ABO blood group antigens, as well as those of the Hh, Lewis, and Ii systems, consist of structurally related polysaccharide molecules. The antigens are formed by specific glycosyl transferases, which add, in sequence, specific sugars on oligosaccharide chains that derive from a common precursor substance. The interactions of the products of the ABO, Hh, Sese,  Se/se and Lele genes affect the expression of the ABO, H, and Lewis antigens, as well as the presence of substance A and B in body secretions.

The ABO system was discovered when Karl Landsteiner recorded the agglutination of human red cells by the sera of other individuals in 1901 and detailed the three patterns of reactivity called groups A, B, and O. He found that serum from group A individuals agglutinated the red cells from group B individuals, and conversely, the serum from group B individuals agglutinated group A. Red cells that were not agglutinated by the serum of either the group A or group B individuals were later called group O; the serum from group O individuals agglutinated the red cells from both group A and group B individuals. A year later a fourth group, named AB was described. Serum of group AB individuals did not agglutinate group A, B, and O red cells; conversely, the red cells from group AB individuals were agglutinate from group A, B, and O serum. From these observations derived two fundamental concepts in immunohematology: antibodies to A and B antigens are present when the corresponding antigen is missing and that these antibodies are almost always present in people who have had no exposure to human red cells (natural antibodies) (Fig. 1).

Fig1. The Karl Landsteiner experiment. Serum from group A individuals agglutinated the red cells from group B individuals, and, conversely, the serum from group B individuals agglutinated group A. Red cells that were not agglutinated by the serum of either the group A or group B individuals were later called group O; the serum from group O individuals agglutinated the red cells from both group A and group B individuals. Serum of group AB individuals did not agglutinate group A, B, and O RBC but red cells from group AB individuals were agglutinate from group A, B and O serum

The loci of the genes H and Se (Secretor), identified, respectively, as FUT1 and FUT2, are located, in close con catenation, on chromosome 19. Each locus can be occupied by two alleles, one of which, respectively, called h and se, is an amorphous gene. The active alleles H and Se encode two glycosyltransfers, which, by acting on a precursor, transform it into H antigen. The H gene encodes a transferase that acts at the cellular level to form the H antigen on red blood cells. The transferase encoded by the Se gene also produces the H antigen, but in secretions, such as saliva. The amorphous h genes and if they behave like recessive genes, the h gene is extremely rare.

The ABO locus is located on chromosome 9, and there are three common alleles: alleles A and B encode transferases, which produce antigens A and B, respectively; the O allele does not code for a functional enzyme. The red blood cells of individuals of group O are therefore devoid of anti gens A and B, but have a high quantity of antigen H. The antigens of the ABO system are oligosaccharide chains, which can be joined to other macromolecules to form glycoproteins, glisfingolipids, glycolipids. The methods of conjugation affect the distribution of antigens. For example, ABO antigens present on the surface of erythrocytes are usually glycoproteins and glycosphingoplipids, in saliva they are present as glycoproteins, in milk they are present as free oligosaccharide.

Glycosyltransferases encoded by alleles A, B, H, and Se add a specific sugar to a preexisting oligosaccharide chain. This additional carbohydrate determines the antigenic specificity, which is, in fact, lost when it is removed (referred to as immunodominant). These reactions can only occur sequentially; therefore, the H gene encodes a fucosyl transferase that adds a molecule of fucose with α1–2 bond to the terminal galactose of the precursor oligosaccharide chain (therefore, fucose is the immunodominant sugar for the antigen H). The A allele encodes an N-acetyl-D- Galactosaminyltransferase, which adds, to the terminal Galactose of substance H, a molecule of N-acetyl-D-galactosamine with α1–3 bond (therefore, the N-acetyl-D- galactosamine is the immunodominant sugar for antigen A). The B allele encodes a galactosyl transferase, which adds a molecule of Galactose with a α1–3 bond to the terminal Galactose of substance H (therefore, Galactose is the immunodominant sugar for antigen B). Individuals of group AB possess both a gene A and a gene B and are therefore able to code for both transferases and express both antigens (A and B). The transformation of substance H into antigens A and B reduces the serological reactivity of antigen H. The sub jects of group O are double-dose carriers of a nonfunctional recessive gene, which is unable to code for any glucosyltransferase. Substance H therefore remains unchanged on the surface of the red cells. The very rare subjects lacking the H gene are unable to modify the pre cursor oligopetide chain into H antigen. Consequently, the transcripts of genes A and B, although present and functioning, cannot carry out their action. These subjects are defined as Bombay phenotypes. If, on the other hand, the sese genotype is associated, these individuals do not present substance A and B even in the secretions, while substances A and B may be present in the secretions if a Se gene is present.

