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In 1900, Karl Landsteiner has developed the ABO system of blood by discovering three blood groups, viz. 'A', 'B' and 'O', that are responsible for acute hemolytic reaction seen in mismatched blood transfusion. Later on in 1902, his students discovered the forth group which was the 'AB'. Today, the blood group matching of the donor and the recipient is essential foundation of the pre-transfusion testing because transfusion of even 10-15 ml of incompatible blood can trigger a life-threatening hemolytic reaction.
ABO System of Blood Groups
The ABO system of blood groups is depends on the existence or lack of three main antigens, viz., 'A', 'B' and 'H' on the red blood cell membrane. The three antigens are oligosaccharide units, attached to either a sphingolipid (ceramide) or a protein, thus forming a glycolipid or a glycoprotein, respectively. Morgan and Watkins (1969), and Kabat et al. (1973) established the antigenic structures responsible for the specificity of blood group A, B and H. The three oligosaccharides have very subtle but immunopotent differences. The basic oligosaccharide unit is a tetra-saccharide which, after taking up a fucose, makes the 'H-substance' and is responsible for the 'O' blood group. Attachment of an N-acetylgalactosamine to the terminal galactose in H-substance transforms it into the 'A' antigen; whereas substitution with a galactose makes the 'B' antigen (Fig. 1).
Fig. 1: Basic structures of ABO antigens
A number of RBC membrane proteins have been implicated as carriers of the blood group determinant oligosaccharide (Hakamori 1999), these include band 3 and band 4.5 glycoproteins. Donald (1981) discovered a short chain trisaccharide (Gail11C3GalNAc) linked to the transmembrane protein 'glycophorin', this glycoprotein could also be an ABH carrier.
Hakamori (1999) studied the red cell membrane glycosphingolipids (GSL) and reported that the ABO oligosaccharide may be composed of different types of chains depending upon the type of glycosidic linkages and branched or unbranched structure. Type 2 chains are most common among ABO antigens, whereas Type 1 chains are more common in other tissues.
Synthesis of ABO antigens
The antigen specificity of an individual develops during 5-6 weeks of the embryonic life when ABO antigen can be detected on the surface of the red cells. Watkins (1980) and Kobata et. al. (1970), clarified the enzymatic basis for synthesis of the blood group antigenic determinants. The H-substance is expressed on the red cell membranes during the earlier stages of development and is modified to A or B antigens with the help of two specific transferase enzymes. The N-acetylgalactosaminyltransferase enzyme, known as 'A-enzyme', coverts the H-substance into A-antigen by transferring an N-acetylgalactosamine residue from UDP-N-acetylgalactosamine to its terminal galactose. The blood group of the individual thus becomes 'A'. Similarly, the 'B-enzyme' (a galactosyl transferase) transfers a galactose from a molecule of UDP-galactose to the H-substance galactose thus transforming the blood group specificity to 'B'. Absence of both the transferases leaves the H-substance galactose open and confers blood group 'O' specificity. The development of the blood group specificity is, thus, dependent upon the expression of the either (or none) of the two transferases.
Genes and inheritance of ABO antigens
The molecular basis of the antigenic diversity of ABO system was elucidated by Yamamato et. al. (1990). The gene for the glycosyltransferase enzymes resides on chromosome 9 on a position known as ABO locus. The genes for H-substance are present on chromosome 19.
AB alleles - There are mainly three alleles responsible for A and B antigens, viz. A1, A2 and B. A1 and A2 - code for the enzyme N-acetylgalactosamine transferase. While B codes for the enzyme galactosyl transferase. The H-substance is must be present for the formation of A or B antigens. The addition of GalNAc or Gal units takes place only if the H-substance has a fucose unit attached to the terminal galactose.
H/h alleles - The H gene on chromosome 19 shows two allele, H and h. The H allele codes for the enzyme L-fucosyltransferase that adds fucose residues to the basic unbranched H-substance. On the other hand, h gene is an amorph and does not code for the enzyme. Presence of at least one H gene is essential to produce mature H-substance and hence O antigen. Inheritance of 'hh' genotype results in a condition in which the individuals lack H-antigen; this phenotype is known as Bombay phenotype (very rare type).
