Following the discovery of the ABO blood group, researchers identified another complex system for classifying human blood. The MNS system, first described in 1927, involves a large collection of antigens on the surface of red blood cells and is one of the most intricate blood groups known. While less familiar than the ABO and Rh systems, it has importance in transfusion medicine and during pregnancy.
Genetic Basis and Antigens
The antigens of the MNS system are on two proteins on the surface of red blood cells: glycophorin A (GPA) and glycophorin B (GPB). These proteins are encoded by two genes, GYPA and GYPB, located close together on chromosome 4. Because of their proximity, the genes for these antigens are inherited together as a single unit, or haplotype.
The difference between the M and N antigens is determined by variations in the GPA protein. These two antigens are antithetical, meaning a person’s genes will code for one or the other based on specific amino acids at two positions on the protein.
A similar principle applies to the S and s antigens, which are on the GPB protein. Like M and N, the S and s antigens are antithetical, and their difference is the result of a single amino acid change in the protein structure.
A related antigen, U, is also carried on the GPB protein and is considered a high-prevalence antigen because it is present on the red blood cells of most people. In rare cases, an individual may inherit genes that result in the complete absence of the GPB protein. These individuals are U-negative and are most commonly found in populations of African descent.
Clinical Significance in Transfusions and Pregnancy
Antibodies to MNS antigens are not present in the blood naturally. They are immune-stimulated, meaning they develop after exposure to red blood cells with MNS antigens different from one’s own. This exposure can happen through a blood transfusion or during pregnancy when fetal red blood cells enter the mother’s circulation.
The antibodies that cause the most concern in transfusions are those directed against the S, s, and U antigens. Anti-S and anti-s can lead to a hemolytic transfusion reaction, which is the destruction of transfused red blood cells. These reactions can be delayed, occurring days or weeks after the transfusion. An antibody to the U antigen can cause severe hemolytic reactions in the rare individuals who are U-negative and receive U-positive blood.
In contrast, antibodies against the M and N antigens are considered less of a threat. Anti-M and anti-N antibodies are sometimes found in individuals who have never had a transfusion or been pregnant. These antibodies often react best at temperatures below normal body temperature and are of a type (IgM) that does not cause significant destruction of red blood cells, though some anti-M can react at body temperature and have been associated with transfusion reactions.
The MNS system is also a concern in obstetrics, where it can be implicated in Hemolytic Disease of the Fetus and Newborn (HDFN). This condition occurs when a pregnant person has antibodies that cross the placenta and attack the red blood cells of the fetus. If a mother develops antibodies to an MNS antigen she lacks, and the fetus inherits that antigen from the father, the attack on fetal red cells can lead to anemia and other serious complications.
Population Distribution and Disease Associations
The frequencies of the main MNS antigens show considerable variation across different global populations. For example, the M and N alleles are found at roughly equal frequencies in many populations, making the M+N+ phenotype the most common. However, some populations show different patterns; the M/M genotype is common among the Inuit but rare in Australian Aborigines, who more frequently have the N/N genotype.
Frequencies of the S and s alleles also differ among ethnic groups. The S allele is present in about 55% of Caucasians but only around 30% of individuals of African descent. Conversely, the s allele is common in both groups, found in approximately 90% of individuals.
Beyond blood compatibility, the glycophorin proteins that carry MNS antigens are involved in interactions with infectious diseases. The malaria parasite, Plasmodium falciparum, uses these proteins, particularly GPA, as receptors to invade red blood cells. This relationship has exerted evolutionary pressure on the MNS system.
Certain MNS phenotypes, especially those involving variants or the absence of glycophorin proteins, can provide resistance to malaria. For instance, individuals who lack the GPB protein (the U-negative phenotype) show resistance to invasion by P. falciparum.
Laboratory Testing and Identification
Typing for the MNS blood group system is not routine like ABO and Rh typing. Instead, specialized blood bank laboratories perform MNS antigen testing when a patient’s pre-transfusion screening reveals an unexpected antibody in their plasma.
The identification process involves testing a person’s red blood cells with commercially prepared antibody reagents, known as antisera. These reagents contain known antibodies like anti-M, anti-N, anti-S, and anti-s. If the red blood cells have a corresponding antigen, they will clump together in a process called agglutination.
Observing which antisera cause agglutination allows laboratory professionals to determine the person’s MNS phenotype. This information is used to select compatible blood for transfusion that lacks the antigen to which the patient has an antibody. This matching is important for patients requiring chronic transfusion support to prevent new antibodies from forming.