The polysaccharide chains that expose the immunodominant sugars H, A, or B can have a linear or multi-branched form, the latter much more efficient in the exposure of the antigen. At the molecular level, it is believed that the ancestral gene is gene A, from which gene B originated by mutation. The two genes differ for seven-point mutations, four of which result in an amino acid substitution (residues in positions 176, 235, 266, and 268). The O gene can result from various mutations. Among these, the identification of a single nucleotide deletion that involves the insertion of a stop codon, which then results in the translation of a truncated protein devoid of transferase activity, is of particular importance.

ABO blood group antigens are not fully developed at birth, and their expression gradually increases to reach adult life levels after 2–4 years of life. It must also be remembered that ABO antigens are ubiquitously expressed on the body’s cells.

Numerous subgroups have been described within the ABO system. The two main subgroups of A are called A1 and A2. On a molecular basis, they differ as the transferase in A2 subjects is 22 amino acids longer than that of A1 subjects and less active than this in the elaboration of highly repetitive and branched antigenic structures. Subjects A1 and A2 (as well as subjects A1B and A2B) can be differentiated by the use of lectins. They have been described under weak groups of A (A3, Ax, Am, Ael). Subgroups of B are much less frequent and of less practical importance.

Antibodies: Adult subjects normally have specific anti bodies against antigen A or B, which is absent on its own erythrocytes. These are IgM class immunoglobulins with a wide thermal optimum (from 4 to 37 °C), able to fix the complement (therefore able to give hemolytic reaction after transfusion), reactive in saline solution. It is believed that the production of these antibodies (which are defined as “natural,” since exposure to nonself-erythrocytes is not demonstrable) derives from the fact that the configurations that confer the antigenic specificities of determinants A and B also exist on the bacterial walls of the germs constituting the intestinal microbiota. At birth these antibodies are normally absent, while antibody production increases between the fifth and tenth year of life until it reaches adult levels and decreases in the latter part of life. IgM represents the pre dominant immunoglobulin class of anti-A produced by group B subjects and anti-B produced by group A subjects. However, modest amounts of IgG class antibodies may still be present in these subjects. IgG, on the other hand, is the dominant antibody class in subjects of group O. Since IgG is able to cross the placenta, infants of group A or B born to mothers of group O may develop neonatal hemolytic dis ease, usually of modest entity. The serum of the subjects of group O contains an antibody that is defined anti-A,B because it reacts with both the A and B red blood cells. The anti-A and anti-B reactivity of this antibody cannot be separated with selective absorption. It is not the sum of two antibodies (one anti-A specificity and one anti-B specificity), but an anti-A,B cross-reactive antibody. For example, an eluate prepared from group A red cells that have reacted with anti-A, B will be reactive with both A and B cells alone. Anti-A1 is detectable, as alloantibody, in a reduced percentage ( (<2% in the serum of A2 subjects while it is more frequent (20–25%) in A2B subjects. This is usually a cold antibody and is considered insignificant. Dolichos biflorus lectin preparations are available, which react with A1 but not with A2 red cells.

H/h System

Group O red cells lack A and B antigens, and the membrane expresses unchanged H antigen. In fact, the red blood cells of group O subjects show a strong agglutination when tested with the anti-H lectin obtained from Ulex europaeus (Fig. 2). The reaction observed is in descending order: O> A2> B> A2B> A1> A1B. The rare subjects with the hh genotype whose red blood cells lack the H antigen (they do not react with the anti-H lectin) at ABO typing are classified as type O subjects but have, in addition to the anti-A and anti-B, an alloantibody anti-H (therefore able to agglutinate normal group O red blood cells). The term Oh Bombay is used to designate subjects with this phenotype. At the genotypic level, the Oh Bombay phenotype arises from the transmission of the hh alleles at the H locus and of sese at the Se locus. Since the If allele is necessary for the formation of the Leb antigen, the Oh red cells will, therefore, be Le (a + b–) or Le (a – b–).