The Rh system of blood group was first explained in year 1940 by Landsteiner and Wiener, when they found that serum from rabbits and guinea pigs immunized with red blood cells of Macacus rhesus could agglutinate 85% of the blood from New York blood donors. The heteroantibody responsible for the agglutination was renamed anti-LW proportion to Landsteiner and Wiener, whereas human alloantibody was called anti-D (Levine et al. 1963).
The system is based on three pairs of common types of Rh antigens called as Rh factor. These antigens are designated D-d, C-d and E-e. The D antigen is much more prevalent in the population and is highly antigenic, presence of 'D' makes the individual positive whereas absence will make Rh negative. There is no 'd' antigen and the letter denotes absence of D antigen. Although Rh system is recognized by DdEeCc antigens, there are at least 45 antigens discovered so far that make the Rh system. The agglutination / hemolytic reactions due to other antigens are milder and hence are not important clinically.
Rh positive individuals are much more (85%) common than Rh negative (15%) in the world. The Rh system appears to have originated from Africa since all Africans blacks are Rh positive.
Structure of Rh Antigens
The Rh system of the blood is the most polymorphic of the human blood groups. The Rh antigen complex on the surface of red cells is formed of two major components, Rh antigens and Rh-associated glycoproteins (RhAG). Presence of RhAG is must for the expression of Rh antigens on the membrane. The proteins Rh and RhAG have ~40% structural homology and collectively termed as Rh protein family. Rh and RhAG proteins have 12 transmembrane spans (Huang 1998), N-terminus and C-terminus supporting the cytoplasm (Figure 2).
Figure 2: Model of topology for RhAG, RhCE, and RhD (Avent and Reid 2000).
Rh protein family
The size of Rh complex has been estimated to be ~170 kDa and consists of a tetramer of two RhAG proteins with two Rh antigen proteins (RhCcEe or RhD). Characteristics of the RhD protein and of the RhCcEe protein are depicted in Fig. 2 and summarized in Table 1.
Table 1: The Rh Complex proteins in Normal red blood cell Membranes (Avent and Reid 2000)
Rh protein family
Ce, CE, ce, cE
Carries MB2D10 epitope
Rh accessary proteins
N, S, s, U
Comparison of ABO and Rh systems
ABO and Rh are the two most important systems used in transfusion medicine; the ABO as well as the Rh of the donor and recipient of the blood transfusion must be matched.
ABO system is also important for the tissue transplants since these antigens are also present on the other tissues cells. The Rh system, on the other hand is more important in materno-fetal situations as discussed below.
Structures of antigens in two systems
ABO antigens, as discussed above, are oligosaccharides attached to sphingolipids or glycoproteins. The Rh antigens on the other hand are complex aggregates of transmembrane proteins.
Inheritance of ABO and Rh blood groups
The inheritance pattern of the two types of blood group system (Table 2) is well established and is regularly used by the clinicians and epidemiologists.
Table 2: The possible blood types of an offspring based on ABO and Rh systems.
O, A, B, AB
A, B, AB
O, A, B, AB
A, B, AB
A, B, AB
A, B, AB
A, B, AB
Rh +, Rh -
Rh +, Rh -
Rh +, Rh -
Immune response against ABO antigens
ABO oligosaccharide antigens are highly immune-potent and hence trigger the generation of antibodies. The ABO antibodies found in different blood groups are natural antibodies, i.e. they are presence in the blood even without a recognised exposure to the incompatible antigen. The ABO antibodies develop in the first 3 to 6 months after birth, continue to rise till the age of 5-6 years when their concentration becomes stable for the life, except in the old age when their levels decline (Spalter et al. 1999).
An individual with A blood group will have anti-B antibodies and vice versa; and O group individuals have antibodies that react with A as well as B antigens. Since these antibodies are being formed due to continuous stimuli of non-self antigens without any exposure to RBCs, they are called 'non-red cell stimulated antibodies'. Majority of these antibodies are IgM immunoglobulins, very small proportion is IgG.
