Review

The Duffy group system: a review

G.M. Meny

Duffy was the fi rst blood group mapped to an autosome (chromo- study. The Un locus causes chromosome 1 to have an un- some 1) using cytogenetic studies. Duffy antigens are located on usual lengthy appearance when viewed in metaphase. De- a glycoprotein that can be found on erythrocytes and other cells scribing a family with an inversion break point provided a b throughout the body. Fy and Fy are products of their respective additional evidence for assigning the Duffy locus to chro- alleles (FY*A, FY*B). Fyx, characterized by weak Fyb expression, is mosome 1. a result of an additional mutation in FY*B. The Fy(a–b–) pheno- type, most commonly found in Blacks, occurs primarily as a result of a GATA promoter region mutation upstream of the FY allele. Genetics and Inheritance This mutation prevents expression of Duffy glycoprotein on eryth- Both FY and RH gene loci reside on chromosome 1. rocytes only, while permitting expression on nonerythroid cells. However, the FY locus is located on the long arm at posi- Other antigens include Fy3, Fy5, and Fy6. Antibodies to Duffy tion 1q22→ q23, whereas RH resides on the short arm.5 Fya antigens are usually clinically signifi cant and have been reported and Fyb are antithetical antigens produced by codominant to cause hemolytic of the fetus and newborn. This review alleles, FYA and FYB. Four phenotypes are defi ned by the provides a general overview of the Duffy blood group system, in- corresponding antibodies, anti-Fya and anti-Fyb (see Table cluding the role of the Duffy glycoprotein as a chemokine receptor 1). The Duffy system antigens are listed in Table 2. (Duffy antigen receptor for chemokines) and in malarial infection. Immunohematology 2010;26:51–56. Table 1. Duffy phenotypes, prevalence, and inherited alleles

Key Words: Duffy antigen receptor for chemokines, DARC, FYA, FYB Red cell Prevalence % phenotype Caucasians Blacks Allele History Fy(a+b–) 20† 10 † FY*01/FY*01 or he initial description related to the Duffy blood group FY*A/FY*A a system was published in 1950 when anti-Fy was Fy(a–b+) 32 20 FY*02/FY*02 or observed during an investigation of a hemolytic FY*B/FY*B T 1,2 transfusion reaction. The antibody was described in a Fy(a+b+) 48 3 FY*A/FY*B 43-year-old group O, D– individual with hemophilia who Fy(a–b–) Very rare 67 FY*/N.01–05, received a 3-unit transfusion for treatment of an episode FY*/N.01–02‡ of spontaneous bruising and bleeding. The transfusions †Present in 70–90% of some Asian populations. were followed by rigors. Jaundice developed the day after ‡Nomenclature pending approval by the ISBT Working Party on transfusion. Investigation revealed an antibody that was Terminology for Red Cell Surface Antigens Table modifi ed from Daniels.6,7 detected only by the IAT and was named anti-Duffy (anti- Fya) after the patient. An Fya phenotype frequency of 64.9 7 percent was calculated, and gene frequencies for both Fya Table 2. Duffy antigens and the hypothetical Fyb were described. Antigen ISBT symbol ISBT no. b 3 One year later, anti-Fy was discovered by Ikin et al. Fya FY1 008001 in a patient 2 days after the birth of her third child. None Fyb FY2 008002 of the children were noted to show signs of HDN. Antibody Fy3 FY3 008003 investigations demonstrated that stronger reactions were 4 observed when the antibody was tested in the presence of Fy FY4 008004 albumin than of saline and at 37°C than at room tempera- Fy5 FY5 008005 ture. Confi rmation of a previously calculated Fyb phenotype Fy6 FY6 008006 frequency was noted. Of interest, the authors speculated on the possibility of a rare third allele, which would react with The Fy(a–b–) phenotype is the major phenotype neither antibody. in Blacks, but is very rarely found in Caucasians. The phe- Duffy was the fi rst blood group locus to be assigned to an notype found in Blacks is characterized by the presence of autosome (a nonsex chromosome). Investigators performed Fyb antigen on nonerythroid cells, but an absence of the Fyb linkage analysis between serologic blood typing results and antigen on RBCs.8 A mutation in the erythroid promoter cytogenetic studies on four families, one of which was a GATA-1 binding motif explains why Fy(a–b–) individuals three-generation family.4 The Duffy locus segregated with do not make anti-Fyb (see Molecular section). The Fy(a–b–) the uncoiler (Un) locus on chromosome 1 in three family phenotype found in Caucasians is characterized by a lack of studies and an inversion of chromosome 1 in one family

