Is it time to standardize granulocyte alloantigen nomenclature? (2002)

TRANSFUSION has adopted specific nomenclature requirements for platelet-specific and RBC antigens,1,2 but not for granulocyte antigens. Two granulocyte antigen nomenclatures have been described. The Granulocyte Antigen Working Party of the ISBT agreed to a new nomenclature system in 1998, but both the new and the old nomenclature systems are still in use.3,4 The use of multiple nomenclatures makes progress in this field difficult to follow, especially for those who are not experts in this field. While changing from the traditional nomenclature to the new system may initially be difficult for individuals who do not work in this field on a regular basis, using two nomenclature systems is even more problematic because it limits the readership of material in this field to experts who have mastered all the nomenclature. The first granulocyte antigens were described by Lalezari and colleagues. These antigens were designated “N” for neutrophil. Each antigen system was described alphabetically in order of discovery and each allele was described numerically in order of discovery. Lalezari and colleagues identified NA1 in 1966 and NA2, encoded by an allele of the gene that encodes NA1, was identified in 1972.5,6 Lalezari and coworkers described another granulocyte antigen, NB1, in 1971.7 Reports of several other antigens followed. NA1, NA2, and NB1 have been well characterized serologically and biochemically. NA1 and NA2 are located on the low-affinity Fc-γ receptor IIIb (FcγRIIIb)8-10 and NB1 on a 56-64kDa glycoprotein belonging to the Ly-6 snake toxin superfamily.8,9 In addition, three other antigens have been partially characterized: 5b, Onda, and Mart.10,11 Antibodies to several other antigens have been described, but these antibodies are either no longer available or the corresponding antigens could not be reproducibly identified.12 As a result, a new nomenclature that only included well-characterized antigens was established in 1998 by an ISBT Working Party3,4(Table 1). Using this nomenclature, antigen systems are referred to as human neutrophil antigens (HNA). The antigen systems, that is, the polymorphic forms of the immunogenic (glyco-) proteins, are indicated by integers. Specific antigens within each system are designated alphabetically by date of publication. Alleles of the coding genes are named according to the Guidelines for Human Gene Nomenclature. When naming new antigens, acronyms are used until they are included in the HNA nomenclature by the Granulocyte Antigen Working Party. In the HNA nomenclature NA1 became HNA-1a, NA2 became HNA-1b, and NB1 became HNA-2a. However, our knowledge of the antigens (polymorphisms) and alleles of FcγRIIIb, which is a frequent target of granulocyte-specific alloantibodies, has been growing. We are finding these antigens to be very complex. The HNA nomenclature is not being used universally and the use of multiple names for antigens and alleles of FcγRIIIb has been especially problematic. In order to follow progress in this system, the use of a single nomenclature is critical. The traditional nomenclature system only addressed antigens, because the genes encoding the antigens had not yet been discovered. The ISBT system provides standard nomenclature for antigens, the molecules carrying the antigens, and the genes encoding each allele. Consequently, the ISBT nomenclature system is well suited to describe complex relationships between new and previously described FcγRIIIb antigens and alleles. In the HNA nomenclature, the NA1 and NA2 antigens of FcγRIIIb became HNA-1a and HNA-1b. The HNA-1a allele of FCGR3B differs from the HNA-1b allele of FCGR3B by only 5 bp in the coding region, at positions 141, 147, 227, 277, and 349.13-15 Alternate forms of the allele are referred to as FCGR3B*1 and FCGR3B*2, respectively. Four of the nucleotide changes result in amino acid sequence changes between the HNA-1a and HNA-1b forms of the glycoprotein. FCGR3B is highly homologous to another Fcγ receptor gene, FCGR3A. However, the product of the latter gene is not expressed on neutrophils. Several additional polymorphisms of FCGR3B have been described. Bux and colleagues described a third FCGR3B allele initially known as SH and NF1, but now known as