Unravelling the biochemical basis of blood group ABO and Lewis antigenic specificity

The ABO blood-group polymorphism is still the most clinically important system in blood transfusion practice. The groups were discovered in 1900 and the genes at the ABO locus were cloned nearly a century later in 1990. To enable this goal to be reached intensive studies were carried out in the intervening years on the serology, genetics, inheritance and biochemistry of the antigens belonging to this system. This article describes biochemical genetic investigations on ABO and the related Lewis antigens starting from the time in the 1940s when serological and classical genetical studies had established the immunological basis and mode of inheritance of the antigens but practically nothing was known about their chemical structure. Essential steps were the definition of H as the product of a genetic system Hh independent of ABO, and the establishment of the precursor-product relationship of H to A and B antigens. Indirect methods gave first indications that the specificity of antigens resided in carbohydrate and revealed the immunodominant sugars in the antigenic structures. Subsequently chemical fragmentation procedures enabled the complete determinant structures to be established. Degradation experiments with glycosidases revealed how loss of one specificity by the removal of a single sugar unit exposed a new specificity and suggested that biosynthesis proceeded by a reversal of this process whereby the oligosaccharide structures were built up by the sequential addition of sugar units. Hence, the primary blood-group gene products were predicted to be glycosyltransferase enzymes that added the last sugar to complete the determinant structures. Identification of these enzymes gave new genetic markers and eventually purification of the blood-group A-gene encoded N-acetylgalactosaminyltransferase gave a probe for cloning the ABO locus. Blood-group ABO genotyping by DNA methods has now become a practical possibility.