IMMUNOHEMATOLOGY, Volume 26, Number 2, 2010 51 G.M Meny

Duffy antigen expression in both erythroid and noneryth- delayed hemolytic transfusion reactions.17,22,23 Of interest, roid tissues. Different mutations are present in either the Vengelen-Tyler17 noted that anti-Fy3 developed after anti- FYA or FYB gene, which prevent the Duffy protein from be- Fya in individuals receiving multiple RBC transfusions for ing formed. These individuals, interestingly, tend to form treatment of , and Olteanu et al.22 report- anti-Fy3.9–11 ed a case of an acute hemolytic transfusion reaction caused Other alleles have been reported at the FY locus. The solely by anti-Fy3 in an 8-year-old Black individual treated Fyx phenotype is associated with weak expression of Fyb, for repair of a femoral neck fracture. Fy3, and Fy5 antigens. Chown et al.12 first reported the Fyx The only example of anti-Fy4 was described by Behzad gene and estimated the phenotype frequency in a Caucasian et al.24 in a 12-year-old patient with sickle cell disease. This population was not more than 2 percent. It is now known antibody appeared to react with Fy(a–b–), some Fy(a+b–) that Fyx is caused by a point mutation in the FYB gene.13,14 or Fy(a–b+), but no Fy(a+b+) RBCs. However, the existence of this antibody is in doubt owing to the lack of consistent Antibodies in the System test results between laboratories and sample instability on Anti-Fya and -Fyb storage and shipment. Anti-Fya and -Fyb are found after transfusion or, less fre- Colledge et al.25 reported the first example of anti-Fy5 in quently, as a result of pregnancy. They are rarely naturally an 11-year-old Fy(a–b–) Black individual who died of acute occurring. Duffy antibodies are predominantly of the IgG1 leukemia shortly after the antibody was discovered. Like subclass, and 50 percent of anti-Fya examples bind comple- anti-Fy3, anti-Fy5 reacted with enzyme-treated Fy(a+) or ment. Anti-Fyb, identified about 20 times less frequently Fy(b+) RBCs. No reactivity was seen with Fy(a–b–) RBCs a than anti-Fy , is usually present in sera with other alloan- from Black individuals, or Rhnull cells with normal expres- tibodies.15 Both antibodies cause immediate and delayed sion of Fya and Fyb antigens. One Fy(a–b–) RBC sample hemolytic transfusion reactions.16 When Fy(a–b–) Black from a Caucasian individual was positive. Anti-Fy5 is re- individuals develop Duffy antibodies, they usually produce ported to cause delayed hemolytic transfusion reactions in anti-Fya, which may be followed by anti-Fy3 or anti-Fy5.17,18 patients with sickle cell disease who develop this antibody Anti-Fyb is not produced. in conjunction with other blood group antibodies such as With regard to hemolytic disease of the fetus and new- anti-Fya,17,26 and anti-K, -E, and -C.27 born (HDFN), anti-Fya was identified in 5.4 percent of No human anti-Fy6 has been identified. Monoclonal atypical alloantibodies in a group of women receiving ob- antibodies have been raised against Fy6 epitopes, as well as stetric care at a tertiary-care center. Of antibodies capable other Duffy blood group epitopes.28–30 of causing HDFN, Kell blood group antibodies were identi- fied most frequently (22%). In contrast, anti-Fyb was infre- Biochemistry quently identified (0.2%). This compares with 0.5 percent The Duffy protein is composed of 336 amino acids. The to 3.1 percent of Duffy system antibodies detected in four numbering of amino acids (and nucleotides) has varied be- other series of obstetric patients.19 cause two kinds of Duffy mRNA have been described: a less Hughes et al.20 reviewed the clinical outcome of 18 abundant form, that was the first to be discovered and cloned, pregnant women between 1959 and 2004 in whom anti- encodes a protein of 338 amino acids whereas the more abun- Fya was the only alloantibody identified and the fetus was dant form encodes a protein of 336 amino acids and is the Fy(a+). Significant HDFN was identified in 2 of 18 (11%) form that is