Glycosphingolipid polymorphisms

The ABO blood group system is a typical antigenic polymorphism related to glycosphingolipids. The structural basis of these polymorphic antigens expressed on red blood cells and mucosal epithelial cells lays in the alleles of the ABO gene, which encode either a α1-3 GalNAc-transferase (A antigen), a α1-3 Gal-transferase (B antigen) or an inactive protein (O antigen). Despite a single N-acetyl group as difference between A and B antigens, humans have high antibody titers recognizing the ABO antigens that are not expressed endogenously. Accordingly, AB-carriers lack anti-A and anti-B antibodies, explaining their status as universal recipients for blood transfusions. Conversely, O-carriers are universal donors since their erythrocytes lack the A and B epitopes.

FIG: ABO BLOOD GROUPS

How come do we build such high antibody titers against carbohydrate antigens anyway? Carbohydrates are supposed to be poorly immunogenic, right? The answer is found in our gut, specifically in the trillions of bacteria colonizing our colon. Intestinal bacteria express carbohydrate structures featuring the A and B antigens as well as several other carbohydrate antigens. Our immune system is constantly stimulated by these bacteria and responds by producing high amounts of antibodies. The antibodies recognizing carbohydrate antigens are of the IgM class because the process is T-cell independent. This lack of IgG response is important in the context of pregnancies. In fact, only maternal IgGs, but not IgMs, cross the placenta and enter the fetal circulation. The introduction of maternal anti-A or anti-B antibodies to a fetus expressing such antigens would lead to erythrocyte aggregation and hemolysis that would seriously compromise the development of the fetus.

Carbohydrate-based polymorphism is not limited to ABO antigens. Another blood group system, called P, also relies on variable expression of glycosphingolipid epitopes. The differential expression of the α1-4 Gal-transferase A4GALT and β1-3 GalNAc-transferase B3GALNT1shaping globosides on erythrocytes and epithelial cells of the urinary tract yields different antigenic structures called P, P₁ and P_k. The P blood group system is clinically not significant since antibody titers to P antigens are usually low. About 75% of humans are of blood group P1 featuring the expression of P, P₁ and P_k antigens, whereas 25% are of blood group P2 with only expression of P and P_k antigens. In rare cases, individuals lack all P antigens and are designated as p phenotype. The P antigen is a receptor for the human pathogen Parvovirus B19, meaning that p individuals are resistant to Parvovirus B19 infection.

FIG: P BLOOD GROUPS

The resistance to common pathogens is a decisive factor that contributed to the maintenance of structural polymorphisms like the ABO and P blood group systems. As mentioned above, the lack of P-related antigens confers resistance to parvovirus B19 infection. Similarly, the ABO and Lewis blood group antigens are used as receptors by noroviruses, which cause stomach flu and diarrhea.

FIG: NOROVIRUS RECEPTORS

The occurrence of A-, B- and O-carriers in a given population means that a portion of this population will not become infected by a norovirus targeting a specific blood group antigen. Noroviruses come in several groups or serotypes, binding differentially to blood-group antigens. Accordingly, cell surface polymorphisms like the ABO and P blood groups contribute to the survival of a large population or even a species by preventing the parallel infection of all individuals by a pathogen binding to a specific receptor.

FIG: ABO SUSCEPTIBILITY TO NOROVIRUS