Blood Groups and Red Cell Antigens [Internet].

Antigens of the Duffy blood group

View in own window

Antibodies produced against Duffy antigens

View in own window

History

The Duffy blood group was discovered in 1950. It was named for a patient withhemophilia who had received multiple blood transfusions and was the first knownproducer of anti-Fy^a. A year later, anti-Fy^b wasdiscovered in a woman who had had several children. The remaining Duffy antigens(FY3, FY4, FY5, and FY6) were discovered 20 years later, but from these, onlyFY3 appears to be clinically significant.

The frequency of the Duffy phenotypes varies in different populations. The Duffynull phenotype, Fy(a-b-), is rare among Caucasian and Asian populations, whereasit is the most common phenotype in Blacks, occurring in over two-thirds of theBlack population. The racial variation in the distribution of Duffy antigens isa result of a positive selection pressure—the absence of Duffyantigens on RBCs makes the RBCs more resistant to invasion by a malarialparasite.

Worldwide, of the fourPlasmodium species that routinely causemalaria in humans,P. falciparum is responsible for themajority of fatal cases (2).But in Asia and the Americas,P. vivax is a more common causeof malaria. To cause disease,P. vivax must first enter thehuman RBC, which it does by binding to the N-terminal extracellular domain ofthe Duffy glycoprotein through the cysteine-rich region of the Duffy bindingprotein (DBP) (3). Individualswith the Duffy null phenotype do not express the Duffy protein on their RBCs andtherefore are immune toP. vivax infection.

Interestingly, the Fy(a-b-) phenotype is most common in areas where there islittleP. vivax malaria (4). In areas of West Africa, there is a highfrequency of the Fy (a-b-) phenotype and a low incidence ofP.vivax malaria. This may be because the pre-existence of a highfrequency of the Fy(a-b-) phenotype preventedP. vivax malariafrom becoming endemic in West Africa (4, 5).

Nomenclature

• Number of Duffy antigens: 6
• ISBT symbol: FY
• ISBT number: 008
• Gene symbol: FY
• Gene name: Duffy blood group

Phenotypes

There are four main Duffy phenotypes:

• Fy(a+b-)
• Fy(a+b+)
• Fy(a-b+)
• Fy(a-b-)

The Fy^a and Fy^b antigens are found relatively frequently inCaucasians (Fy^a 66% and Fy^b 83%) and Asians(Fy^a 99% and Fy^b 18.5%) but are far less common in Blacks(Fy^a 10% and Fy^b 23%). In fact, the Fy(a- b-)phenotype is present in two-thirds of African-American Blacks but is very rarein Caucasians (1).

An important minor Duffy phenotype is the Fy^x [Fy(b+^x)].The FYX allele encodes the Fy^b antigen, but it is only weaklyexpressed because a reduced amount of Duffy protein, and it is not alwaysdetected by anti-Fy^b.

Expression of Duffy antigens

Duffy antigens are expressed on many different types of cells. Even Fy(a-b-)individuals who do not produce Duffy antigens on their RBCs do express Duffyantigens elsewhere, including endothelial cells that line blood vessels,epithelial cells of kidney collecting ducts, lung alveoli, and Purkinje cells ofthe cerebellum. Duffy antigens are also expressed in the thyroid gland, thecolon, and the spleen.

Function of Duffy glycoprotein

The Duffy glycoprotein is also called the Duffy-Antigen Chemokine Receptor(DARC). As a chemokine receptor, it binds to the chemicals that are secreted bycells during inflammation and recruits other blood cells to the area of damage.These chemokines include C-X-R (acute inflammation chemokine) and C-C (chronicinflammation chemokine), IL-8 (interleukin 8), and RANTES (regulated onactivation, normal T-expressed and secreted) (6).

Animal studies suggest that the function of Duffy as a chemokine receptor is notphysiologically important because mice that lacked the mouse homolog of theDuffy gene (Dfy) were not more susceptible to infection than mice that expressedDfy (7). Indeed, individualswith the null Duffy phenotype appear to have normal RBCs and a normal immunesystem.

Transfusion reactions

Antibodies against the Duffy antigens Fy^a (8), Fy^b (9, 10), Fy3 (1), and Fy5 (11,12) have all been implicated as the cause ofa transfusion reaction. Anti-Fy^a is more commonly found in patientswho are of African descent (in whom the Duffy null phenotype is more common) andhave sickle cell anemia (and therefore may require multiple blood transfusions).

Hemolytic disease of the newborn

Maternal-fetal incompatibilities within the Duffy blood group system is anuncommon cause of HDN. The disease tends to be mild in nature. The Duffyantigens known to have caused maternal immunization and subsequent hemolyticdisease are Fy^a (13-16), Fy^b (17), and Fy3 (1).

Gene

The Duffy locus,FY, is located on chromosome 1 at position q22-q23. It consists oftwo exons that span over 1,500 bp of genomic DNA. The two main alleles, FYA andFYB, differ by a single nucleotide at position 125 (G and A, respectively) andthey likewise encode Fy^a and Fy^b antigens that differ by asingle amino acid at residue 42 (glycine and aspartic acid, respectively).

There are two genetic backgrounds that give rise to the Duffy negative phenotypeFy(a-b-) (18). Most commonly,a mutation in the promoter region of the FYB allele abolishes the expression ofthe Duffy glycoprotein in RBCs, but the protein is still produced in other typesof cells. This erythroid-specific mutation is found in African Americans (70%)and West Africans (approaching 100%) (19). Perhaps because the Duffy antigens areexpressed in other tissues, these patients do not generally make anti-Fyb oranti-Fy3 (20).

Less commonly, the Fy(a-b-) phenotype is a result of point mutation thatintroduces a premature stop codon into the coding sequence. It is unlikely thatthe truncated Duffy protein is transported to the cell surface, and it is likelythat the Duffy protein would be absent from all tissues in individuals who carrythis type of mutation. There may be strong anti-Fy3 in these patients (20).

The molecular basis of the F^x [Fy(b+^x)] phenotype is amutation in the coding sequence 265C→T (Arg897Cys), which always occurswith another mutation, 298G→A (Ala100Thr) (18).

Protein

The Duffy glycoprotein is a transmembrane protein that spans the RBC membraneseven times and has an extracellular N-terminal domain and a cytoplasmicC-terminal domain. It shares structural similarity with G-protein coupledreceptors but so far, it has not been shown to be a member of this family.

The binding site for chemokines, the binding site forP. vivax,and the major antigenic domains are all located in overlapping regions in theextracellular N-terminal domain.