represented in Figure 1.31,32 The Duffy protein is pregnancies, resulting in exchange transfusion or intrauter- likely organized in the RBC membrane as an N-glycosylated ine transfusion. Maximum serum titers in these cases were protein that spans the membrane seven times (Fig. 1). Fya and 32 and 128. Hydrops fetalis was not identified in any fetus, Fyb differ by a single amino acid change at position 42 on the and no deaths attributable to HDFN were reported. A rare extracellular domain, with glycine resulting in Fya expression case of HDFN caused by anti-Fyb has been reported.21 and aspartic acid resulting in Fyb expression.5,33 Both Fya and Fyb are sensitive to destruction when RBCs are treated with Anti-Fy3, -Fy4, -Fy5, and -Fy6 proteolytic enzymes such as papain or ficin. Trypsin treatment Anti-Fy3 was first described by Albrey et al.9 in a Cauca- of RBCs does not result in destruction of Fya or Fyb.6 sian individual who was pregnant with her third child. The The Fy(a–b+w) phenotype is associated with weak Fyb, authors noted that this antibody’s reactivity “suggests that Fy3, and Fy6 expression. This phenotype results from a mu- the Duffy system is more complicated than it seemed be- tation in the FYB gene. The Fyx-associated mutation at posi- fore.” Anti-Fy3 was unique in that it reacted with enzyme- tion 89 in the first cytoplasmic loop (Fig. 1) causes the Duffy treated Fy(a+) or Fy(b+) RBCs, but failed to react with protein to be unstable. This intracellular amino acid change Fy(a–b–) RBCs from Black individuals. Clinically, the baby causes a quantitative reduction in the amount of Duffy protein was reported to have mild HDFN (weakly positive DAT), and, hence, a decreased amount of Fyb, Fy3, and Fy6 expres- but no treatment was required. sion. The Arg89Cys change was found in 3.5 percent of Cau- Subsequent reports of anti-Fy3 have also been de- casians, but was not found in Blacks. Another mutation in the scribed in Black individuals during investigation of acute or same area (Ala100Thr) does not alter Duffy expression.13,34

52 IMMUNOHEMATOLOGY, Volume 26, Number 2, 2010 Duffy blood group system

not on other cells.39 Thus, Duffy mRNA can be detected in nonerythroid cells such as lung, spleen, and colon of Black individuals with a mutated GATA box. However, bone mar- row cells from the same individuals are negative for Duffy mRNA expression. The genetic mutations found in Fy(a–b–) Caucasians do not resemble those identified in Black individuals. Three individuals from multiple ethnic backgrounds (Cree Indi- an, Lebanese Jewish, and Caucasian English) were found to have point mutations that encoded premature stop codons in either FY*A or FY*B. These mutated genes, if translated Fig. 1. The predicted Duffy glycoprotein seven-transmembrane into proteins, result in unstable products that are quickly domain structure. Amino acid changes responsible for the Fya/ degraded. Thus, the Duffy proteins in Caucasian individu- Fyb polymorphism, the Fyx mutation, and Fy3 and Fy6 regions are als are absent from all tissues, including RBCs.11 indicated. N-glycosylation sites are shown as Y. Reprinted with 32 permission from Westhoff and Reid. Clinical Significance Duffy Glycoproteins and Chemokines Chemokines are proteins secreted by cells, such as im- The epitopes identified by monoclonal antibodies to mune cells, which are used as communication signals to Fy3 and Fy6 have been characterized. The Fy3 epitope is guide their interactions.40 Chemokine messages secreted present on the third extracellular loop.35 Fy3, like Fy5, is from one cell are received and decoded by another cell via resistant to destruction when RBCs are treated with prote- specific receptors, leading to various responses such as olytic enzymes.6 The Fy6 epitope is located N-terminal to leukocyte chemotaxis and adhesion. Similar to the Duffy the Fya/Fyb site and is composed of multiple amino acids glycoprotein, many chemokine receptors have seven trans- located between positions 19 and 25.28 Unlike Fy3, Fy6 is membrane domains. However, whereas other chemokine destroyed when RBCs are treated with proteolytic enzymes. receptors specifically bind chemokines of a single class, the Like Fya and Fyb, trypsin treatment of RBCs does not result Duffy glycoprotein