DIAGRAMMATIC REPRESENTATION OF THE RH BLOOD TYPES*

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1 DIAGRAMMATIC REPRESENTATION OF THE RH BLOOD TYPES* ALEXANDER S. WIENER, M.D. From the Serological Laboratory to the Office of the Chief Medical Examiner of New York City The clinical pathologist and the medical technician who do not specialize in blood grouping may find it difficult to learn or remember all the intricate relationships and reactions of the blood groups, such as those of the subgroups of A and AB, and of anti0 serums. In a previous paper 21, some diagrammatic illustrations of the blood groups and subgroups were presented. The newer knowledge 18 of the Rh blood types and Hr factors have added to the burdens of the clinical pathologist because the serology and genetics of these factors are far more involved than those of the blood groups and subgroups. The purpose of this paper is to present a simple diagrammatic method in order to enable one to learn and to remember the facts concerning the Rh blood types, and to facilitate a wider application of the recent findings in this field. Since this presentation is diagrammatic and figurative, one must not subject every statement in this paper to exact interpretation. To simplify the problem of the Rh blood types, we.shall start with a brief discussion of the four blood groups and their diagrammatic representation. As is well known, the four blood groups depend on the existence in certain human red blood cells of either, or both, of two agglutinogens, designated by the letters A and B, and the existance in certain human serums of either, or both, of two corresponding agglutinins, antia (or alpha) and antib (or beta). The agglutinins can only combine with their specific agglutinogens, in the same way that a key can only fit the lock for which it is made. (We are not concerned here with certain exceptions to this rule, like the ability of antia serums to hemolyze sheep blood; a situation which may be compared to the use of skeleton keys for all locks of the same make.) These relationships between the agglutinogens and agglutinins can be represented in any number of ways; one convenient way to do so is to use the right and left foot to represent the agglutinogens A and B (see Fig. 1), while the right and left shoes are used to represent the corresponding isoagglutinins, antia and antib, respectively. Applying Landsteiner's law that the serum of every individual contains those agglutinins corresponding to the agglutinogens A and/or B which are lacking from their erythrocytes, it becomes a simple matter to symbolize the four blood groups as shown in Figure 2. Thus, group 0 is represented by a pair of shoes; group A by the left foot together with the right shoe; group B by the right foot together with the left shoe; and group AB by a pair of feet without shoes. For transfusion purposes, it is sufficient to remember that no individual may be given blood containing a "foot" for which he has the corresponding "shoe". It is also important to remember that infants during the neonatal period "go around without shoes", that is, the agglutinins are usually not fully developed until the age of three * Received for publication, January 17,

2 234 A. S. WIENER FIG. 1. BLOOD GROUP FACTORS. AGGLUTINOGENS A AND B OF THE RED CELLS ARE SYMBOLIZED BY THE RIGHT AND LEFT FOOT, RESPECTIVELY; AGGLUTININS ANTIA AND ANTIB BY THE CORRESPONDING SHOES Group 0 43 % Group A.38% Group 6 Group AB Ml C^3 C^D AntiA AntiB A 3Cb AntiB '\ i FIG. 2. SYMBOLIZATION OF THE FOUR BLOOD GROUPS

3 EH BLOOD TYPES 235 Anti Rho"2^"^^ Rho qntioen,\. ~1 1 ^^Antirhesus c^2f ^rhesus HUMAN RHESUS Anti Rh rhesus *Jfr\^ 'w /"^^Swhesus <r ^* N*AntiRho FIG. 3. SYMBOLIZATION OF THE REACTIONS OF ANTIRHESUS SERUM FIG. 4. Rh BLOOD FACTORS. AGGLUTINOGENS Rh, Rh' AND Rh" OF THE RED CELLS ARE SYMBOLIZED BY THE HEAD, RIGHT HAND AND LEFT HAND, RESPECTIVELY; THE CORRESPONDING AGGLUTININS ANTIRh 0, ANTIRh'AND ANTIRh" BY THE HAT AND RIGHT AND LEFT GLOVES, RESPECTIVELY

