The Gerbich blood group system, more than most others, owes its definition to the membrane protein chemists than to the serologists. The system now contains seven antigens of which the majority were included in the system by molecular or biochemical studies. Serology contributed to their discovery but could not resolve the group relationships of one antigen to another.

In 1960, Rosenfield et al. described three examples of an antibody reactive with a high incidence antigen they named Gerbich (Ge) after one of the first individuals. Cleghorn (1961) found that the anti-Ge producing patient reported by Barnes and Lewis (1961) was serologically reactive with the serum of one of the original three reported by Rosenfield et al. Thus soon after its description, the Ge group was shown to be subdivisible into at least two sets. Booth and McLoughlin (1972) added further complexities to this quandary when they reported that some Melanesians of Papua New Guinea had an antibody non-reactive with all Ge- cells (both sets) and 15% of the Ge+ Melanesians. At this point, there appeared to be at least three subdivisions of the high incidence antigens within the Gerbich group. Despite numerous serological tests of Ge- individuals and their families little was resolved except that these factors appeared to be unrelated to any of the other known blood groups systems.

Testing monoclonal antibodies to red cells membranes revealed some which were non-reactive with Ge- red cells. Anstee et al. (1984) reported serological tests of such an antibody and described the extremely rare "Leach phenotype", the null phenotype for the Gerbich system. The red cells of this individual where found to lack Glycophorin C and D, in addition to being elliptocytic. This supported previous red cell membrane studies that had indicated that Ge antigens were located on Glycophorin C and/or D. Using immunoblotting techniques, other antibodies against low incidence factors were located on these glycophorins.

Glycophorin C and D, products of a single gene located on the long arm of chromosome 2 (2q14-q21) are single-pass membrane sialoglycoproteins. They may function in membrane integrity and interact with protein 4.1; similiarly, they are markedly reduced in protein 4.1 deficient red cells (which is associated with hereditary elliptocytosis). The various antigens of the Gerbich system are associated with amino acid substitutions on Glycophorin C and/or D. The Leach phenotype (less than 10 known through out the world) arises from either of two types of gene mutations, ie. either a 2kb deletion in exons 3-4 or a frameshift causing a premature stop codon. None of the presently known Gerbich systems antigens appear to be products of allelic genes, as has been found in other systems.

Antibodies to the Gerbich antigens have been associated with transfusion reactions and mild hemolytic disease of the newborn. Red cells with the Leach phenotype have reduced in vitro invasion by malaria parasites, specifically Plasmodium falciparum. It has been suggested that the high incidence of the Ge-negative phenotype in Melanesians may be related to the high prevalence of malaria in Northern New Guinea. In addition, GP C/D, band 4.1 and p55 form a ternary complex which is critical for the red cell stability.