was found to bind a variety of chemok- in destruction of Fy6.6 ines and is known as the Duffy antigen receptor for chemok- ines (DARC).41,42 Molecular The function of DARC is yet to be clearly defined. It has FYA and FYB been suggested that DARC may permit the erythrocyte to The biochemical differences in Fya and Fyb antigens serve as a chemokine “sink” or scavenger, thus limiting ac- can be explained at a molecular level by a single nucleotide tivation of leukocytes in the systemic circulation. However, substitution. This substitution (G codes for Fya and A codes it is unclear how long chemokines remain bound to the cell for Fyb) allowed DNA typing of the main Duffy antigens to surface or what happens to the chemokines at the end of be performed as the FY*A sequence correlated with a BanI the erythrocyte lifespan. In addition, it is unclear as to the restriction site.36 importance of this function in inflammatory or infectious disease as Fy(a–b–) erythrocytes do not bind chemokines, Fy(a–b–) Phenotype although Fy(a–b+w) erythrocytes bind reduced amounts The Fy(a–b–) phenotype, detected in approximately 70 compared with Fy(a–b+) cells.34,41–43 percent of Black individuals, is identified very rarely in Cau- casians. The molecular basis for this disparity is not only DARC and Renal Disease interesting from a scientific perspective, but has clinical im- If DARC serves as a scavenger or chemokine sink as part plications as well (see Clinical Significance). Erythroid-only of an effort to limit inflammation, what role could DARC suppression of Duffy antigen expression occurs because of a play in modulating an immune response in renal disease point mutation in the GATA-1 binding site in Black individ- and renal transplantation? Using an anti-Fy6 monoclo- uals who have the Fy(a–b–) phenotype.8 GATA sequences nal antibody, Liu et al.44 performed immunohistochemical are plentiful in the genome and function as promoters of studies of renal biopsies from children with renal disease many genes, including those involved in hematopoiesis.37 to examine Duffy antigen expression. Renal cell DARC ex- The mutation present in the GATA promoter region of pression was found to be upregulated in multiple causes of FY*B (–67, T to C) disrupts a binding site for the GATA-1 renal cell injury, including HIV nephropathy and hemolytic erythroid transcription factor. A similar mutation has been uremic syndrome. The authors speculate that the increased identified in the GATA-1 promoter region ofFY*A as well.38 DARC expression may be the kidney’s attempt to bind and Duffy antigen expression is prevented on erythrocytes, but neutralize chemokines and control inflammation. They also

IMMUNOHEMATOLOGY, Volume 26, Number 2, 2010 53 G.M Meny speculate that the high incidence of HIV nephropathy in with sickle cell disease, and any patient who makes one al- Black individuals may thus be associated with the Fy(a–b–) loantibody are at a higher risk of forming multiple antibod- phenotype. ies.52 Duffy genotyping may be of assistance in providing Other groups have attempted to find a correlation be- matched blood by determining, for example, which Fy(a– tween Duffy antigen expression and renal graft survival, with b–) patients carry the GATA-1 mutation in the promoter re- mixed results. Akalin and Neylan45 found Duffy-negative gion of FY*B, as it is theorized that they can receive Fy(b+) graft recipients had lower allograft survival compared with blood without risk of forming anti-Fyb or anti-Fy3.53 Issues recipients of other phenotypes and speculated that a loss to consider in the use of Duffy genotyping include the need of ability to bind chemokines leads DARC-negative recipi- to detect silencing mutations, the potential for contamina- ents to be more vulnerable to poor graft function. Mange et tion of PCR-based assays, and the importance of correlating al.46 did not confirm an association between a graft recipi- genotype results with phenotype results. ent with a null DARC phenotype and an increased incidence of acute renal allograft rejection or delayed graft function. Summary One recent paper examined Duffy antigen mismatches be- “Kell Kills, Duffy Dies, Lewis Lives” tween recipient and donor renal transplants and suggests a Me d i c a l s t