4 236 A. S. WIENER months or later, so that newborn infants may even be given blood of an incompatible group without harmful effects. (Of course, such a procedure is not recom mended except under unusual circumstances.) The Rh blood types are more complicated because there are three sorts of anti Rh serums instead of two as in the case of the blood groups. Let us first consider the properties and behavior of the most important Rh factor, namely, the original rhesus or Rh 0 factor. In the original technic 2, the antiserums were prepared by injecting blood of a rhesus monkey into rabbits (or preferably into guineapigs 3 ), and had the property of agglutinating the blood of approximately 85 per cent of all persons of the Caucasian race, without regard to their blood group, MN type, and P factor. The most common antirh serum obtained from human beings who were sensitized to the Rh factor, corresponds exactly with the rhesus antiserum, and is designated antirh 0 serum. However, while the antirhesus serum reacts with human Rhpositive blood, human antirh 0 serum is incapable of agglutinating rhesus blood. Such nonreciprocal reactions are frequently encountered in immunology. One may perhaps find it easier to accept this apparently paradoxical situation with the aid of the diagrams given in Figure 3. Here the antirhesus agglutinin is represented by a small hat which fits precisely on the flat surface of the rhesus monkey's head (the rhesus antigen). On the other hand, the antirh 0 agglutinin is represented by a larger hat, which fits the human Rh 0 antigen (fiat surface of the human head). It will be seen that the antirhesus agglutinin can rest on the human head, though somewhat insecurely, while the human hat (antirho) is a complete misfit for the head of the rhesus monkey. This analogy may also make it clearer why human Rhpositive blood gives stronger and clearer reactions with human antirho serums than with animal antirhesus serums. At present almost all work on the Rh factor is done with human antiserums because of their higher specificity and avidity. Another apparently paradoxical fact, first disclosed by Fisk and Foord 1, is the ability of the antirhesus serums to agglutinate blood from human fetuses and infants, both Rhpositive and Rhnegative, agglutination with such blood being stronger than with Rhpositive blood of an adult person. This phenomenon has been explained by Wiener 25 as due to the presence in the blood of fetuses and infants of an agglutinogen which is lacking from adult blood, and apparently represents another instance of "ontogeny recapitulating phylogeny." The phenomenon will be easier to remember, if one visualizes the "heads" of newborn infants as much smaller than the "heads" of adult human beings so that the rhesus "hat" (antirhesus agglutinin) can fit it better, even in the case of an Rhnegative infants. While the antirhesus serums all have the same specificity, antirh serums obtained from senstitized human patients vary in their reactions, so that in addition to an antirho agglutinin, two other antirh agglutinins have been identified, namely, antirh' (positive in 70 per cent of Caucasians) 9,22, and antirh" (positive in 30 per cent of Caucasians) 10,23. As in the case of the three Rh agglutinins, one must postulate the existence of three Rh factors instead of only one, namely, Rh 0, Rh' and Rh". The Rh' and Rh" factors are on about an equal

