The term “Rh” was originally an abbreviation of “Rhesus factor.” It was discovered in 1937 by Karl Landsteiner and Alexander S. Wiener, who, at the time, believed it to be a similar antigen found in rhesus macaque red blood cells. It was subsequently discovered that the human factor is not identical to the rhesus monkey factor, but by then, “Rhesus Group” and like terms were already in widespread, worldwide use. Thus, notwithstanding it is a misnomer, the term survives (e.g., rhesus blood group system and the obsolete terms rhesus factor, rhesus positive, and rhesus negative – all three of which actually refer specifically and only to the Rh D factor and are thus misleading when unmodified). Contemporary practice is to use “Rh” as a term of art instead of “Rhesus” (e.g., “Rh Group,” “Rh factors,” “Rh D,” etc.).
[1946 Awards Presentation]: [Dr. Philip Levine (center) and Dr. Alexander S. Wiener (right)]
Albert Lasker Award for clinical research awarded jointly with Karl Landsteiner and Philip Levine for their work on the Rhesus factor, HDN and blood transfusion
The significance of their discovery was not immediately apparent and was only realized in 1940, after subsequent findings by Philip Levine and Rufus Stetson.
This report deals with a rare property in the blood of a patient whose serum showed an iso-agglutinin of moderate activity, which agglutinated about 80 per cent of the bloods of her own group. In view of the fact that this agglutinin tended to disappear after an interval of several months and the fact that this agglutinin gave an equally strong reaction at 37 and 20 C., it would seem to resemble agglutinins resulting from iso-immunization following repeated transfusions. This phenomenon is readily reproduced in some species (cattle, chickens, rabbits), by several repeated transfusions, but in the case of man only two clearcut instances of such iso-immunization to cellular elements are described in the literature.1 The case to be described differs from these in that the immune iso-agglutinin must have been stimulated by a factor other than repeated transfusion. The nature of this factor becomes evident from a summary
https://jamanetwork.com/journals/jama/article-abstract/290521
AN UNUSUAL CASE OF INTRA-GROUP AGGLUTINATION
The serum that led to the discovery was produced by immunizing rabbits with red blood cells from a rhesus macaque. The antigen that induced this immunization was designated by them as Rh factor to indicate that rhesus blood had been used for the production of the serum.
Studies are reported on an individual agglutinogen (Rh) in human blood which has been found to be of clinical importance because occasionally it gives rise to the formation of immune isoantibodies in man, a peculiarity which leads to untoward transfusion reactions. A method for the determination of the presence or absence of the new blood factor is described, which can be used for typing patients and prospective blood donors. Examination of families showed that the agglutinogen is inherited as a simple Mendelian dominant. The distribution of the factor Rh among white individuals and negroes may indicate racial differences. The property is probably genetically independent of the blood groups and the factors M and N.
STUDIES ON AN AGGLUTINOGEN (Rh) IN HUMAN BLOOD REACTING WITH ANTI-RHESUS SERA AND WITH HUMAN ISOANTIBODIES
In 1939, Phillip Levine and Rufus Stetson published in a first case report the clinical consequences of non-recognized Rh factor, hemolytic transfusion reaction, and hemolytic disease of the newborn in its most severe form.
The capacity possessed by some rabbit immune sera produced with blood of Rhesus monkeys, of reacting with human bloods that contain the agglutinogen M has been reported previously. 1 , 2 Subsequently it has been found that another individual property of human blood (which may be designated as Rh) can be detected by certain of these sera. Upon exhaustion of such a serum with selected bloods, for instance OM, the absorbed serum still agglutinated the majority (39 out of 45) of other human bloods, independently of the group or the M, N type; moreover, reactions took place with bloods lacking the property P. An example of the reactions is given in Table I. The results are of some interest in that they suggest a way of finding individual properties in human blood, namely, with the aid of immune sera against the blood of animals. As an analogy may be cited the demonstration of differences in sheep erythrocytes with immune sera for human A blood 3 The reactions described, although of moderate intensity only, were obtained with immune sera produced at different times. Whether these observations may possibly lead to a method suitable for routine work is still under investigation.
