The biological significance of blood group antigens

The functions of several red cell membrane protein structures bearing blood group antigenic determinants are known, or can be deduced from their structure (Table 14.1). Some are membrane transporters, facilitating the transport of biologically important molecules through the lipid bilayer: band 3 membrane glycoprotein, the Diego antigen, provides an anion exchange channel for HCO- and Cl- ions; the Kidd glycoprotein is a urea transporter; the Colton glycoprotein is aquaporin 1, a water channel; the GIL-antigen is aquaporin 3, a glycerol transporter; and the Rh protein complex might function as an ammonium transporter or a CO2 channel. The Lutheran, LW, and Indian (CD44) glycoproteins are adhesion molecules, possibly serving their functions during erythropoiesis. The Duffy glycoprotein is a chemokine receptor and might function as a 'sink' or scavenger for unwanted chemokines. The Cromer and Knops antigens are markers for decay accelerating factor and complement receptor 1, respectively, which protect the cells from destruction by autologous complement. Some blood group glycoproteins have enzyme activity: the Yt antigen is acetylcholinesterase and the Kell antigen is an endopeptidase with the ability to cleave a biologically inactive peptide to produce the vasoconstrictor endothelin-3. The C-terminal domains of the Gerbich antigens, GPC and GPD, and the N-terminal domain of the Diego glycoprotein, band 3, are attached to components of the cytoskeleton and function to anchor the membrane to it skeleton. The carbohydrate moieties of the membrane glycoproteins and glycolipids, especially those of the most abundant glycoproteins, band 3 and GPA, constitute the glycocalyx, an extracellular coat that protects the cell from mechanical damage and microbial attack.

The difference between allelic red cell antigens (e.g. A and B, K and k, Fya and Fyb) is small, often being just one monosac-charide or one amino acid. The biological importance of these differences is unknown and there is little evidence to suggest that one antigen confers any significant advantage over another. Most blood group systems have a null phenotype in which the whole blood group protein is absent from the red cells or any other cells. These usually result from homozygosity for gene deletions or inactivating mutations within the genes. In most cases, individuals with these null phenotypes are apparently healthy, suggesting that, whatever the precise function of the missing structure may be, some other structure must be able to substitute in its absence. However, there are exceptions; 15% of Caucasians lack the D protein of the Rh system with no ill effect, but those rare individuals who lack both D and CcEe Rh proteins have chronic haemolysis, which may be compensated by increased red cell production, but may require splenectomy for stabilization. Absence of the Kx protein causes weakness of expression all Kell system antigens, as a result linkage between the two proteins in the membrane, but is also associated with acanthocytosis and neurological and muscular disorders. Individuals lacking the Diego antigen, the anion transporter, can only survive with extreme medical intervention, and no person with Yt-null phenotype and absence of the neurotransmitter acetylcholinesterase has been found. People with the rare Bombay phenotype lack ABH antigens from all tissues, with no apparent ill effect or red cell abnormality.

Some blood group antigens are exploited by pathological micro-organisms as receptors for attaching and entering cells. Consequently, in some cases absence of antigens can be beneficial. The Duffy glycoprotein, expressing Fya or Fyb, is used by Plasmodium vivax to penetrate red cells. The Fy(a-b-) phenotype is common in Africans and confers resistance P. vivax malaria. Fy(a-b-) in Africans results from homozygosity for a mutation in an erythroid-specific transcription factor binding site, meaning that the Duffy glycoprotein is absent from red cells but is expressed in other tissues. It is likely that interaction between cell surface molecules and pathological micro-organisms has been a major factor in the evolution of blood group polymorphism.

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