Fig2. ABO molecules. Alleles A, B, H encode for specific Glycosyltransferases that add a specific sugar to a preexisting oligosaccharide chain. This additional carbohydrate determines the antigenic specificity. These reactions occur sequentially: Therefore, the H gene encodes a fucosyl transferase that adds a molecule of fucose with α1–2 bond to the terminal galactose of the precursor oligosaccharide chain (therefore, fucose is the immunodominant sugar for the antigen H and for group O individuals). The A allele encodes an N-acetyl-D- Galactosaminyltransferase, which adds, to the terminal Galactose of substance H, a molecule of N-acetyl-D-galactosamine with α1–3 bond (therefore, the N-acetyl-D-galactosamine is the immunodominant sugar for antigen A). The B allele encodes a galactosyltransferase which adds a molecule of Galactose with a α1–3 bond to the terminal Galactose of substance H (therefore, Galactose is the immunodominant sugar for antigen B). Individuals of group AB possess both a gene A and a gene B and are therefore able to code for both transferases and express both antigens (A and B)

I/i System

 Antigens: Antigens I and i are expressed on the erythrocyte membrane on the same glycoproteins and glycosphingolipids that carry H, A, and B antigens and, in the secretions, on the same glycoproteins that carry H, A, B, Lea, and Leb. Nonetheless, antigens I and i are not antithetical, but are expressed in temporal succession. At birth, neonatal red blood cells are rich in i antigens, so for practical purposes, cord blood cells are considered I−i +. During the first 2 years of life, the expression of antigen I gradually increases, while that of antigen i decays. In adults, red blood cells are usually highly reactive with anti-I and are considered I + i−. There is a rare I−i + phenotype in adults. From a structural point of view, antigen i appears to consist of a linear chain with at least two repeating units Galactose-N-acetyl galactosamine, joined by a β1–4 glycosidic bond. To the surface of the red blood cells of adults, to give specificity I, these linear chains are modified by the addition of branched structures consisting of N acetyl galactosamine that join the linear chains by means of a β1–6 glycosidic bond.

Antibodies: Anti-I and anti-i antibodies are often auto- antibodies, are usually active in saline with thermal optimum at 4 °C, and are commonly identified with cold agglutinins, which can take on clinical significance if present at a titer greater than 1/64 and, with a wide thermal range, are able to fix the complement. Anti-I auto antibodies are often produced by patients with Mycoplasma pneumoniae pneumonia. These patients may have transient hemolytic episodes determined by the antibody. Patients with infectious mononucleosis often have anti-i antibodies.

Lewis System

Antigens: Antigens of the Lewis erythrocyte blood group system are called Lea and Leb originate from the activity of a glycosyltransferase encoded by the allele Le (or FUT3) located on chromosome 19. This glycosyltransferase adds a glucose residue to a precursor chain. The Lewis system appears associated with the Sese system. In fact, the Lea antigen is produced when the Le gene is inherited together sese, and Leb is produced when it is inherited together with Sese or SeSe. Therefore, Lea and Leb are not antithetical antigens produced by alleles but depend on the interaction of alleles inherited independently (Le, Se, se). The antigens of the Lewis system are also not intrinsic to the erythrocyte membrane, but are expressed on the Type 1 glycosphingolipid chains, which are adsorbed by the plasma on the red cell membrane. Also in this case, four different phenotypes are possible, which present very different frequencies in the various ethnic groups: Le (a + b−) is present in 20% of the Caucasian and African population, Le (a−b +) is present in 75% of Caucasians and 55% of black subjects, Le (a−b−) is present in 5% of Caucasians and 25% of black subjects, Le (a + b +) is rare in European populations and of African ancestry, while it is common in Asian populations.

From a biochemical point of view, the synthesis of Lewis antigens derives from the interaction of two different fucosyltransferases. One of them is produced by the Se locus and one by the Le locus. Both enzymes act on the same substrate. The fucosyltransferase encoded by the Le allele attaches a molecule of fucose with α1–4 bond to the oligosaccharide chain of the precursor. In the absence of the transferase encoded by the Se allele, this configuration gives rise to the Lea antigen. On the other hand, the Leb antigen is formed when the fucosyltransferase encoded by the Se gene and then, in sequence, the fucosyltransfease encoded by the Le gene acts on the oligosaccharide chain of the precursor. In this configuration, two fucose residues are added to the original oligosaccharide chain. The Leb antigen therefore reflects the presence of both the Le and Se alleles; while Lea antigen reflect the presence of Le without Se alleles. Lewis antigens are rapidly adsorbed and eluted by the erythrocyte mem brane. The transfused red blood cells lose their Lewis anti gens and assume the recipient’s Lewis phenotype within a few days of being released into the circulation.

Antibodies: Antibodies to Lea (more frequently) or Leb (more rarely) are detectable, almost exclusively, in the sera of Le (a−b−) subjects, usually in the absence of antigenic stimulation evident from previous exposure to nonself red blood cells. self. These are generally IgM antibodies. Therefore, considering that Lewis antigens are also underdeveloped at birth, these antibodies are not associated with MEN. Lewis antibodies can bind complement and fresh sera containing anti-Lea can hemolyze incompatible red blood cells in vitro. Being IgM i, these antibodies react in saline solution, forming rather fragile agglutinates that can be easily dispersed during too vigorous manipulation.

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