Main Theories Used In Rhesus

The Rh system was not recognized until several years after the discovery of the ABO system. The Rh blood group system is a polymorphic (having multiple alleles of a gene within a population, usually expressing different phenotypes) with more than 40 antigens recognized. The antigens are well developed at birth and suitable for use in paternity testing. The genes that control this system are autosomal codominanat and located on chromosome number one. The name Rh is actually a misnomer (is a misapplied or inappropriate name or designation or an error in naming a person or thing). The system was erroneously named after the rhesus monkey when it was believed that an antigen on the red cells of rhesus monkies was identical to an antigen on human red cells thus it was named the Rh antigen. 5 principle antigens: D, C, c, E, e and their corresponding antibodies are the most clinical significant. The Rhesus system is named after the Rhesus Macaque, following experiments by Karl Landsteiner and Alexander S. Wiener, which showed that rabbits, when immunized with rhesus monkey red cells, produce an antibody that also agglutinates the red blood cells of many humans. Landsteiner and Wiener discovered this factor in 1937 (publishing in 1940). The significance of the Rh factor was soon realized. Dr. Phillip Levine working at the Newark Beth Israel Hospital made a connection between the Rh factor and the incidence of erythroblastosis fetalis, and Wiener realized adverse reactions from transfusions were also resulting from the Rh factor. Wiener then pioneered the exchange transfusion to combat erythroblastosis fetalis in newborn infants. This transfusion technique saved the lives of many thousands of infants before intrauterine transfusion was invented which enabled much more severely affected foetuses to be successfully treated. Alexander Wienner next went on to discover and name other antigens in this system and thus in the process developed an Rh nomenclature which was named Wienner Theory. Fisher – Race Theory is named after the two British workers in England which were Ronald Fiesher and Rober R whom proposed it in the 1940’s. Although too simplistic to explain this complex system, the theory is useful to explain routine inheritance of D, C, E, c, and e antigens. On the other hands in 1962 Rosenfield and associates introduced numerical designations for the Rh antigens to more accurately represent the serological data to be free of genetic interpretation and to be more compatible for computer use. However, this numerical nomenclature is not widely used in the clinical lab. (John C. Flynn, 1998)

WIENER THEORY

According to Wiener theory, Wiener and Landsteiner discovered the rhesus blood group was distinguished Rh Positive and Rh negative by using a serum. Wiener also believes that gene is responsible to detect the Rh system by the agglutination that may be present due to the binding of antigen (at RBC surface) with the antibody inside the body plasma. The agglutinogen in the Wiener nomenclature actually represent the presence of a single haplotype composed of three different antigens that are R that indicated the presence of D antigen c antigen indicated by ( ′ ) symbol and the presence of antigen E and e indicated by ( ″ ) symbol. Wiener differentiates the E and C antigen with “e” and “c” antigen by the “rh” and “hr” symbol. The “rh” symbol indicated the “E” and “C” antigen while the “hr” indicated the presence of e and c antigen. (J.J Van Loghem, 2000)

(J.J Van Loghem, 2000) pointed out, the three varieties of antigens, later called by Wiener Rh0, rh′, rh″, were sometimes found to exist independently in the human blood though more often two varieties were found in the same sample of blood. He the further explained, the antigen Rh0 and rh′ are sometimes preset together and the blood is then known as type Rh1 or Rh0′. While when Rh0 and rh″ are found together the blood is typing as Rh2 or Rh0″. But when all are found together, the blood is said to be Rh1,Rh2 or Rhz. For the rh′ and rh″ found together with the presence of Rh0 is rarely occur and this type is described by the symbol rh′ rh″ or Rhy. For the complete absence of this three antigens is indicated by the rh symbol. (J.J Van Loghem, 2000)