u d e n t m a n t r a r e l a t e d t o alloantibody c l i n i c a l s i g - potential role for Duffy as a minor histocompatibility anti- n i f i c a n c e gen.47 Many of the important discoveries in blood group se- DARC and rology in the first half of the last century were descriptive in In addition to serving as a chemokine receptor, the nature and focused on identification of RBC antigens and Duffy glycoprotein has been shown to be the erythroid re- the clinical significance of their corresponding antibodies. ceptor for Plasmodium vivax and Plasmodium knowlesi. The Duffy blood group system illustrates the progress made Initially, P. knowlesi, a monkey malaria parasite, was used in elucidating the structure and function of blood group as an in vitro model to study human malaria. However, antigens. The Duffy glycoprotein acts as an erythrocyte re- Miller et al.48 performed blood typing on 11 volunteers ex- ceptor for certain malarial parasites and as a chemokine posed to P. vivax–infected mosquitoes and found that those receptor (DARC). DARC may play a role in modulating the who contracted malaria were Fy(a+) or Fy(b+), whereas effects of certain renal , as well as other disease 54 55 those whose erythrocytes were resistant to parasitic inva- states such as HIV or malignancy. Although significant sion were Fy(a–b–). Evidence has since shown that the P. progress has been made, much research remains to be com- vivax Duffy-binding protein (PvDbp) interacts with Duffy pleted to understand the structure and function of DARC. antigens on RBCs to permit RBC infection and that PvDbp may be a candidate for vaccine development.49 Acknowledgment P. vivax malaria is the most widely distributed malar- The author thanks Connie Westhoff for her discussion ia in the world, with approximately 70 to 80 million cases and helpful comments during preparation of this manu- occurring per year.50 Individuals with the Fy(a–b–) phe- script. notype may have a selective advantage in that their RBCs are resistant to P. vivax invasion. This is evident in West References Africa, where P. vivax malaria is absent and greater than 1. Cutbush M, Mollison PL. The Duffy blood group sys- 95 percent of the population is Fy(a–b–). However, a few tem. Heredity 1950;4:383–9. contradictions to a genetic adaptation hypothesis remain 2. Cutbush M, Mollison PL, Parkin DM. A new human to be explained: the Fy(a–b–) phenotype is not common in blood group. Nature 1950;165:188–9. Southeast Asia, another endemic area of P. vivax malaria, 3. Ikin EW, Mourant AE, Pettenkofer JH, Blumenthal G. b and P. vivax malaria infection is not lethal.5,50 Discovery of the expected haemagglutinin, anti-Fy . Nature 1951;168:1077–8. The Clinical Value of Duffy Genotyping 4. Donahue RP, Bias WB, Renwick JH, McKusick VA. The use of Duffy DNA-based genotyping determina- Probable assignment of the Duffy blood group locus tions can be an adjunct to traditional phenotyping in clinical to chromosome 1 in man. Proc Natl Acad Sci U S A situations such as assessing for risk of HDFN and locating 1968;61:949–55. matched blood for alloimmunized patients. Goodrick et 5. Pogo AO, Chaudhuri A. The Duffy protein: a malarial and al.51 noted that although anti-Fya rarely causes significant chemokine receptor. Semin Hematol 2000;37:122–9. HDFN, the ability to perform Duffy genotyping of fetal am- 6. Daniels G. Duffy blood group system. In: Human niocytes can be of benefit when the father is heterozygous blood groups. 2nd ed. Malden, MA: Blackwell Science, for FY*A. Regularly transfused patients, such as individuals 2002:324–41.

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7. Daniels G. Terminology for blood groups. Avail- 22. Olteanu H, Gerber D, Partridge K, Sarode R. Acute able at: http://ibgrl.blood.co.uk/ISBTPages/Allele hemolytic transfusion reaction secondary to anti-Fy3. Terminology/Allele-Terminology.htm. (last accessed Immunohematology 2005;21:48–52. 05/23/2010). 