The Blood Group Rh: Part II
Authors: D. F. Cappell
Journal: BMJ (1946)

The discovery of the Rh factor illustrates very strikingly how pure scientific research may yield unforeseen results of great practical importance. Physicians who frequently practised blood transfusion had long been aware that, in spite of the most careful matching of the donor's blood by the methods then in use, some patients receiving repeated transfusions be came progressively more difficult to transfuse owing to the occurrence of severe reactions. It was also known that such intra-group transfusion reactions occasionally occurred at the first transfusion, but only where the patient was pregnant or had been recently delivered. The finding of  irregular  iso agglutinins in the blood of such a case had also been recorded (Levine and Stetson, 1939). The term  irregular  implied that these agglutinins did not conform to the scheme of the four blood groups, A, B, AB, 0. But these observations remained isolated and uncoordinated until the discovery of the Rh factor by Landsteiner and Wiener in 1940. These workers observed that the injection of blood from rhesus monkeys into rabbits or guinea-pigs led to the develop ment of antibodies which reacted not only with the red blood cells of those monkeys but also with the cells of 85% of the white population; such persons were termed Rh-positive and the remaining 15% Rh-negative. It is interesting to note that the cells of some primate monkeys-e.g., chimpanzees-are uniformly Rh-negative (Wiener and Wade, 1945). Almost im mediately Wiener and Peters (1940) applied the discovery of the Rh factor in man to the identification of the irregular iso-agglutinins found in three sufferers from incompatible intra group transfusion reactions.t It was shown that all three recipients were Rh-negative, while the transfused blood was Rh-positive; accordingly they explained the intra-group incom patibility by the hypothesis that the Rh factor of the transfused blood had acted as an antigen and had brought about iso immunization of the Rh-negative recipients. Levine and his co-workers (1941) then demonstrated that the liability to severe intra-group transfusion reactions in the puerperium, usually associated with some foetal abnormality such as hydrops or erythroblastosis, was due to iso-immunization of Rh-negative women by pregnancy with a Rh-positive foetus, and they suggested that not only the maternal transfusion reaction but also the foetal disease was brought about by the action of Rh antibodies. These fundamental observations were quickly confirmed by workers in this country (Boorman, Dodd, and Mollison, 1942; Race, Taylor, Cappell, and McFarlane, 1943), and the various disorders-hydrops foetalis, icterus gravis, and congenital anaemia-were included under the heading  haemo lytic disease of the newborn. The significance of iso-immuni zation of Rh-negative mothers was shown by statistical studies: hus abou 90% of the mothers of infants with haemolytic vdi ase were f und to be Rh-negative, while all the infants were Rh-positive. Wartime difficulties made. it impossible for most workers in Great Britain to use immune sera prepared against the cells of rhesus monkey , but sera from Rh-negative persons who had suffered intraroup transfusion reactions and sera from the mothers of erythroblastotic babies were found to be suitable f r the classification of human bloods into the Rh-positive and Rh-negative types. Family studies have shown that the Rh fact r is nherited as a simple Mendelian dominant: determined by an allelomo phic pair of genes-Rh and rh-but it must be not d that the Rh-neg ive quality of blood (rh) does not imply merely th absence of the Rh-positive quality (Rh), for it will be shown later that both Rh and rh are responsible for the pr sence of antigens in the red cells each of which can be detected in specific fashion by its appropriate antiserum. The Rh-rh genes are situated upon a different pair of chromosomes from those for the ABO and MN groups. When an individual possesses two similar genes for a character he is said to be homozyg us; when dissimilar genes are present he is hetero zygous for that character. There are thus three genetic classes of p rso she homozygous Rh-positive (RhRh), the hetero zy ous Rhositive (Rhrh) and the homozygous Rh-negative (rhrh). Further, it will be shown below that Rh and rh are not simple entiti s, but represent gene-complexes, each of which is c mposed of three closely linked genes, and some at least of the ge e loci are the seat of multiple allelomorphism.