5 BH BLOOD TYPES 237 plane serologically and genetically, while Rh 0 holds a special position 10. Factor Rh 0 is also the most important of the three Rh factors in clinical medicine, since antigenically it is by far the strongest in human beings and therefore the usual cause of Rh sensitization, while Rh' and Rh" are responsible for reactions in only a small percentage of the clinical cases. 15 These concepts are illustrated diagrammatically in Figure 4, in which the head represents the Rh 0 factor, while the right and left hands represent factors Rh' and Rh", respectively; the corresponding agglutinins are represented by a hat and a pair of gloves. If one were to consider only the reactions of the antirh' and antirh" serums, there would be four possible Rh types which would be analogous serologically and genetically to the four blood groups. 10 But when the reactions of the anti Rh 0 agglutinin also are taken into account, the number of possible Rh types is increased to eight, so that the resulting scheme of Rh types is double that of the blood groups 24 ' 16 (figure 5). The antibodies, antirh 0, antirh' and anti Rh", are not preformed in the normal human individual, but are only potentially present when the corresponding factors are lacking from the erythrocytes. The situation is somewhat comparable to that which exists in newborn infants with regard to the four blood groups. To indicate that the Rh antibodies are only potentially present, the outlines of the hat and gloves in Figure 5 have been made with interrupted lines rather than solid lines. As shown in the figures, Rhnegative individuals do not possess any of the Rh antigens in their erythrocytes, and therefore may potentially become sensitized against all three factors, Rho, Rh', and Rh". Also, type Rhi individuals have factors Rh 0 and Rh' in their erythrocytes, and potentially may form antibodies only for factor Rh". As has already been mentioned, the most potent antigen of the three Rh factors is Rh 0 and this is the most important factor clinically. All individuals whose types fall in the upper half of Figure 5 (types Rh negative, Rh', Rh", and Rh' Rh") have blood which lacks the Rh 0 factor, and for clinical purposes should therefore be considered as Rh negative; 12 the blood of such individuals will show negative results when tested with standard antirh 0 serum. When selecting donors for blood transfusion, however, individuals of types Rh', Rh" and Rh'Rh" should be considered Rhpositive, because the use of their blood for those rare individuals who are sensitized against factors Rh' and/or Rh" could cause a hemolytic reaction. From a study of Figure 5, it may be perceived that type Rhi individuals who are repeatedly transfused with type Rh 2 blood might eventually become sensitized against the Rh" factor present in the latter blood; while such cases are rare because of the poor antigenicity of factor Rh", at least one instance of this sort has been encountered by the author. 19 Similarly, type Rh 2 individuals could become sensitized by repeated transfusions of type Rhi blood. Since true Rhnegative blood (13 per cent of the Caucasian population) lacks all three Rh factors, it can be used in problems of intragroup incompatibility due to the Rh factors, just as group 0 blood is employed for universal donorblood* in the case * In fact, Rhnegative blood is safer as regards intragroup reactions based on the 8 Rh blood types than is group O blood with respect to intergxonp reactions, since group O blood occasionally contains dangerously high titers of isoagglutinins antia and antib.

6 1. : * A. S. WIENER H,','! 1 > /" L \ ^ ^y^.** y ^ s ^!c» ci "J 1 v ? a:,0 % /! 5? *«4, c or r* "irj; \r=

7 RH BLOOD TYPES 239 of the four blood groups. 12 For example, a type Rhi individual sensitized to Rh 2 blood may be transfused either with type Rhi or Rhnegative blood, just as group A individuals may be given either group A or group 0 blood. In addition to the three Rh factors, other blood factors have been discovered which are intimately related to the Rh blood types, namely, the socalled Hr factors. To explain the nature of the Hr factors, it is first necessary to present briefly the mechanism of inheritance of the eight Rh blood types. It has been shown (Wiener 11 ) that the three Rh factors occur in various combinations in human blood due to the existence of five principal Rh agglutinogens, namely, Rho, Rh', Rh", Rh]. (an agglutinogen consisting of factors Rh' and Rh 0 in combination) and Rh 2 (an agglutinogen consisting of factors Rh 0 and Rh" in combination). To account for these five agglutinogens and their hereditary transmission, it is necessary to postulate the existence of a series of at least six*allelic genes, Rho, Rh', Rh", Rhi, Rh 2 and rh (the last being the recessive gene, determining the Rhnegative TABLE 1 THE EIGHT Rh TYPES AND THEIR GENOTYPES Rh TYPES GENOTYPES Neg Rh' Rh" Rh'Rh" Rh 0 Rh,(Rho) Rh 2 (Rho) Rh!Rh 2 (RhoRho'). rhrh Rh'Rh' and Rh'rh Rh"Rh" and Rh"rh Rh'Rh" RhoRho and Rh 0 rh RhRhi, RhiRh', Rh x rh, RhiRho and Rh'Rh 0 Rh 2 Rh 2, RhiRh", Rh 2 rh, Rh 2 Rh 0, and Rh"Rh RhiRhi, RhiRh", and Rh'Rh type). Since every individual has two genes from every allelic series of genes, one derived from the paternal parent and the other from the maternal parent, the six genes in combination give rise to 21 possible genotypes, which correspond to the eight Rh blood types as shown in table 1. In this discussion, we have taken into account the ability or inability of the various Rh genes to cause the formation of Rh factors; e.g., gene rh is incapable of determining any Rh factor, gene Rhi conveys the ability to form agglutinogen Rhi composed of the two Rh factors Rh 0 and Rh', etc. As Fisher 7 was the first to point out, it seems that while each of the six Rh genes determines the formation of a different agglutinogen, every agglutinogen is really composed of three factors. According to this concept, if an agglutinogen lacks any of the factors Rho, Rh 1 and/or Rh", it has in its place another contrasting factor. Thus, three such contrasting factors are theoretically possible, which may be designated 13 * 17 as Hr 0, Hr' and Hr", respectively, and the six agglutinogens determined by the six standard allelic Rh genes can then be represented as shown in Figure 6. As has just been pointed out, each person's Rh type depends on his genotype *For the sake of simplicity, no attempt is made in this discussion to include the genes Rh y and Rhi of Race and Taylor, 6 or Wiener's socalled intermediate genes. 14