If one blood type is transfused into a recipient who has an incompatible blood type, a transfusion reaction is likely to occur in which the RBCs of the donor blood are agglutinated. It is rare that the transfused blood causes agglutination of the recipient's cells, because the plasma, and hence antibodies, of the donor blood get diluted by the plasma of the recipient. But the recipient's agglutinins do agglutinate and hemolyse the mismatched donor cells. The red cells are phagocytosed and destroyed. The hemoglobin released from RBCs is converted into bilirubin in liver and is excreted into the intestines. Jaundice usually does not appear in an incompatible tranfusion unless >400 milliliters of blood is hemolysed in a day. The antibodies can also stimulate the complement system and release of cytotoxins that can trigger a potentially fatal anaphylactic reaction.
Immune response against Rh system
So-called "natural" antibodies to Rh do not exist in humans, as they do for the AB antigens. When RBCs containing Rh factor are mixed with or injected into an Rh-negative person, anti-Rh agglutinins develop slowly, reaching maximum concentration about 2 to 4 months later. With multiple exposures to the Rh factor, an Rh-negative person eventually becomes strongly "sensitized" to Rh factor. If a negative person has never before been exposed to Rh+ blood, transfusion of Rh-positive blood will cause no immediate reaction. However, anti-Rh antibodies can develop in sufficient quantities during the next 2 to 4 weeks to cause agglutination of the transfused cells. These cells are then hemolyzed by the tissue macrophage system. Thus, a delayed transfusion reaction occurs. On subsequent transfusion of Rh-positive blood the transfusion reaction is greatly enhanced and can be immediate and as severe as a transfusion reaction caused by mismatched type A or B blood.
Rh-incompatibility and RhoGam Therapy
The Rh factor assumes a special importance in maternal-fetal interactions. If an Rh- mother gets pregnant with a Rh+ fetus (if the father is Rh+), since there are no natural anti-Rh antibodies, this poses no special risk for the first pregnancy. At the time of delivery, a significant amount of fetal blood can get mixed with the maternal circulation; and may stimulate a strong anti-Rh response in the mother. If the same mother then bears a second Rh+ child, the existing anti-Rh antibodies can cross the placenta during the pregnancy and cause agglutination and phagocytosis of the fetal red blood cells and can cause severe damage to the vital organs. The condition is known as Hemolytic Disease of the Newborn (HDN). The production of anti-Rh antibodies in an Rh- mother can be prevented by injecting a large dose of anti-Rh antibody (Anti-D or RhoGam) into the mother within 72 hours of the birth of her Rh+ baby. These antibodies result in rapid removal of the infant's red blood cells from the maternal circulation and can greatly reduce the likelihood of sensitization of the mother's immune system.
The ABO antigens are present on cells of most of the organs of our body, and each bodily tissue has its own additional complement of antigens. Consequently, foreign cells transplanted anywhere into the body of a recipient can produce immune reactions (Warner and Nester 2006). However, unlike the A and B antigens, the Rh antigens are present only on RBCs. Therefore, while they are important for blood transfusion, they do not normally play a role in organ transplantation.
ABO Antigens and disease
The ABO blood groups also show variation in the susceptibility to certain diseases. The incidence of malaria is lesser in people with O blood group (Cserti and Dzik 2007). Similarly, incidence of tumor occurrence in blood group A individuals compared to O individuals was higher for gastric cancer and ovarian cancer, clearly higher for vulvar cancer and much higher for salivary gland cancer (Anstee 2010). The O blood group people are more susceptible to H.pilori infection.
The ABO and Rh are the two most important system of blood groups in human being. ABO antigens are oligosaccharide in nature and are attached to glycosphingolipids or glycoproteins, whereas the Rh antigens are transmembrane proteins complexes that interact with other membrane proteins. Antibodies to ABO antigens are naturally occurring and are important for blood transfusion as well as organ transplants. The Rh antibodies are provoked only after red cell exposure and are important for materno-fetal system incompatibilities.