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Blood Genetics & Biochemistry8. Blood Genetics & BiochemistryABO genes consist of multiple alleles which are located on the long arm of chromosome 9. The four major alleles are A1,A2, B and 0. 0 is a ‘silent’ gene or ‘amorph’ and no gene product is expressed. The A and B genes are codominant and 0 is recessive.The ABO blood group genes do not code directly for the specific antigens instead they code for specific transferases namely N-acetyl galactosaminyl transferase and D-galactosyl transferase. These enzymes in turn transfer the immunogenic sugars N-acetyl galactosamine and D-galactose respectively to H substance to confer A and B specificity. The H gene and its allele h are present at a separate locus from the ABO genes and are independent of them. The H gene produces an enzyme L-fucosyl transferase which is responsible for transfer of the specific sugar fucose to the precursor carbohydrate chains to form the H antigen. The H antigen forms the substrat” for A and B enzymes. The allele h is an amorph. The homozygous hh is exceedingly rate and results in the production of the Bombay phenotype which is characterized by absence of H antigen. Secretor Status The ability to secrete A,B and H substances is determined by either the homozygous SeSe or heterozygous Sese state. This is and Hh genes, eighty percent of the population are secretors and H antigens. Table for Secretor System
ABH Antigens A,B and H antigens are present not only on the red cells but are also widely distributed throughout the body tissues except in the central nervous system. All individuals possessing the secretor gene (SeSe or Sese) secrete these antigens in all body fluids except the cerebrospinal fluid. Subgroups of A Individuals of group A can be divided into several subgroups (Al,A2,A3,Am,Ax,etc). Cf these the Al and A2 (or A1B and A2 B) are most frequent (with an approximate frequency of 80% and 20%respectively). Al and A2 can be distinguished by their reactions with the extract of the lectin Dolichus biflorus. This agglutinates Al and A1B cells but not A2 and A2B cells. It is not necessary to classify group A patient or donors as Al or A2 except when the serum contains anti-Al. Anti-Al causes discrepancies between ABO cell and serum grouping. It may also cause crossmatch incompatibilities but is considered clinically significant only if it reacts at 37°C. Bombay (Oh) blood group The Bombay blood group was discovered in 1952 by Bhende et al. It is characterized by the absence of A, B and H antigens on red cells and in the body secretions and is expressed as phenotype Oh. The sera of these individuals show the presence of anti-A, anti-B and anti-H and react with 0 group cells which express H antigen. These individuals possess normal ABO and secretor genes, however, the A,B and H antigens are not expressed because of the absence of H gene.
The frequency of Oh individuals in India is approximately 1:7600. On routine grouping Oh individuals are grouped as 0 and are detected because of incompatible crossmatch with 0 group blood. Since Oh individuals have anti-H in their plasma they can only be transfused Oh blood. This is most easily obtained from close relations. The lectin of Ulex europeus has anti-H activity and can be used to detect H antigen. There is considerable variation in the H antigen content in different individuals of the same ABO groups, but the general pattern indicates their strength as O>A2>B>B>Al>A1B. ABO Antibodies ABO antibodies are of two types - naturally occurring and immune. Naturally occurring antibodies are found in all individuals lacking the corresponding antigen and are formed without obvious exposure to an immunogen. They are IgM in nature. Many plants, animals and bacteria possess antigens that have A,B and H-like specificity. Exposure to these is believed to result in the production of naturally occurring IgM antibodies. Immune antibodies in the ABO system are mostly produced after immunization either as a result of pregnancy or transfusion. These are IgG in nature. Anti-A and anti-B are usually not produced by infants till 3 to 6 months of age. By 5 to 10 years, the antibodies reach a maximum titre which gradually declines thereafter. The antibodies found in the serum of infants at birth are mostly of maternal origin, therefore, only cell grouping is recommended in newborns. Anti-A is found in group B and group 0 individuals and reacts strongly with Al and A2 cells but not as well with weaker subgroups of A. Anti-B is found in group A and 0 individuals. It reacts strongly with B groups cells but less effectively with weaker variants of B group. Anti-AB (A,B) an inseparabit anti-AB is found in group 0 individuals. Serum from 0 group individuals is particularly useful in detecting some weak A and B antigens. Anti-Al is found in 1-8% of A2 and 22 - 35% of A2B individuals. It is usually active at room temperature or below; and is rarely clinically significant, except if it reacts at 37°C. Anti-H in Oh individuals reacts