Blood group systems
Blood groups or blood types are the classification of blood based on the presence and absence of antigens on the surface of RBCs. Currently, there are a total of 43 human blood group systems that have been recognized by the International Society of Blood Transfusion (ISBT). The major blood grouping systems have been discussed below:
1. ABO system
The ABO blood grouping system is the classification of human blood into different groups (A, B, AB, and O) based on the presence or absence of A and B antigens on the surface of RBCs. The ABO blood groups were discovered by an Austrian immunologist Karl Landsteiner in 1901 who noticed that blood from different individuals sometimes agglutinates (forms clumps) when mixed together.
The ABO blood grouping is the most clinically significant system. During a blood transfusion, it is important that the blood group of donor is compatible with the recipient. Receiving blood from the wrong group can be potentially fatal. Example: If an individual with blood group B is transfused with group A blood, the anti-A antibodies of the recipient will attack the donor red blood cells triggering an immune response that can be life threatening.
Formation of A and B antigens
All RBCs have oligosaccharide precursor on their surface. An enzyme called fucosyltransferase (FUT1) transfers a fucose molecule to the oligosaccharide, resulting in the formation of H antigen. The H antigen can be further modified to A or B antigens (Blood group A/B/AB) or remain unmodified (Blood group O). The addition of N-Acetylgalactosamine on H antigen results in A antigen, whereas the addition of Galactose on H antigen results in B antigen.
✏️ Bombay Phenotype
The ‘Bombay phenotype’ is a rare blood group that lacks H antigen on their RBCs. It is named after the city where it was first discovered and is found in 1 of 10,000 individuals in India. A functional copy of FUT1 gene (H/H or H/h) is required for the synthesis of fucosyltransferase and formation of H antigen. The presence of homozygous recessive alleles (h/h) of FUT1 gene leads to inability in synthesis of fucosyltransferase, resulting in absence of H antigen. Individuals with Bombay phenotype produce antibodies against A, B and H antigens. Therefore, they can only receive blood from other Bombay phenotype donors.
✏️ Secretor vs Non Secretor
People are classified as secretors or non-secretors depending on whether they secrete ABO antigens in their body fluids other than blood like saliva, tears, breast milk, urine, and semen. Individuals who secrete these antigens in their body fluids are called secretors, while those who no not are called non-secretors. Secretor status is determined by FUT2 gene, also known as Se gene. The Se gene encodes the enzyme fucosyltransferase which controls the formation of H antigen in bodily secretions. An individual must inherit at least one functional copy of Se gene (Se/Se or Se/se) to express the secretor phenotype. Non-secretor is a recessive trait determined by se/se genotype.
Inheritance of ABO Blood groups
Humans inherits two copies of every gene, one from each parent. The inheritance of human blood group is controlled by the gene ‘I’ that has three allelic forms: IA, IB, and i. The allele IA and IB are co-dominant and i is recessive.
The allele IA codes for an enzyme ‘transferase A’ (also known as N-Acetylgalactosaminyl transferase) that carries out the transfer of N-Acetylgalactosamine on H antigen, in turn producing A antigen. An individual must have at least one functional copy of IA allele for the synthesis of A antigen i.e. they must inherit IA from at least one of their parents. Similarly, an individual must have at least one functional copy of IB that codes for ‘transferase B’ (also known as galactosyl transferase) for synthesis of B antigen. Therefore, the genotype for blood group A would be IAIA or IAi; and the genotype for blood group B would be IBIB or IBi. If an individual inherits a copy of IA from one parent and IB from another, i.e. genotype: IAIB, the resultant blood group will be AB. On the other hand, an individual can only have blood group O if they inherit the recessive allele from both parents, i.e. genotype ii.
2. Rh system
The Rh blood group system was discovered in 1940 by Karl Landsteiner and A.S. Weiner. The scientists injected a few rabbits with the blood of rhesus monkey and observed that the RBCs of rhesus monkey agglutinated (formed clumps). Similar phenomenon was also noted with the RBCs of 85% humans. It was speculated that some humans have antigens on the surface of their RBCs that are similar to Rhesus monkey, while others do not. These antigens were called ‘Rh factors’, named after Rhesus monkey (Macacus rhesus) in which it was first discovered. The Rh system is the classification of human blood into two groups (Rh+ and Rh-) based presence or absence of Rh antigens or Rh factors on the surface of RBCs.
Rh Factors
There are currently 49 known Rh antigens among which antigen D, C, E, c and e are the most significant. D antigen is the most immunogenic of them all. If an individual who does not produce D antigen has been transfused with the donor blood that produces D antigen, the recipient will produce anti-D antibodies against the donor RBCs and cause an immune response to destroy donor RBCs. Rh+ and Rh- are terms used to describe the presence or absence of D antigen.