HNA-1c.16 The gene encoding HNA-1c is similar to the gene encoding HNA-1b, except for a 266C>A substitution in FCGR3B that results in an A78D change. This third allele is referred to as FCGR3B*3. FCGR3B*3 is present in 4 to 5 percent of white people and 25 to 38 percent of black people.16-18 In this issue of TRANSFUSION, Flesch and colleagues report on the possibility of linkage between the genes encoding HNA-1a and HNA-1c.19 They use the ISBT nomenclature recommendations for both antigens and genes and this makes complicated material much easier to follow. Antigens and alleles can be easily distinguished, relationships among antigens and alleles are obvious, and their findings can be readily compared to the work of other investigators. Flesch and colleagues19 studied HNA-1a, HNA-1b, and HNA-1c genotypes in people from northern Germany and Uganda. They found FCGR3B*3 in 5 percent of people from northern Germany and in 34.7 percent of people from Uganda. They also confirmed the finding of others in that most FCGR3*3-bearing white donors carry all three FCGR3B alleles, FCGR3B*1, FCGR3B*2, and FCGRB*3,17,20-23 whereas most FCGR3*3-bearing black donors have the expected two alleles. The three FCGR3B allele genotype is probably the result of gene duplication. Since these three alleles have been found in several individuals, Steffensen and colleagues have suggested that the gene encoding HNA-1c be considered a separate gene locus,24 but this is controversial.22,25 As part of their studies, Flesch and colleagues19 cloned and sequenced the portion of FCGR3B carrying four of the five polymorphic sites that distinguish HNA-1a, HNA-1b, and HNA-1c. Because of the high degree of homology between FCGR3B and FCGR3A, both genes were cloned and sequenced. Flesch et al. identified several variant genes with single base substitutions at one of the polymorphic sites that distinguish FCGR3B*1 and FCGR3B*2. They described variant alleles as FCGR3*V1, FCGR3*V2, FCGR3*V3, FCGR3*V4, and FCGR3*V5. All five variants were found among three donors from Germany and FCGR3*V5 was found in one donor from Uganda. Only a portion of the FCGR3 genes were sequenced, but within the sequenced portion of the variant FCGR3B gene FCGR3*V1 appeared to be an FCGR3B*1 gene with a 277G>A substitution and FCGR3*V4 appeared to be an FCGR3B*1 gene with a 141G>C substitution. FCGR3*V2 appeared to be an FCGR3A gene with a 277G>A substitution and FCGR3*V5 appeared to be an FCGR3A gene with a 141G>C substitution. FCGR3*V3 is more complicated, because it could be an FCGR3B*3 gene with 141C>G and 147T>C substitutions, or an FCGR3A gene with 266C>T and 277G>A substitutions. Matsuo and colleagues have also described several people with FCGR3B alleles that were the same as FCGR3B*1 or FCGR3B*2 except for a single nucleotide polymorphism.26 These single base pair differences occurred at one of the five bases that differed between FCGR3B*1 and FCGR3B*2. One variant FCGR3B*1 and four variant FCGR3B*2 genes were described. Variant FCGR3B alleles that more closely resembled the FCGR3B*2 occurred more often in black people than in white or Japanese people.26 Matsuo et al. also identified in two donors the same variant allele that Flesch named FCGR3*V3. Between the studies of Flesch et al. and Matsuo et al., 10 variant genes have been described. Because of this large number of genes, it would be helpful to give the variant genes descriptive names rather than acronyms. For example, when a variant gene differs from a described allele with a difference at only a single nucleotide, a convention could be used that refers to the variant gene by the name of the original gene, followed by the single-letter abbreviation for the nucleotide changed, the number of the nucleotide change, and finally the abbreviation for the nucleotide in the variant gene. FCGR3*V1 could be called FCGR3B*1 G277A, FCGR3*V4 could be called FCGR3B*1 G141C, FCGR3*V2 could be called FCGR3A G277A, and FCGR*V5 could be called FCGR3A G141C. While some aspects of nomenclature involving HNA-1c remain controversial, this should not prevent the use of this important nomenclature system. We recommend that TRANSFUSION use ISBT nomenclature for granulocyte antigens. We also encourage investigators to use the ISBT nomenclature when writing for other journals.