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Wiener has discovered that one gene reside at one locus at expressed several distinguishable antigens. Wiener also discovered there was one gene complex with a number of alleles resulting in the presence of various Rh antigens. Based on Wiener there were 8 alleles, R°,R¹,R²,Rz,r´,r˝,ry,which ended up with different antigens on the red cell. (J.J Van Loghem, 2000)

FISHER – RACE THEORY

Fisher-race theory is the part of the terminology is most common and widely used even today. From their theorizes too, they assumed that the separate genes, C, c, D, E, and e are so closely located and linked on the chromosomes, due of that they always “travel” an inherited together. By replacing a single gene at the Rh locus, there were three gene are located close together and each of them will gave rise to its own antigen like, D gene will express D antigen and same like C and E. Historically, the present or absence of D antigen on the red blood cells will stated as Rh positive or Rh negative. For instance, persons who is A positive, it means both A and D antigens are present on their red blood cells. So, this person assume as Rh negative. For those who is A negative, the A antigen is present but the D antigen is absent. So, this person assume as Rh negative. The Fisher-Race theory consists of three separate genes. (J.J Van Loghem, 2000)

They are genes D, genes C and their alleles is c and genes E which is their alleles is e. For gene D, its alleles are said to be amorphic or in other words it is known as silent alleles which are absenece on the chromosome since anti-d never be found. Fisher-race has their own nomenclature and it is written based on the presence of the antigen that attach on the RBC. DCE is chosen in alphabets as the order in this theory. Each gene is responsible to control the product of the corresponding antigen. One haplotype is produced from each partner or set of Rh antigens. Based on their theorized that the Rh antigens are controlled by a complex of 3 sets of genes with closely linked loci.Dce genes complex codes for D, C, e antigens respectively on the red blood cells.Red cells which is fail or cannot react with anti-D are described as d or in the same meaning, it is known as amorphic which is already stated above and it is also known as silent alleles. (J.J Van Loghem, 2000)

These three genes are closely linked on the same chromosome in the group 3 and are inherited together. CDe is the most common group of 3 genes that inherited and ce (d negative) is the second most common. The nomenclature of the Fisher-Race based on totally different conception of the genetic structure of the Rh factor. The letters C, D and E were chosen in correspondence with the already know blood groups A, B and O. As blood samples sometimes do not react with anti-D, he or she is said that an allelemorph on their gene d was also not present. For another reasons for this case, there should be an allelemorph e as well as E. According to Fisher-Race, anti-d and anti-e will stimulated as the formation antibodies based on hypothetical antigens and also genes, d and e, which is would be able or in favourable circumstances. He also believed that there is no possibility for this three genes C or c, D or d, E or e are not occur any crossing over between them due to their placed at the same chromosome in the closely loci. They are stated that in the fisher-race theory, there can be 8 possibilities.Both CDE and cde make it easy that this 8 possibilities or as known as 8 Rh types are conceivable, namely CDe, cDE, cDe,Cde, cdE,cde, CDE and Cde, the last one not having been discovered at the time. This theory is widely and commonly used because they can fit most easily and fastly with serologic reactions obtained in practice or doing some test in the laboratory. For DCe/DCe combination, it is known as homozygous as DCe gene which is one from each parent, the individual is negative for E, c. For DCe/dcE combinations, it is known as heterozygous pattern for C, D, E, e, c which is all alleles from parents. (J.J Van Loghem, 2000)

ROSENFIELD NOMENCLATURE

The Rh or Rhesus blood factor has applied the key to two medical mysteries, namley, the cause of Hemolytic Transfusion Reaction (HTR) and Hemolytic Disease of the Newborn (HDN). In view of the importance of the Rh blood factor, it is natural that curiosity exists regarding the events leading to its discovery. Karl Landsteiner investigated the cases. (Journal of the History of Medicine, 2010)