Rh positive (+): presence of D antigen on the surface of RBCs
Rh negative (-): absence of D antigen on the surface of RBCs
Rh null: absence of D, C, E, c and e antigens on the surface of RBCs
Using the Rh system in combination with ABO blood grouping system results in eight blood groups: A+, B+, O+, AB+, A-, B-, O-, and AB- that are cross-matched between donor and recipient before blood transfusion in clinical practices.
The inheritance of Rh factor is controlled by two alleles, the dominant Rh+ allele and the recessive Rh- allele. Individuals with ‘Rh positive’ blood type must inherit at least one Rh+ allele. Their genotype could be either Rh+/Rh+ or Rh+/Rh-. Individuals can only have the ‘Rh negative’ if they are homozygous for the recessive allele (i.e. they have inherited Rh- allele from both their parents), resulting in the genotype of Rh-/Rh-.
Rh Incompatibility
Rh incompatibility can be encountered during pregnancy if the mother is Rh negative and the fetus is Rh positive.
Usually, your blood doesn't mix with your baby's blood during pregnancy. However, a small amount of your baby's blood could come in contact with your blood when the baby is born. It can also happen if you have bleeding or trauma to your abdomen during pregnancy.
If you're Rh negative and your baby is Rh positive, your body might produce proteins called Rh antibodies if your blood and the baby's blood mix. Those antibodies aren't a problem during the first pregnancy. But problems can happen if you become pregnant again.
If the second baby is also Rh positive, the already formed Rh antibodies can cross the placenta and destroy the RBCs of the foetus, leading to life-threatening anaemia. Rh negative pregnant patients undergo regular antibody screening to detect the presence of Rh antibodies. Patients that are at risk of producing Rh antibodies are usually injected with Rh immune globulin that inhibits its production.
Expression of Rh antigens
Expression of the common Rh antigens is controlled by two genes: RHD and RHCE. The RHD gene encodes for D antigen and RHCE gene encode the C/c and E/e antigens. The Rh antigens are present on Rh proteins: RhD (carrying the D antigen) and RhCE (carrying the C/c and the E/e antigens). Both RhD and RhCE are multi-pass transmembrane proteins of the RBC membrane.
3. MNS system
After the discovery of ABO blood groups, Karl Landsteiner and Philip Levine continued their experiments on blood groups and discovered the second blood group system, MN in 1927. 20 years later in 1948, the S and s antigens were identified and the blood group system was renamed to MNS system. Presently (till 2019), there are 49 known antigens in this blood group, but M, N, S, s and U antigens are the most significant.
These antigens are present on Glycophorins, which are carbohydrate containing protein present on the surface of RBCs. The antigen ‘M and N’ are present on glycophorin A (GPA), and antigen ‘S, s and U’ are present on glycophorin B (GPB). These antigens are encoded by two genes known as GYPA (encodes for glycophorin A) and GYPB (encodes for glycophorin B).
Inheritance of MNS blood groups
The MNS blood grouping system has two pair of co-dominant alleles: M and N; S and s. The ‘U’ allele is universal allele, i.e. it is present in 99.9% of the population.
M and N antigens: Glycophorin A can either have the expression of antigen M (M+N-), antigen N (M-N+), or both antigens M and N (M+N+). The rare cases in which an individual does not have either M or N antigen (M-N-) can only occur when they lack glycophorin A on their RBCs.
S, s and U antigens: Glycophorin B can either have the expression of antigen S (S+s-), antigen s (S-s+), both S and s (S+s+), or none (S-s-). Antigen U is located near the base of glycophorin B, and is always present. The cells cannot express ‘S or s’ without the presence of antigen U. Therefore, the above mentioned ‘S+s-’, ‘S-s+’, ‘S+s+’, and ‘S-s-’ are actually ‘S+s-U+’, ‘S-s+U+’, ‘S+s+U+’, and ‘S-s-U+’. Since, U is an universal antigen, its presence is not required to be mentioned. The U antigen is only mentioned in the rare cases in which an individual does not have the U antigen (s-s-U-), which can only occur when an individual lacks glycophorin B on their RBCs.
The absence of all the antigens (M-N-S-s-U-) indicates the absence of both glycophorin A and glycophorin B on the surface of RBCs.
4. Kell system
The Kell blood group system was discovered in 1946. It was named after Mrs. Kelleher, a patient whose anti-K antibodies caused her newborn child to develop hemolytic disease. The infant's RBCs expressed K antigen, while the mother’s RBCs did not. The incompatibility between the blood types of the mother and baby, resulted in destruction of the child’s RBCs by the anti-K antibodies in mother’s serum.