An Agglutinable Factor in Human Blood Recognized by Immune Sera for Rhesus Blood
It was recognized that the serum of the reported woman agglutinated with red blood cells of about 80% of the people although the then known blood groups, in particular ABO were matched. No name was given to this agglutinin when described. In 1940, Karl Landsteiner and Alexander S. Wiener made the connection to their earlier discovery, reporting a serum that also reacted with about 85% of different human red blood cells.
In 1941, Group O: a patient of Dr. Paul in Irvington, NJ, delivered a normal infant in 1930:
Graduated from St. Leo’s School in Irvington, NJ, and was valedictorian of his graduating class at Seton Hall Prep in West Orange, NJ, in 1948. He then graduated for Immaculate Conception Seminary in Darlington, and went on to the North American College in Rome, Italy, where he was ordained on Dec. 17, 1955. First assigned to Holy Trinity parish in Westfield, NJ. His second assignment was with Sacred Heart Church in Bloomfield, NJ, where he was in charge of ecumenicism programs. His third church was the Blessed Sacrament Roman Catholic Church in Newark. His fourth church was St. Columba’s Church in inner-city Newark. And lastly his fifth church was St. Augustine’s in Union City, NJ.
Rev Bernard Charles “Bernie” Schlegel
this pregnancy was followed by a long period of sterility. The second pregnancy (April, 1941) resulted in an infant suffering icterus gravis.
Based on the serologic similarities, Rh factor was later also used for antigens, and anti-Rh for antibodies, found in humans such as those previously described by Levine and Stetson. Although differences between these two sera were shown already in 1942 and clearly demonstrated in 1963, the already widely used term “Rh” was kept for the clinically described human antibodies which are different from the ones related to the rhesus monkey. This real factor found in rhesus macaque was classified in the Landsteiner-Weiner antigen system (antigen LW, antibody anti-LW) in honor of the discoverers.
The Rh blood group system is one of the most polymorphic and immunogenic systems known in humans. In the past decade, intense investigation has yielded considerable knowledge of the molecular background of this system. The genes encoding 2 distinct Rh proteins that carry C or c together with either E or e antigens, and the D antigen, have been cloned, and the molecular bases of many of the antigens and of the phenotypes have been determined. A related protein, the Rh glycoprotein is essential for assembly of the Rh protein complex in the erythrocyte membrane and for expression of Rh antigens. The purpose of this review is to provide an overview of several aspects of the Rh blood group system, including the confusing terminology, progress in molecular understanding, and how this developing knowledge can be used in the clinical setting. Extensive documentation is provided to enable the interested reader to obtain further information. (Blood. 2000;95:375-387)
The Rh blood group system: a review
It was recognized that the Rh factor was just one in a system of various antigens. Based on different models of genetic inheritance, two different terminologies were developed; both of them are still in use.
The clinical significance of this highly immunizing D antigen (i.e., Rh factor) was soon realized. Some keystones were to recognize its importance for blood transfusion (including reliable diagnostic tests), hemolytic disease of the newborn (including exchange transfusion), and very importantly the prevention of it by screening and prophylaxis.
The discovery of fetal cell-free DNA in maternal circulation by Holzgrieve et al. led to the noninvasive genotyping of fetal Rh genes in many countries.
Also, in conjunction with Philip Levine’s separate work which helped identify the Rh factor as a major cause of erythroblastosis fetalis, or Rh disease, he was able to help solve a major cause of infant fatality. In 1946, Dr. Wiener created the first medical procedure to combat the problem, which he called an exchange transfusion. It consisted of a complete blood transfusion for the affected baby. The method was further refined by Harry Wallerstein, a transfusionist.
Since then, less extreme methods have been found to deal with erythroblastosis fetalis. However, at the time, the procedure was able to save over 200,000 lives.