The discovery of rhesus was no accident, but the inevitable result of Karl Landsteiner’s earlier work on blood groups and his basic investigations on the nature of antigens, antibodies and their reactions. By applying and developing his ideas in later investigations on the complex Rh-Hr system of blood types, I succeeded in elucidating their serology and their heredity by a series of multiple allelic genes, at the same time devising a simple, compact method of designating the Rh-Hr types. The fact that even today a large number of workers still advocate and use the different, elaborate, alternate nomenclature for the Rh-Hr types which does not represent the facts correctly demonstrates that the basic immunological principles discovered by Landsteiner are not widely known and understood. In presenting this historical account, therefore, it wil be necessary to explain basic principles as well as the earlier history of blood grouping and transfusion, which led up to the discovery of the Rh factor. (Journal of the History of Medicine, 2010)

In Rosenfield cases, there are no genetic theories that relate to it like Fisher-Race and Weiner theories. It only comes up with a numerical terminology or nomenclature for the Rhesus groups based on a proposal by Murray in 1994 to eliminate certain complications and problems during classification using the Fisher-Race and Weiner nomenclature. This also may help in the way for the storage of such information in computers. He also added that this nomenclature proposes a system that defines reaction with particular anti-sera, is free of any genetic implication and gives equal importance to positive and negative reactions. (Muhammad Tayyab, 2000)

The antigens are numbered in chronological order or discovery, refer to Table 3, and the system has certain obvious advantages. In practical, however, it is difficult to apply; for example, a phenotype given as Rh: 1,2,3,4,5 and so on, depending on how many further antigens had been tested, for instant, recognition of the involved antigens. The negative sign designates absence of the antigen. If an antigen is not tested for, its number does not appear in the sequence. (Muhammad Tayyab, 2000)

Antigen

Rosenfield Nomenclature

D

Rh1

C

Rh2

E

Rh3

c

Rh4

e

Rh5

Table 3: The Rhesus antigens and its corresponding Rosenfield Nomenclature

COMPARISON BETWEEN THREE THEORIES USED IN RHESUS STUDY :

FISHER-RACE THEORY, WIENER THEORY AND ROSENFIELD THEORY

Based on Fisher-Race theory, Ronald Fisher and Robert R. Race theorized that there are three closely loci attach on each of the chromosome of a homologous pair. Every locus has its own set of allele which is Dd, Cc and Ee and there is very little chance of being separated during cross-linking. In terms of nomenclature, Fisher-Race named the Rh antigens as C, D, E, c and e. and these antigens can be assembled in eight different ways such as CDe, cDE, cde, Cde, cdE, cde, CDE and CdE. (Muhammad Tayyab, 2000)

According to Wiener theory, Alexander Wiener postulated that at one Rh there is one Rh locus occur, but this gene has multiple alleles. In terms of nomenclature, Wiener discovered that there were five nomenclature of the major Rh antigens like Rh°, rh’, rh”, hr’ and hr”. (Muhammad Tayyab, 2000)

Otherwise, Rosenfield did not propose any inheritance but he assigned that each antigen is numbered in chronological order or discovery. For example, Rh1, Rh2, Rh3, Rh4 and Rh5. Thus, to identify the negative sign the numerical code can be used. (Muhammad Tayyab, 2000)

In comparing the theories, Fisher – Race theory means that one chromosome have three genes that attach at different locus and closely linked together but it can expressed one antigen only while in the Wiener theory there is one gene attach at one chromosome and it can expressed several antigens. Thus, it becomes obvious that the only practical difference between the two is that Fisher-Race envisions a complex gene, whereas Wiener envisions a complex antigen. While for the Rosenfield theory, there is no genetic theory like Fisher-Race theory and Wiener theory. (Muhammad Tayyab, 2000)

WIENER THEORY

FISHER-RACE THEORY

ROSENFIELD THEORY

Rh°

D

Rh1

rh’

C

Rh2

rh”

E

Rh3

hr’

c

Rh4

hr”

e

Rh5

Comparison in Nomenclature between Fisher-Race theory, Wiener theory and Rosenfiled theory