Since then, a total of 39 Kell antigens have been discovered (till 2019) that expressed in different frequencies in different populations. However, the main antigens of the Kell blood group system are: K, k, Kpa, Kpb, Kpc, Jsa, and Jsb. The K antigen is more effective at triggering an immune reaction among all the Kell antigens. After the ABO and Rh antigens, the K antigen is the most immunogenic and one of the most clinically relevant antigens.
Inheritance of Kell antigens
Kell antigens are present on a single pass glycophorin (called Kell glycophorin) containing three main antigenic sites: K/k, Kp (a/b/c), and Js (a/b). Site 1 can either have the antigen K or k; site 2 can either contain Kpa, Kpb or Kpc; and site 3 can either contain Jsa or Jsb. The Kell antigens are encoded by the KEL gene. (Note: Humans are diploid organisms with two copies of each gene, one inherited from each parent).- Most individuals contains both copies of the non-mutated form of the KEL gene (i.e. KEL/KEL) that results in the formation of high frequency antigens k, Kpb, and Jsb at the three antigenic sites.
- Some individuals can have one copy of the non-mutated allele with one copy of mutated allele (i.e. KEL/K or KEL/Kpa or KEL/Kpc or KEL/Jsa). This will result in the formation of all the high frequency antigens with ONE low frequency antigen. The resulting phenotype will either be k, K, Kpb, Jsb or k, Kpa, Kpb, Jsb or k, Kpb, Kpc, Jsb or k, Kpb, Jsa, Jsb, depending on which mutated allele is inherited.
Ko or K null phenotype: It is a rare phenotype that lacks all the Kell antigens on the surface of their RBCs. Individuals with Ko phenotype produce an antibody called ‘anti-Ku’, that reacts with all red blood cells except other Ko cells. This makes it incredibly challenging to get compatible blood for patients with Ko phenotype.
5. Duffy system
The Duffy blood group system was discovered in 1950, and named after the patient in which it was discovered. A total of 6 antigens are present in the Duffy blood group system: Fya, Fyb, Fy3, Fy4, Fy5, and Fy6. But, Fya and Fyb are the most clinically significant.
Inheritance of Duffy antigens
The Duffy antigens are glycoproteins present on the surface of RBCs. These antigens differ in the sequence of amino acids that makes up the glycoprotein. the duffy glycoprotein is encoded by the FY gene which has two main co-dominant alleles: FYA and FYB.
There are four main duffy phenotypes: Fy(a+b-), Fy(a-b+), Fy(a+b+), and Fy(a-b-).
If an individual has inherited two functional copies of FYA (one from each parent), the resultant phenotype would be Fy(a+b-). Similarly, if an individual has inherited two functional copies of FYB, the phenotype would be Fy(a-b+). Alternatively, an individual can have one functional copy of FYA and other copy of FYB, resulting in Fy(a+b+) phenotype. On the other hand, individuals with the Fy(a-b-) phenotype (also known as the duffy null phenotype) have inherited two non-functional copies of the alleles FYA and FYB.
Malaria resistance of Duffy null: The duffy glycoprotein is also the receptor for two malaria causing parasites: Plasmodium vivax and Plasmodium knowlesi. These parasites invades the human RBCs through the duffy glycoprotein. The duffy null phenotype individuals i.e. Fy(a-b-) do not express duffy antigens on the surface of their RBCs and are therefore resistant to malaria caused by Plasmodium vivax and Plasmodium knowlesi.
6. Kidd system
The Kidd blood group system was discovered in 1951, when a patient called Mrs. Kidd was found to have produced antibodies targeted against some antigens on the RBCs of her foetus, resulting in destruction of RBCs of the newborn. Currently, three antigens have been identified in the Kidd blood group system: Jka (or Jk1), Jkb (or Jk2) and Jk3. The antigens ‘Jk’ were named after the initials of the baby ‘John Kidd’. The Kidd antigens (also known as Jk antigens) are glycoproteins that act as a urea transporter, and are present on surface of RBCs as well as renal endothelial cells.
Inheritance of Kidd blood groups
The inheritance of Kidd blood groups is controlled by the co-dominant alleles Jka and Jkb; and the silent allele JK. An individual can either inherit at least one functional copy of JKa, at least one functional copy of Jkb, one functional copy of Jka along with a functional copy of Jkb, or two copies of the silent allele Jk.
The four possible Kidd phenotypes are: Jk (a+b-), Jk (a+b+), Jk (a-b+), and Jk (a-b-). The antigen Jk3 is present in all individuals except Jk (a-b-). The rare phenotype Jk (a-b-), also known the ‘Jk null phenotype’ do not contain Jka, Jkb, or Jk3 antigens. Individuals with the Jk null phenotype can produce anti-Jk3 antibodies and cause hemolysis of the donor RBCs that contain either Jka or Jkb antigens.