8 A. S. WIENER rh Rh c Rh" Rh, (RK) \Rh. Rh* Rhg Hf\ FIG. 6. SYMBOLIZATION OF THE SIX STANDARD Rh GENES

9 BH BLOOD TYPES 241 as determined by a pair of genes, one derived from the father and the other from the mother. The 21 possible Rh genotypes can now be fully represented with the aid of Figure 6, by using a male torso for the gene contributed by the paternal parent and a female torso for the gene contributed by the female parent. For example, the Rhnegative type of blood (genotype rhrh) is not agglutinable by any of the three Rh antisera, but contains all three Hr factors, Hr', Hr" and Hro (table 2). Type Rh' reacts with antisera for Rh', Hr" and Hr 0 ; the two genotypes Rh'Rh' TABLE 2 SEROLOGICAL REACTIONS OF THE VARIOUS Rh BLOOD TYPES AND GENOTYPES Rh BLOOD TYPES GENOTYPES REACTIONS WITH Rh ANTISERA Rh' Rh" Rho REACTIONS WITH Hr ANTISERA Hr' Hr" Hro Negative rhrh Rh' Rh" Rh'Rh" Rh'Rh' Rh'rh Rh"Rh" Rh"rh Rh'Rh" Rh 0 Rhi Rh 2 RiuRha RhoRho Rh 0 rh Rhtfhi RhxRh' Rhirh RhiRho Rh'Rho RhzRhz Rh 2 Rh" Rh^rh RhzRho Rh"Rh 0 RhiHh^ RhiRh" Rh'Rh 2 1 ' and Rh'rh can be differentiated by the fact that the former is not agglutinated by antihr' serum while the latter is agglutinated. Similarly, homozygous and heterozygous type Rh" blood could be differentiated with the aid of antihr" serum. In fact, if all three Hr antisera were available as well as the three Rh antisera, 15 of the 21 theoretically possible genotypes could be recognized directly, leaving only three pairs which could not be distinguished, Rhirh and Rh'Rho, Rh 2 rh and Rh"Rh<,, and RhiRh" and Rh'Rh. In practice, however, the