over a wide thermal range (between 4 and 37°C) and is haemolytic antibody which may cause severe haemolytic spisodes. Rh blood group system After the ABO, Rh blood group system is the most important in clinical practice. The majority of Rh-negative individuals transfused with Rh-positive blood produce immune Rh antibodies. Rh antibodies are an important cause of haemolytic disease of the newborn (HDN) and can occasionally cause haemolytic transfusion reactions (HTR). Of more than 40 described antigens, only five Rh antigens are common. These antigens are protein products of a complex system of three closely related genes present on chromosome 1. Three alleles D,d; C c and E, e are inherited as a single unit (haplotype) and d allele is amorphic. The concept of Fisher-Race (DCE) is adequate for description and understanding of clinically important problems. Rh antigen (D,C,c E &e) are the products of corresponding genes. D antigen is highly immunogenic and is more clinically important than the other Rh antigens. Wiener (Rh-Fir) model attributes control of these antigens to a single gene on each of a pair of homologus chromosomes. Since the antigenic control of D, C and E are on different polypeptide molecules, this model is not useful except for retention of Rh (D). Phenotype & genotype in the Rh system Phenotype denotes the expression of antigens on the red blood cells. Genotype denotes the gene combination in a particular individual. Five antisera are routinely used to detect the phenotype. The phenotype thus detected permits probable genotyping. Prediction of the possible genotype can be made from the known frequencies of the Rh genotype in the population. In Wiener’s terminology genes are designated as a single italic letter with superscript symbols and gene products as Roman letters with subscripts for R and superscript for r. Below table: RH nomenclature
Rh antigens Rh antigens are integral proteins of the red cell membrane. Unlike ABO antigens, D antigens are present only on red blood cells. Rho (D) antigen is clinically the most important in the Rh system because of its high immunogenicity which is greater than that of the other blood group antigens. An individual is designated Rh (D) positive or Rh (D) negative depending on the presence or absence of Rho antigen. Ninety-five percent of the Indian population is Rh-positive and 5% is Rh-negative, while in Caucasians 85% of the population if Rh-positive and 15% is Rh-negative. Du phenotype A weaker variant of the D antigen is termed Du and is detected only by the antigloblin (AHG) technique. Significance of Du 1. If transfused with Du blood an individual who has anti-D antibodies (through previous sensitization by transfusion or pregnancy) is likely to develop severe haemolysis. 2. A sensitized Rh-negative mother having anti-D antibodies can produce haemolytic disease of the new born (I-IDN) in a Du-positive foetus. 3. Transfusion of Du blood to an Rh-negative individual can theoretically produce antibodies against D or Du. However, in practice, this has not been substantiated. 4. In theory, a Du recipient can produce antibodies to transfused D-positive cells. This also is extremely uncommon in practice. Recently introduced monoclonal anti-D reagent gives positive reaction in 95% Du individuals in the tube technique and 99-100% in the microtitre plate. Thus, with these techniques, practically all subjects with Du will be interpreted as D-positive. Though on theoretical consideration Du subjects should be classified as D-negative recipients, and as D-positive donors, recent evidence suggests that for all practical purposes Du-positive individuals behave as D-positive. Other Rh antigens are C, c, E and e and are less immunogenic than the D antigen. In decreasing order of immunogenicity after D the antigens are c, C,E and e. Rh antibodies Barring anti-A and anti-B, Rh antibodies are clinically the most significant. These antibodies are almost always immune (IgG) in nature and are formed secondary to transfusion or pregnancy. The antibodies are incomplete antibodies and do not complement. About 50-70% Rh negative persons develop anti-D if transfused with Rh positive blood Rh antibodies are the major cause of HDN and lead to destruction of transfused Rh-positive cells. Occasional examples of naturally occurring IgM anti-Rh antibodies primarily to D & E antigens have been found. Rh antibodies are best demonstrated by the antiglobulin test. Reactivity is also enhanced by treatment of red cells with proteolytic enzymes like papain, ficin or bromelin and by albumin or other potentiating media at 370 C. IgM anti-Rh antibodies are capable of causing direct agglutination of red cells in saline without addition of potentiating media. Rh antibodies show dosage effect i.e, a stronger reaction occurs with red cells having homozygous Rh antigens than with heterozygous Rh antigens. Anti-e is uncommon and may be formed in autoimmune haemolytic anaemia. Other Blood group systems
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