At the beginning of the 20th century an Austrian scientist, Karl Landsteiner, noted that the RBCs of some individuals were agglutinated by the serum from other individuals. He made a note of the patterns of agglutination and showed that blood could be divided into groups. This marked the discovery of the first blood group system, ABO, and earned Landsteiner a Nobel Prize.
Agglutination occurred when the RBC antigens were bound by the antibodies in the serum. He called the antigens A and B, and depending upon which antigen the RBC expressed, blood either belonged to blood group A or blood group B. A third blood group contained RBCs that reacted as if they lacked the properties of A and B, and this group was later called "O" after the German word "Ohne", which means "without". The following year the fourth blood group, AB, was added to the ABO blood group system. These RBCs expressed both A and B antigens.
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In 1910, scientists proved that the RBCs antigens were inherited, and that the A and B antigens were inherited codominantly over O. There was initially some confusion over how a person's blood type was determined, but the puzzle was solved in 1924 by Bernstein's "three allele model".
The ABO blood group antigens are encoded by one genetic loci, the ABO locus, which has three alternative (allelic) forms-A, B, and O. A child receives one of the three alleles from each parent, giving rise to six possible genotypes and four possible blood types (phenotypes).
The four basic ABO phenotypes are O, A, B, and AB. After it was found that blood group A RBCs reacted differently to a particular antibody (later called anti-A1), the blood group was divided into two phenotypes, A1 and A2.
The immune system forms antibodies against whichever ABO blood group antigens are not found on the individual's RBCs. Thus, a group A individual will have anti-B antibodies and a group B individual will have anti-A antibodies. Blood group O is common, and individuals with this blood type will have both anti-A and anti-B in their serum. Blood group AB is the least common, and these individuals will have neither anti-A nor anti-B in their serum.
ABO antibodies in the serum are formed naturally. Their production is stimulated when the immune system encounters the "missing" ABO blood group antigens in foods or in micro-organisms. This happens at an early age because sugars that are identical to, or very similar to, the ABO blood group antigens are found throughout nature.
The ABO locus has three main allelic forms: A, B, and O. The A allele encodes a glycosyltransferase that produces the A antigen (N-acetylgalactosamine is its immunodominant sugar), and the B allele encodes a glycosyltransferase that creates the B antigen (D-galactose is its immunodominant sugar).
The O allele encodes an enzyme with no function, and therefore neither A or B antigen is produced, leaving the underlying precursor (the H antigen) unchanged. These antigens are incorporated into one of four types of oligosaccharide chain, type 2 being the most common in the antigen-carrying molecules in RBC membranes. Some of the other enzymes involved in the earlier stages of ABO antigen synthesis are also involved in producing antigens of the Hh blood group and the Lewis blood group.
The ABO locus encodes specific glycosyltransferases that synthesize A and B antigens on RBCs. For A/B antigen synthesis to occur, a precursor called the H antigen must be present. In RBCs, the enzyme that synthesizes the H antigen is encoded by the H locus (FUT1). In saliva and other bodily secretions, the enzyme that synthesizes the H antigen is encoded by the Se locus (FUT2).
The ABO locus
The ABO locus is located on chromosome 9 at 9q34.1-q34.2. It contains 7 exons that span more than 18 kb of genomic DNA. Exon 7 is the largest and contains most of the coding sequence. Exon 6 contains the deletion that is found in most O alleles and results in a loss of enzymatic activity.
The A and B alleles differ from each other by seven nucleotide substitutions, four of which translate into different amino acids in the gene product (R176G, G235S, L266M, G268A). The residues at positions 266 and 268 determine the A or B specificity of the glycosyltransferase they encode (16).
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The O allele differs from the A allele by deletion of guanine at position 261. The deletion causes a frameshift and results in translation of an almost entirely different protein that lacks enzymatic activity (16).
There are many variant ABO alleles that encode a number of variant ABO phenotypes, but they do not encode specific antigens other than the A and B antigens. For example, weak A subgroups, such as A3, Ax, and Ael, express the A antigen, and weak B subgroups, such as B3 and Bx, express the B antigen.
The H locus (FUT1)
The H locus is located on chromosome 19 at 19q13.3. It contains three exons that span more than 5 kb of genomic DNA, and it encodes a fucosyltransferase that produces the H antigen on RBCs.
Individuals who are homozygous for null alleles at this locus (h/h) do not produce H antigen, and because the H antigen is an essential precursor to the ABO blood group antigens, they cannot produce A and B antigens. Therefore, their serum contains anti-A and anti-B, in addition to potent anti-H. This rare phenotype of H-deficient RBCs is called the "Bombay phenotype" (Oh) after the city in which it was first discovered. Individuals with the Bombay phenotype are healthy, but if they ever needed a blood transfusion, the antibodies in their serum would place them at a high risk of having an acute haemolytic transfusion reaction. This can be avoided by using only blood products from a donor who also has the Bombay phenotype (usually a relative).
The Se locus (FUT2)
The Se locus is located on chromosome 19 at 19q13.3. It contains two exons that span about 25 kb of genomic DNA.
The Se locus encodes a specific fucosyltransferase that is expressed in the epithelia of secretory tissues, such as salivary glands, the gastrointestinal tract, and the respiratory tract. The enzyme it encodes catalyses the production of H antigen in bodily secretions.