10 242 A. S. WIENER situation is not quite so simple because there are actually more than six genes in the Rh allelic series, and besides only one of the three theoretically possible Hr antisera is available at the present time. The original description by Levine and Javart 4 of the properties of an irregular agglutinin in the serum of an Rhpositive mother of an erythroblastotic infant were somewhat vague due to the low potency of the serum they used. They reported that this serum gave 30 per cent positive reactions, agglutinating all Rhpositive bloods which failed to clump in antirh' serum and also all Rhnegative bloods. Because of the latter property, the factor detected by this antiserum was designated Hr by Levine. When under similar circumstances, Race and Taylor 8 later found an agglutinin which also clumped all Rhnegative bloods but gave a total of 80 per cent positive reactions, they thought that the antibody in their serum, designated antist after the first two letters of the patient's name, was different from Levine's antihr. The British workers then suggested that antist corresponded to antihr', while Levine's antihr corresponded to antihr 0. Wiener 20 has shown, however, that the socalled antist and Levine's antihr are the same agglutinin, the difference in percentage of positive reactions being due to the low potency of Levine's antiserum, so that heterozygous bloods failed to agglutinate. Thus, the Hr antiserums found by the British workers and Levine, as well as three serums* tested by the author, all corresponded in specificity to antihr'. Recently, a serum was encountered by Mourant, 6 which gave reactions corresponding to antihr", but to date no serum has been found corresponding to antihr 0. SUMMARY A diagrammatic representation is offered to enable one to learn and remember the relationships among the various Rh blood types and genotypes and the Hr factors. REFERENCES 1. FISK, R. T., AND FOORD, A. G.: Observations on the Rh agglutinogen of human blood. Am. J. Clin. Path., 12: 545, LANDSTEINER, K., AND WIENER, A. S.: An agglutinable factor in human blood recognizable by immune sera for rhesus blood. Proc. Soc. Exper. Biol, and Med., 43:223, LANDSTEINER, K., AND WIENER, A. S.: Studies on an agglutinogen of human blood (Rh) reacting with antirhesus sera and human isoagglutinins. J. Exper. Med., 74: 309, Cited by LEVINE, P., BURNHAM, L., KATZIN, E. M., AND VOGEL, P.: The r61e of isoimmunization in the pathogenesis of erythroblastosis fetalis. Am. J. Obst. andgynec, 42: 925, MOURANT, A. E.: A new rhesus antibody. Nature, 155: 542, MURRAY, J., RACE, R. R., AND TAYLOR, G. L.: Serological reactions caused by the rare human gene Rh z. Nature, 155: 112, Cited after RACE, R. R.: An "incomplete" antibody in human serum. Nature, 153:771, RACE, R. R., AND TAYLOR, G. L.: A serum that discloses the genotype of some Rhpositive people. Nature, 152: 300, * One serum was studied with Dr. Davidsohn and Dr. Potter, 20 the other two serums were studied with Dr. Peter Vogel.

11 KH BLOOD TYPES WIENER, A. S.: Hemolytic reactions following transfusions of blood of the homologous group. II. Further observations on the role of property Rh, particularly in cases without demonstrable antibodies. Arch. Path., 32: 227, WIENER, A. S.: Distribution and heredity of variants of Rh. Science, 98: 182, WIENER, A. S.: Genetic theory of the Rh blood types. Proc. Soc. Exper. Biol, and Med., 54: 316, WIENER, A. S.: Rdle of the subtypes of Rh in hemolytic transfusion reactions and in erythroblastosis. Am. J. Clin. Path., 14: 52, WIENER, A. S.: Nomenclature of the Rh blood types. Science, 99: 532, WIENER, A. S.: The Rh series of allelic genes. Science, 100: 595, WIENER, A. S.: The Rh blood types and some of their applications. Am. J. Clin. Path., 15: 106, WIENER, A. S.: Competition of antigens in isoimmunization by pregnancy. Proc. Soc. Exper. Biol, and Med., 58: 133, WIENER, A. S.: Theory and nomenclature of the Hr blood factors. Science, 102: 479, WIENER, A. S.: Rh factors in clinical medicine. J. Lab. and Clin. Med., 30: 957, WIENER, A. S.: Unpublished observations. 20. WIENER, A. S., DAVIDSOHN, I., AND POTTER, E. L.: Heredity of the Rh blood types. II. Observations on the relation of factor Hr to the Rh blood types. J. Exper. Med., 81: 63, WIENER, A. S., AND KAROWE, E.: Diagrammatic representation of the human blood group reactions. J. Immunol., 49: 51, WIENER, A. S., AND LANDSTEINER, K.: Heredity of variants of the Rh type. Proc. Soc. Exper. Biol, and Med., 53: 569, WIENER, A. S., AND SONN, E. B.: Additional variants of the Rh types demonstrable with a special human antirh serum. J. Immunol., 47: 461, WIENER, A. S., SONN, E. B., AND BELKIN, R. B.: Heredity and distribution of the Rh blood types. Proc. Soc. Exper. Biol, and Med., 54: 238, WIENER, A. S., SONN, E. B., AND BELKIN, R. B.: Heredity of the Rh blood types. J. Exper. Med., 79: 235, 1944.

THE Rh BLOOD FACTOR; AN ANTIGENIC ANALYSIS* I. DAVIDSOHN AND B. TOHARSKY

THE Rh BLOOD FACTOR; AN ANTIGENIC ANALYSIS* I. DAVIDSOHN AND B. TOHARSKY From the Department of Pathology, ount Sinai Hospital, Chicago, Illinois Landsteiner and Wiener discovered in 94 the existence of