genes located on the same chromosome, it is referred to as the cis effect; if it occurs between genes placed on homologous chromosomes, it is indicated as a trans effect. In example (cis effect), the E antigen produced by DcE appears quantitatively less expressed than the E antigen produced by cE. It was also observed that both C and E were less expressed when they were encoded by the DCe/DcE genotype than the antigens encoded by DCe/ce or DcE/ce (trans effect).

Usually positive D red cells show, when tested with anti-D antiserum, strong agglutination, appreciable macroscopically, which allows rapid and safe classification. The classification of red blood cells that do not agglutinate after being tested with an anti-D is not so simple. Reactivity can in fact be reactive-dependent or can only be revealed by the antiglobulin test. These “weak” Ds (formerly called Du) are determined in most cases by an RHD gene that encodes a RhD protein with reduced quantitative expression of the D antigen on the erythrocyte membrane. This phenotype is quite common in populations of African origin. In example, erythrocytes of some subjects with the Dce/Ce genotype show a weak D antigenic expression due to a suppressor effect exerted by RHC in the trans position with respect to RHD. Moreover, it is well known that the D antigen consists of numerous distinct structural components; RBCs that lack some components of the D antigen are referred to as “partial D” and, especially those with the DVI phenotype, can react only with some anti-D monoclonal antisera and can produce anti-D antibodies. There are many other antigens belonging to the Rh erythrocyte blood group system. Only some of them, such as Cw (antithetic to C), the G antigen (characterized by a serine in position 103 of the Rh polypeptide), the f antigen (ace fusion antigen), have practical importance. Very rare family groups are also described, whose red blood cells appear to be devoid of all Rh (Rh null) antigens. The Rh null phenotype can be of the “regulatory” type and therefore derive from a mutation of the RHAG gene, or of the “amorphous” type because of mutations of RHCE genes associated with deletion of the RHD gene.

Antibodies: Usually the antibodies directed towards antigens of the Rh system are of the immune type and derive from exposure to nonself red blood cells. It is therefore IgG with thermal optimum at 37 °C, which react with enhancing media or with the antiglobulin test. In some cases, the anti-Rh antibodies may be natural (for example, anti-E or anti-Cw). As regards the ability to induce the production of antibodies after stimulation, antigen D is undoubtedly the most powerful immunogen, followed in descending order by antigens c, E, C, and e. It must be remembered that individuals with partial D may develop an anti-D alloantibody. Rh antibodies do not generally fix complement. They therefore result in extra-vascular hemolysis in vivo. They are considered clinically significant, as they are potentially associated with even severe HDFN and post transfusion hemolysis (mainly extra-vascular).

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