"Secretors" have at least one copy of the Se gene that encodes a functional enzyme-their genotype is Se/Se or Se/se. They secrete H antigen which, depending on their ABO genotype, is then processed into A and/or B antigens.
Non-secretors are homozygous for null alleles at this locus (se/se). They are unable to produce a soluble form of H antigen and hence do not produce A and B antigens.
In 1939, Haemolytic Disease of the Newborn (HDN) wasÂ first described by Levine and Stetson. The cause of haemolytic disease was not specifically identified but maternal antibody suspected. A year later (1940) Karl Landsteiner and Alexander Wiener injected animals with Rhesus monkey cells to produce an antibody which reacted with 85% of human red cells, which they named anti-Rh.Â Within a year Levine made connection between maternal antibody causing HDN and anti-Rh.Â Between 1943 and 1945 the other common antigens of the Rh system were identified.Â For many years the exact inheritance of the Rh factors were debated, with Weiner promoting Rh and hr terminology and Fisher-Race utilizing DCcEe for the various Rh antigens.Â In 1993,Â Tippett discovered the true mode of Rh inheritance using molecular diagnostics.
D (Rho) is the most important antigen after A and B antigens.Â Unlike the anti-A and anti-B antibodies, anti-D antibodies are only seen if a patient lacking D antigen is exposed to D+ cells.Â The exposure of D+ cells usually occurs through pregnancy or transfusion.Â
There are 5 principle antigens that may be found in most individuals. They are:Â D, C, E, c, e, and d (which has never been identified but refers to people who have no D antigen).
There are at over 50 Rh antigens that have been identified including those that are either combinations of these antigens or weak expressions of the above antigens, but most Rh problems are due to D, C, E, c or e.
The common alleles are:
C and c are alleles with Cw occasionally seen as a weaker expression of C;
E and e are alleles although E is seen only a third as often as e;
D and the lack of D (or d) are alleles.Â
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Characteristics of Rh antigensÂ
The Rh antigens together are proteins of 417 amino acids. These proteins cross the red cell membrane 12 times.Â There are only small loops of the protein on the exterior of the cell membrane.Â Â
Therefore the Rh antigens are not as available to react with their specific antibodies and there are fewer antigen sites than ABO.Â Unlike the ABO system the Rh antigens are not soluble and are not expressed on the tissues.Â They are well developed at birth and therefore can easily cause HDN if the baby has an Rh antigen that the mother lacks.Â Besides the antigens being well-developed at birth, they are very good immunogens.Â This is especially true to D, which is the most immunogenic after A and B antigens.
Unlike the ABO antibodies that are mainly IgM, the Rh antibodies are commonly IgG.Â They are not naturally occurring and therefore are formed by immune stimulus due to transfusions or baby's red blood cells during pregnancy.Â The most common antibody to form is anti-D in Rh negative individuals.Â
Both HDN and Haemolytic Transfusion Reactions can occur due the various Rh antibodies. Anti-D has been the biggest concern since it was recognized in the 1940's as being the most common cause of HDN.Â Since the D antigen is so immunogenic, all donors are screened for the D antigen.Â Therefore if an individual is A+, it means both the A and the D antigens are present.Â On the other hand, if an individual is A-, the A antigen is present and the D antigen is absent.
Rh System InheritanceÂ
From the 1940's to the 1990's the mechanism for inheritance of the Rh Blood Group System was in question.Â The terminology that is part of the Fisher-Race Theory is most commonly used even today.
The Fisher-Race theory involved the presence of 3 separate genes D, C, and E and their allele's c and e and the absence of D since anti-d has never been found.Â These three genes are closely linked on the same chromosome and are inherited as a group of 3.Â The most common group of 3 genes inherited is CDe and ce (D negative) is the second most common.
Weiner believed there was one gene complex with a number of alleles resulting in the presence of various Rh antigens.Â According to Weiner there were 8 alleles, Ro, R1, R2, Rz, r, r', r", ry , which ended up with different antigens on the red cells that he called Rho, rh', rh", hr', hr".Â Weiner's terminology is not used as often today, but you will often see Rho(D) when a person is considered to be Rh-positive.Â At times the gene terms are easier to use than Fisher-Race.Â If a person has the Fisher-Race genotype of DCe/DCe, it is easier to refer to that type as R1R1.
In 1986, Tippett predicted that there are two closely-linked genes - RHD and RHCE.Â The RHD gene determines whether the D antigen that spans the membrane is present. Caucasians who are D negative have no gene at that gene locus.Â In the Japanese, Chinese, and Blacks of African descent have an inactive or partial gene at this site.
The RHCE gene determines C, c, E, and e antigens produced from the alleles RHCe, RHCE, RHcE and RHce.
Rh Gene Complexes, Antigens, Possible Combinations and Percentages
(more common in Blacks)
Weak D phenotype
Weak D is different from full D only in quantity of antigens and has no extracellular structural difference. The weak D phenotype cannot be stimulated to produce allo-anti-D. Furthermore, weak D is either inherited or a result of inheriting C in trans position to D, known as the "Ceppellini" effect.