Duffy antigen

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Duffy antigen
Identifiers
Symbol(s) DARC
Entrez 2532
OMIM 110700
RefSeq NM_002036
UniProt Q16570
Other data
Locus Chr. 1 q21-q22

The Duffy antigen is a pair of proteins which appears on the outside of red blood cells.

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[1]. 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+).

Contents

[edit] 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).[2] 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. [3]

This antigen along with other blood group antigens was used to identify the Basques as a genetically separate group. [4] Its use in forensic science is under consideration. [5]

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. [6]

In the Yemenite Jews the frequency of the Fy allele is 0.5879. [7] 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 Hans and the Shes - the frequencies of Fya and Fyb alleles were 0.94 and 0.06 and 0.98 and 0.02 respectively. [8]

In Grande Comore Island - also known as Njazidja - the frequency of the Fy(a- b-) phenotype is 0.86. [9]

[edit] 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)[10], regulated upon activation normal T expressed and secreted (RANTES; CCL5)[11], monocyte chemotatic protein-1 (MCP-1; CCL2) [12]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. [13]

While Duffy is expressed on erythrocytes the Duffy antigen is found on some epithelial cells, Purkinje cells of the cerebellum [14] endothelial cells of thyroid capillaries, the post-capillary venules of some organs [15] 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 were believed to be resistant to infection,[16] although the American journal of tropical medicine and hygiene has reported P. vivax infection in Duffy negative children in Kenya. PMID 17038676 [17] 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 [18] 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 [19] and in modulating the inflamatory response [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] It may also play a role in the control of cancer. [30]