23. Went R, Wright J, Webster R, Stamps R. Anti-Fy3 in 8. Tournamille C, Colin Y, Cartron JP, Le Van Kim C. Dis- sickle cell disease: a difficult transfusion problem. Br J ruption of a GATA motif in the Duffy gene promoter Haematol 2009;144:621–2. abolishes erythroid gene expression in Duffy-negative 24. Behzad O, Lee CL, Gavin J, Marsh WL. A new anti- individuals. Nat Genet 1995;10:224–8. erythrocyte antibody in the Duffy system: anti-Fy4. Vox 9. Albrey JA, Vincent EE, Hutchinson J, et al. A new an- Sang 1973;24:337–42. tibody, anti-Fy3, in the Duffy blood group system. Vox 25. Colledge KI, Pezzulich M, Marsh WL. Anti-Fy5, an Sang 1971;20:29–35. antibody disclosing a probable association between 10. Mallinson G, Soo KS, Schall TJ, Pisacka M, Anstee the Rhesus and Duffy blood group genes. Vox Sang DJ. Mutations in the erythrocyte chemokine receptor 1973;24:193–9. (Duffy) gene: the molecular basis of the Fya/Fyb anti- 26. Bowen DT, Devenish A, Dalton J, Hewitt PE. Delayed gens and identification of a deletion in the Duffy gene haemolytic transfusion reaction due to simultane- of an apparently healthy individual with the Fy(a−b−) ous appearance of anti-Fya and anti-Fy5. Vox Sang phenotype. Br J Haematol 1995;90:823–9. 1988;55:35–6. 11. Rios M, Chaudhuri A, Mallinson G, et al. New genotypes 27. Chan-Shu SA. The second example of anti-Duffy5. in Fy(a−b−) individuals: nonsense mutations (Trp to Transfusion 1980;20:358–60. stop) in the coding sequence of either FY A or FY B. Br 28. Waśniowska K, Blanchard D, Janvier D, et al. Identifi- J Haematol 2000;108:448–54. cation of the Fy6 epitope recognized by two monoclo- 12. Chown B, Lewis M, Kaita H. The Duffy blood group sys- nal antibodies in the N-terminal extracellular portion tem in Caucasians: evidence for a new allele. Am J Hum of the Duffy antigen receptor for chemokines. Mol Im- Genet 1965;17:384–9. munol 1996;33:917–23. 13. Olsson ML, Smythe JS, Hansson C, et al. The Fyx phe- 29. Wasniowska K, Petit-LeRoux Y, Tournamille C, et al. notype is associated with a missense mutation in the Structural characterization of the epitope recognized by Fyb allele predicting Arg89Cys in the Duffy glycopro- the new anti-Fy6 monoclonal antibody NaM 185–2C3. tein. Br J Haematol 1998;103:1184–91. Transfus Med 2002;12:205–11. 14. Gassner C, Kraus RL, Dovc T, et al. Fyx is associated 30. Wasniowska K, Lisowska E, Halverson GR, Chaudhuri with two missense point mutations in its gene and A, Reid ME. The Fya, Fy6 and Fy3 epitopes of the Duffy can be detected by PCR-SSP. Immunohematology blood group system recognized by new monoclonal 2000;16:61–7. antibodies: identification of a linear Fy3 epitope. Br J 15. Klein HG, Anstee DJ. Mollison’s in Haematol 2004;124:118–22. clinical medicine. 11th ed. Malden, MA: Blackwell Pub- 31. Iwamoto S, Li J, Omi T, Ikemoto S, Kajii E. Identification lishing, 2005. of a novel exon and spliced form of Duffy mRNA that is 16. Issitt PD, Anstee DJ. Applied blood group serology. 4th the predominant transcript in both erythroid and post- ed. Durham, NC: Montgomery Scientific Publications, capillary venule endothelium. Blood 1996;87:378–85. 1998. 32. Westhoff CM, Reid ME. Review: the Kell, Duffy, 17. Vengelen-Tyler V. Anti-Fya preceding anti-Fy3 or and Kidd blood group systems. Immunohematology -Fy5: a study of five cases (abstract). Transfusion 2004;20:37–49. 1985;25:482. 33. Chaudhuri A, Zbrzezna V, Johnson C, et al. Purification 18. Le Pennec PY, Rouger P, Klein MT, Robert N, Salmon and characterization of an erythrocyte protein complex C. Study of anti-Fya in five black Fy(a−b−) patients. Vox carrying Duffy blood group antigenicity. Possible recep- Sang 1987;52:246–9. tor for Plasmodium vivax and Plasmodium knowlesi 19. Geifman-Holtzman O, Wojtowycz M, Kosmas E, Artal malaria parasite. J Biol Chem 1989;264:13770–4. R. Female alloimmunization with antibodies known to 34. Yazdanbakhsh K, Rios M, Storry JR, et al. Molecular cause hemolytic disease. Obstet Gynecol 1997;89:272–5. mechanisms that lead to reduced expression of Duffy 20. Hughes LH, Rossi KQ, Krugh DW, O’Shaughnessy RW. antigens. Transfusion 2000;40:310–20. Management of pregnancies complicated by anti-Fy(a) 35. Lu ZH, Wang ZX. Horuk R, et al. The promiscuous alloimmunization. Transfusion 2007;47:1858–61. chemokine binding profile of the Duffy antigen/re- 21. Vescio LA, Fariña D, Rogido M, Sóla A. Hemolytic dis- ceptor for chemokines is primarily localized to se- ease of the newborn caused by anti-Fyb. (Letter) Trans- quences in the amino-terminal domain. J Biol Chem fusion 1987;27:366. 1995;270:26239–45.

