Genesis of ABO blood group system
The ABO system discovered by Landsteiner in 1901 is clinically most significant and is of great importance in transplantation immunology and transfusion medicine. The ABO grouping is the single most important serological test performed in compatibility testing. It is a major blood group system with enormous diversity consisting of three carbohydrate antigens (A, B and H) under the control of A & B genes (of 175 alleles) present on the chromosome 9. The organ/tissue transplantation and blood transfusion depends on the successful matching of these blood groups. These antigens are widely distributed and are present not only on RBCs and platelets but also on endothelial cells of various tissues in human body. An interesting co-evolutionary relationship exists between the ABO blood group system and the useful microbial flora (bacteria) in human body.
As far as their development is concerned, the A and B antigens are produced by the addition of N-acetylgalactosamine (UDP-GalNAc) and galactose (UDP-Gal), respectively, to a common acceptor substrate called as H substance or antigen already present on the RBC membrane. The H substance is made by the enzyme H transferase by adding a fucose residue to a terminal galactose. It is important to mention that H antigens are secondarily adsorbed onto RBCs from the plasma and are actually synthesized by fucosyl transferase enzyme, the products of Lewis blood group system present on exocrine epithelial cells.
The biosynthesis of A and B antigens is catalysed by two enzymes called as alpha-1-3-N-acetylgalactosaminyltransferase A and alpha 1-3-galactosyltransferase A & B, the products of the A and B alleles of ABO system. It is the presence or absence of these two enzymes which determine the blood group of a particular individual with A, B or AB blood group. Individuals with blood group O lack such activity because the O allele produces no active transferase (enzyme), hence no antigen on RBC membrane.
The blood type of an individual ultimately depends on the blood type received from the parents as per its inheritance pattern. The negative and positive blood type develops depending on the presence or absence of other factors in the blood called as Rh Factors. Therefore, the generation and integrity of ABO blood group system is dependent on two additional systems- the Lewis system and the gut microbial system.The gut microbial system provides the similar antigenic determinants as of the ABO system to assist in the generation of natural antibodies by B lymphocytes against non-RBC A & B antigens to maintain the integrity of the ABO blood group system.
Due to the combined action of these three systems (the ABO system, the Lewis system and the Microbial system), four main blood groups with variable frequency in different populations (A, B, AB & O) in the human ABO system are created depending upon the genotype of the individual. Blood group A has A antigens called as agglutinogens on the RBCs with anti-B antibodies in the serum capable of agglutinating the agglutinogens of B type. Blood group B has B antigens with natural anti-A antibodies in the serum. Blood group O has no antigens, but both anti-A and anti-B natural antibodies in the serum. Blood group AB has both A and B antigens, but no natural antibodies in the serum. The presence of natural antibodies pre-existing in the serum of naive healthy individuals directed against A and B allo-antigens that are not expressed on the individual’s RBCs before blood transfusion or tissue/ organ transplantation looks quite surprising and interesting too.
It is an established immunological fact that an antigenic exposure is essential for the production of a specific antibody within the body. Now, the question is: in the absence of a particular antigen on the RBC membrane in the body, how is a natural antibody produced against this?
The beauty of the useful gut microbial system is that the antibodies against absent blood group ABO antigens (autologous) are naturally produced by exposure to similar antigenic determinants (as of the AB blood groups) expressed on a variety of bacteria of the normal gut flora (allo ABO antigens). This is a typical case of molecular mimicry wherein the antigenic determinants of some microorganisms resemble the antigenic determinants of blood group A and B antigens and assist our body in natural antibody production. For example, an individual with blood group A will recognize B like antigenic determinants on normal gut bacteria and produce natural antibodies to B like antigenic determinants. This same individual will not respond to A like determinants on same microbes, because these A like epitopes are too similar to self and a state of self-tolerance develops. Because of this reason, the serum of healthy individuals contains natural antibodies only against those blood groups A or B antigens that are not expressed on the individual’s RBCs. (Thanks to the molecular mimicry exhibited by the microbiota). These ABO antigens are present in the fetus as early as 5-6 weeks gestation but are not fully expressed until 2–4 years of age. ABO antibodies at the birth of a child are antibodies from the mother that have crossed the placenta into the fetal circulation. The infant’s own antibodies generally develop at 3-6 months of age but may also take as long as a year. Full adult antibody levels are reached at 5-10 years of age.
The biosynthesis of A and B antigens is catalysed by two enzymes called as alpha-1-3-N-acetylgalactosaminyltransferase A and alpha 1-3-galactosyltransferase A & B, the products of the A and B alleles of ABO system. It is the presence or absence of these two enzymes which determine the blood group of a particular individual with A, B or AB blood group. Individuals with blood group O lack such activity because the O allele produces no active transferase (enzyme), hence no antigen on RBC membrane.
The blood type of an individual ultimately depends on the blood type received from the parents as per its inheritance pattern. The negative and positive blood type develops depending on the presence or absence of other factors in the blood called as Rh Factors. Therefore, the generation and integrity of ABO blood group system is dependent on two additional systems- the Lewis system and the gut microbial system.The gut microbial system provides the similar antigenic determinants as of the ABO system to assist in the generation of natural antibodies by B lymphocytes against non-RBC A & B antigens to maintain the integrity of the ABO blood group system.
Due to the combined action of these three systems (the ABO system, the Lewis system and the Microbial system), four main blood groups with variable frequency in different populations (A, B, AB & O) in the human ABO system are created depending upon the genotype of the individual. Blood group A has A antigens called as agglutinogens on the RBCs with anti-B antibodies in the serum capable of agglutinating the agglutinogens of B type. Blood group B has B antigens with natural anti-A antibodies in the serum. Blood group O has no antigens, but both anti-A and anti-B natural antibodies in the serum. Blood group AB has both A and B antigens, but no natural antibodies in the serum. The presence of natural antibodies pre-existing in the serum of naive healthy individuals directed against A and B allo-antigens that are not expressed on the individual’s RBCs before blood transfusion or tissue/ organ transplantation looks quite surprising and interesting too.
It is an established immunological fact that an antigenic exposure is essential for the production of a specific antibody within the body. Now, the question is: in the absence of a particular antigen on the RBC membrane in the body, how is a natural antibody produced against this?
The beauty of the useful gut microbial system is that the antibodies against absent blood group ABO antigens (autologous) are naturally produced by exposure to similar antigenic determinants (as of the AB blood groups) expressed on a variety of bacteria of the normal gut flora (allo ABO antigens). This is a typical case of molecular mimicry wherein the antigenic determinants of some microorganisms resemble the antigenic determinants of blood group A and B antigens and assist our body in natural antibody production. For example, an individual with blood group A will recognize B like antigenic determinants on normal gut bacteria and produce natural antibodies to B like antigenic determinants. This same individual will not respond to A like determinants on same microbes, because these A like epitopes are too similar to self and a state of self-tolerance develops. Because of this reason, the serum of healthy individuals contains natural antibodies only against those blood groups A or B antigens that are not expressed on the individual’s RBCs. (Thanks to the molecular mimicry exhibited by the microbiota). These ABO antigens are present in the fetus as early as 5-6 weeks gestation but are not fully expressed until 2–4 years of age. ABO antibodies at the birth of a child are antibodies from the mother that have crossed the placenta into the fetal circulation. The infant’s own antibodies generally develop at 3-6 months of age but may also take as long as a year. Full adult antibody levels are reached at 5-10 years of age.
This article appeared in Kashmir Reader on March 21,2018
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