[edit] References

  1. ^ Nickel RG, Willadsen SA, Freidhoff LR, Huang SK, Caraballo L, Naidu RP, Levett P, Blumenthal M, Banks-Schlegel S, Bleecker E, Beaty T, Ober C, Barnes KC. Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides. Hum Immunol. 1999 Aug;60(8):738-42. PMID 10439320
  2. ^ Levinson, W. 2004. Medical Microbiology and Immunology. Lange Medical Books: New York. ISBN 0-07-143199-3
  3. ^ Estalote AC, Proto-Siqueira R, Silva WA Jr, Zago MA, Palatnik M. (2005) The mutation G298A --> Ala100Thr on the coding sequence of the Duffy antigen/chemokine receptor gene in non-caucasian Brazilians. Genet Mol Res. 4(2):166-173
  4. ^ Bauduer F, Feingold J, Lacombe D. (2005) The Basques: review of population genetics and Mendelian disorders. Hum Biol. 77(5):619-637
  5. ^ Ferri G, Bini C, Ceccardi S, Ingravallo F, Lugaresi F, Pelotti S. (2006) Minisequencing-based genotyping of Duffy and ABO blood groups for forensic purposes. J Forensic Sci. 51(2):357-360
  6. ^ Das MK, Singh SS, Adak T, Vasantha K, Mohanty D. (2005) The Duffy blood groups of Jarawas - the primitive and vanishing tribe of Andaman and Nicobar Islands of India. Transfus Med. 15(3):237-240
  7. ^ Kobyliansky E, Micle S, Goldschmidt-Nathan M, Arensburg B, Nathan H. (1980) Duffy, Kell and P blood group systems in some Jewish populations of Israel. Acta Anthropogenet. 4(3-4):173-179
  8. ^ Yan L, Zhu F, Fu Q, He J. (2005) ABO, Rh, MNS, Duffy, Kidd,Yt, Scianna, and Colton blood group systems in indigenous Chinese. Immunohematol. 21(1):10-14
  9. ^ Chiaroni J, Touinssi M, Frassati C, Degioanni A, Gibert M, Reviron D, Mercier P, Boetsch G. (2004) Genetic characterization of the population of Grande Comore Island (Njazidja) according to major blood groups. Hum Biol. 76(4):527-541
  10. ^ Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, Miller LH. A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Science. (1993) 261, 1182-1184
  11. ^ Horuk R, Wang ZX, Peiper SC, Hesselgesser J. Identification and characterization of a promiscuous chemokine-binding protein in a human erythroleukemic cell line. J Biol Chem. (1994) 269(26):17730-17733.
  12. ^ Chaudhuri A, Zbrzezna V, Polyakova J, Pogo AO, Hesselgesser J, Horuk R. Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor. J Biol Chem. (1994) 269(11):7835-7838.
  13. ^ Lu ZH, Wang ZX, Horuk R, Hesselgesser J, Lou YC, Hadley TJ, Peiper SC. The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain. J Biol Chem. (1995) 270(44):26239-26245.
  14. ^ Horuk R,Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC. Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol. (1997) 158(6):2882-2890,
  15. ^ Hadley TJ, Lu ZH, Wasniowska K, Martin AW, Peiper SC, Hesselgesser J, Horuk R. Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen. J Clin Invest. (1994) 4(3):985-991.
  16. ^ Miller LH, Mason SJ, Clyde DF, McGinniss MH. "The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy." N Engl J Med. 1976 Aug 5;295(6):302-4. PMID 778616
  17. ^ Ryan JR, Stoute JA, Amon J et. al, "Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in Western Kenya". Am J Trop Med Hyg. 2006 Oct;75(4):575-81.
  18. ^ Fukuma N, Akimitsu N, Hamamoto H, Kusuhara H, Sugiyama Y, Sekimizu K. A role of the Duffy antigen for the maintenance of plasma chemokine concentrations. Biochem Biophys Res Commun. (2003) 303(1):137-139.
  19. ^ Lee JS, Frevert CW, Wurfel MM, Peiper SC, Wong VA, Ballman KK, Ruzinski JT, Rhim JS, Martin TR, Goodman RB. Duffy antigen facilitates movement of chemokine across the endothelium in vitro and promotes neutrophil transmigration in vitro and in vivo. J Immunol. (2003) 170(10):5244-5251.
  20. ^ Dawson TC, Lentsch AB, Wang Z, Cowhig JE,Rot A, Maeda N, Peiper SC. Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC). Blood. (2000) 96(5):1681-1684.
  21. ^ Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J. Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. J Pathol. (2002) 197(1):108-116.
  22. ^ Liu XH, Hadley TJ, Xu L, Peiper SC, Ray PE. Up-regulation of Duffy antigen receptor expression in children with renal disease. Kidney Int. (1999) 55(4):1491-500.
  23. ^ Rot A. Contribution of Duffy antigen to chemokine function. Cytokine Growth Factor Rev. (2005) 16(6):687-694.
  24. ^ Segerer S, Regele H, MacK M, Kain R, Cartron JP, Colin Y,Kerjaschki D, Schlondorff D. The Duffy antigen receptor for chemokines is up-regulated during acute renal transplant rejection and crescentic glomerulonephritis. Kidney Int. (2000) 58(4):1546-1556
  25. ^ Segerer S, Cui Y, Eitner F, Goodpaster T, Hudkins KL, Mack M, Cartron JP, Colin Y, Schlondorff D, Alpers CE. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis. (2001) 37(3):518-531.
  26. ^ Bruhl H, Vielhauer V, Weiss M, Mack M, Schlondorff D, Segerer S. Expression of DARC, CXCR3 and CCR5 in giant cell arteritis. Rheumatology (Oxford). (2005) 44(3):309-313.
  27. ^ Middleton J, Americh L, Gayon R, Julien D, Mansat M, Mansat P, Anract P, Cantagrel A, Cattan P, Reimund JM, Aguilar L, Amalric F, Girard JP. A comparative study of endothelial cell markers expressed in chronically inflamed human tissues: MECA-79, Duffy antigen receptor for chemokines, von Willebrand factor, CD31, CD34, CD105 and CD146. J Pathol. (2005) 206(3):260-268.
  28. ^ Segerer S, Bohmig GA, Exner M, Colin Y, Cartron JP, Kerjaschki D, Schlondorff D, Regele H. When renal allografts turn DARC. Transplantation. (2003) 75(7):1030-1034
  29. ^ Pruenster M, Rot A. Throwing light on DARC. Biochem Soc Trans. (2006) 34(Pt 6):1005-1008
  30. ^ Zijlstra A, Quigley JP. The DARC side of metastasis: shining a light on KAI1-mediated metastasis suppression in the vascular tunnel. Cancer Cell. (2006) 10(3):177-178.

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