Duffy antigen system

The Duffy antigen system is a blood system in which a pair of proteins appears on the outside of red blood cells. It was named after the patient in which it was discovered. ^[1]

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A person who has "Duffy negative" blood (no Duffy antigen naturally present) may be allergic, perhaps seriously allergic, to a blood transfusion which is "Duffy positive" (has this pair of proteins). Nearly all Caucasians are Duffy-positive, and a majority of those of African descent are Duffy-negative.^[2] Since most Duffy-negative people are of African origin, this is one reason why encouraging blood donations from people of African origins is critically important to the health of other people of the same race.

In 1950 the Duffy antigen was discovered in a multiply transfused hemophiliac whose serum contained the first example of anti-Fya. In 1951 the antibody to a second antigen, Fyb, was discovered in the serum of a woman who had been pregnant three times. Using these antibodies three common phenotypes were defined: Fy(a+b+), Fy(a+b-), and Fy(a-b+).

Genetics and genomics

The Duffy antigen gene (gp-Fy; CD234) is located on the long arm of chromosome 1 (1.q22-1.q23) and was cloned in 1993. It is a single copy gene and encodes a 336 amino acid acidic glycoprotein. The gene carries the antigenic determinants of the Duffy blood group system consisting of four alleles - FY*A and FY*B - coding for the Fya and Fyb antigens respectively, FY*X and FY*Fy, five phenotypes (Fy-a, Fy-b, Fy-o, Fy-x and Fy-y) and five antigens. Fya and Fyb differ by in a single amino acid at position 43: aspartic acid in Fya and glycine in Fyb. The genetic basis for the Fy(a-b-) phenotype is a point mutation in the erythroid specific promoter.

The Duffy antigen/chemokine receptor gene (DARC) is composed of a single exon. Most Duffy negative blacks carry a silent Fy-b allele with a single T to C substitution at nucleotide -46, impairing the promoter activity in erythroid cells by disrupting a binding site for the GATA1 erythroid transcription factor. The gene is still transcribed in non erythroid cells in the presence of this mutation.

Differences in the racial distribution of the Duffy antigens were discovered in 1954 when it was found that the majority of blacks had the erythrocyte phenotype Fy(a-b-): 68% in African Americans and 88-100% in African blacks (including more than 90% of West African blacks).^[3] This phenotype is exceedingly rare in whites.

The mutation Ala100Thr (G -> A in the first codon position - base number 298) within the FY*B allele was thought to be purely a Caucasian genotype, but has since been described in Brazilians.^[4]

This antigen along with other blood group antigens was used to identify the Basque people as a genetically separate group.^[5] Its use in forensic science is under consideration.^[6]

The Andaman and Nicobar Islands, now part of India, were originally inhabited by 14 aboriginal tribes. Several of these have gone extinct. One surviving tribe - the Jarawas - live in three jungle areas of South Andaman and one jungle area in Middle Andaman. The area is endemic for malaria. The causative species is Plasmodium falciparum: there is no evidence for the presence of Plasmodium vivax. Blood grouping revealed an absence of both Fy(a) and Fy(b) antigens in two areas and a low prevalence in two others.^[7]

In the Yemenite Jews the frequency of the Fy allele is 0.5879.^[8] The frequency of this allelle varies from 0.1083 to 0.2191 among Jews from the Middle East, North Africa and Southern Europe.

In the Chinese ethnic populations - the Han and the She people - the frequencies of Fya and Fyb alleles were 0.94 and 0.06 and 0.98 and 0.02 respectively.^[9]

In Grande Comore (also known as Ngazidja) the frequency of the Fy(a- b-) phenotype is 0.86.^[10]

Molecular biology

Duffy has been found to act as a multispecific receptor for chemokines of both the C-C and C-X-C families, including: melanoma growth stimulatory activity (MGSA),^[11] regulated upon activation normal T expressed and secreted (RANTES; CCL5)^[12] monocyte chemotatic protein-1 (MCP-1; CCL2)^[13] and the angiogenic CXC chemokines interleukin-8 (IL-8, CXCL8), growth related gene alpha (GRO-α, CXCL1), neutrophil activating peptide-2 (NAP-2, CXCL7) and ENA-78 (CXCL5). Consequently the Fy protein is also known as DARC (Duffy Antigen Receptor for Chemokines). The binding site appears to be localised to the amino terminus.^[14]

While Duffy is expressed on erythrocytes the Duffy antigen is found on some epithelial cells, Purkinje cells of the cerebellum,^[15] endothelial cells of thyroid capillaries, the post-capillary venules of some organs^[16] and the large pulmonary venules.

The antigen is predicted to have 7 transmembrane domains, an exocellular N-terminal domain and an endocellular C-terminal domain. Alignment with other seven transmembrane G-protein-coupled receptors shows that DARC lacks the highly conserved DRY motif in the second intracellular loop of the protein that is known to be associated with G-protein signaling. Consistent with this finding ligand binding by DARC does not induce G-protein coupled signal transduction nor a Ca2+ flux unlike other chemokine receptors. Based on these alignments the Duffy antigen is considered to be most similar to the interleukin-8B receptors.

On erythrocytes the Duffy antigen acts as a receptor for invasion by the human malarial parasites Plasmodium vivax and Plasmodium knowlesi; Duffy negative individuals whose erythrocytes do not express the receptor are believed to be resistant to merozoite invasion,^[17] although the American journal of tropical medicine and hygiene has reported P. vivax infection in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection.^[18] This antigen may also play a role in erythrocyte invasion in the rodent malarial parasite Plasmodium yoelii.

In DARC-transfected cells, DARC is internalized following ligand binding and this led to the hypothesis that expression of DARC on the surface of erythrocytes, endothelial, neuronal cells and epithelial cells may act as a sponge and provide a mechanism by which inflammatory chemokines may be removed from circulation as well as their concentration modified in the local environment.^[19]

This hypothesis has also been questioned after knock out mice were created. These animals appeared healthy and had normal responses to infection. While the function of the Duffy antigen remains presently (2006) unknown, evidence is accumulating that suggests a role in neutrophil migration from the blood into the tissues^[20] and in modulating the inflammatory response.^{[21][22][23][24][25][26][27][28][29][30]} It may also play a role in the control of cancer.^[31]

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