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36. Tournamille C, Le Van Kim C, Gane P, Cartron JP, Colin Y. 47. Lerut E, Van Damme B, Noizat-Pirenne F, et al. Duffy Molecular basis and PCR-DNA typing of the Fya/fyb blood and Kidd blood group antigens: minor histocompatibil- group polymorphism. Hum Genet 1995;95:407–10. ity antigens involved in renal allograft rejection? Trans- 37. Ferreira R, Ohneda K, Yamamoto M, Philipsen S. fusion 2007;47:28–40. GATA1 function, a paradigm for transcription factors 48. Miller LH, Mason SJ, Clyde DF, McGinniss MH. The in hematopoiesis. Mol Cell Biol 2005;25:1215–27. resistance factor to Plasmodium vivax in blacks. The 38. Zimmerman PA, Wooley I, Masinde GL, et al. Emer- Duffy-blood-group genotype, FyFy. N Engl J Med gence of FY*Anull in a Plasmodium vivax-endemic re- 1976;295:302–4. gion of Papua New Guinea. Proc Natl Acad Sci U S A 49. King CL, Michon P, Shakri AR, et al. Naturally ac- 1999;96:13973–7. quired Duffy-binding protein-specific binding inhibi- 39. Chaudhuri A, Polyakova J, Zbrzezna V, Pogo AO. The tory antibodies confer protection from blood-stage coding sequence of Duffy blood group gene in humans Plasmodium vivax infection. Proc Natl Acad Sci U S A and simians: restriction fragment length polymor- 2008;105:8363–8. phism, antibody and malarial parasite specificities, and 50. Langhi DM Jr, Bordin JO. Duffy blood group and ma- expression in nonerythroid tissues in Duffy-negative laria. 2006;11:389–98. individuals. Blood 1995;85:615–21. 51. Goodrick MJ, Hadley AG, Poole G. Haemolytic disease 40. Rot A, von Andrian UH. Chemokines in innate and of the fetus and newborn due to anti-Fy(a) and the po- adaptive host defense: basic chemokinese grammar for tential clinical value of Duffy genotyping in pregnancies immune cells. Annu Rev Immunol 2004;22:891–928. at risk. Transfus Med 1997;7:301–4. 41. Horuk R, Chitnis CE, Darbonne WC, et al. A receptor 52. Westhoff CM, Sloan SR. Molecular genotyping in trans- for the malarial parasite Plasmodium vivax: the eryth- fusion medicine. Clin Chem 2008;54:1948–50. rocyte chemokine receptor. Science 1993;261:1182–4. 53. Castilho L. The value of DNA analysis for anti- 42. Pruenster M, Rot A. Throwing light on DARC. Biochem gens in the Duffy blood group system. Transfusion Soc Trans 2006;34:1005–8. 2007;47(Suppl):28S–31S. 43. Darbonne WC, Rice GC, Mohler MA. Red blood cells 54. He W, Neil S, Kulkarni H, et al. Duffy antigen receptor are a sink for interleukin 8, a leukocyte chemotaxin. J for chemokines mediates trans-infection of HIV-1 from Clin Invest 1991;88:1362–9. red blood cells to target cells and affects HIV-AIDS sus- 44. Liu XH, Hadley TJ, Xu L, Peiper SC, Ray PE. Up-regulation ceptibility. Cell Host Microbe 2008;4:52–62. of Duffy antigen receptor expression in children with 55. Shen H, Schuster R, Stringer KF, Waltz SE, Lentsch renal disease. Kidney Int 1999;55:1491–500. AB. The Duffy antigen/receptor for chemokines 45. Akalin E, Neylan JF. The influence of Duffy blood (DARC) regulates prostate tumor growth. FASEB J group on renal allograft outcome in African Americans. 2006;20:59–64. Transplantation 2003;75:1496–500. 46. Mange KC, Prak EL, Kamoun M, et al. Duffy antigen Geralyn M. Meny, MD, Medical Director, American Red receptor and genetic susceptibility of African Ameri- Cross, Penn-Jersey Region, 700 Spring Garden Street, cans to acute rejection and delayed function. Kidney Int Philadelphia, PA 19123. 2004;66:1187–92.

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56 IMMUNOHEMATOLOGY, Volume 26, Number 2, 2010