Classifications of Human Neutrophil Antigens
Human neutrophil antigens definition and associated nomenclature are regulated by the International Society of Blood Transfusion Granulocyte Immunology Working Party (ISBT GIWP) (Flesch and International Society of Blood Transfusion (ISBT) HNA nomenclature Subcommittee). Currently, there are officially five groups/systems, HNA-1 through to HNA-5, consisting of fourteen officially assigned alleles.
Neutrophil antigens possess a huge impact on various clinical conditions including neonatal immune neutropenia, transfusion - related acute lung injury, autoimmune neutropenia, refractoriness to granulocyte transfusions and drug induced immune neutropenia. Currently seven antigens categorized under five major groups have been approved, of which six antigens have been characterized biochemically and molecularly. In most cases, a combination of granulocyte agglutination and immunofluorescence tests have been the best means of detection.
Class I HNAs
HNA-1 was first described in 1960 and is a class of alleles encoded by FCGR3B. In humans, transmembrane Fc gamma receptor exists in two homologous forms. Transmembrane Fc gamma receptor IIIa (FcγRIIIa) is expressed in macrophages and natural killer cells and transmembrane Fc gamma receptor IIIb (FcγRIIIb) is expressed only in neutrophil granulocytes. This was originally described as the bi-allelic system with alloantigens including NA1 (HNA-1a), NA2 (HNA-1b) and later included SH (HNA-1c) and HNA-1d. Nucleotide substitutions spanning exon 3 of FCGR3B gene underlies the HNA-1 polymorphisms. HNA class I officially comprises five different FCGR3B alleles with 4 underlying missense mutations at amino acids sites 36, 65, 82, and 106. HNA-1 is the most common antigen in autoimmune neutropenia of infancy (ANI). Population studies suggest that approximately 1/1,000 Caucasians and 1/100 Africans/African Americans are HNA-1 null although frequencies have been shown to vary markedly. Other studies have shown HNA-1 null incidence from being undetectable to approximately 1/5 in indigenous Taiwanese tribes and <1/20,000 in Thai populations. Details on extensive annotation of HNA class I alleles can be found in the file provided below.
Class II HNAs
HNA-2 (CD177) was first described in 1971 in a case of neonatal neutropenia. HNA-2 is encoded on chromosome 19 at position 19q13.31, consists of nine exons, 437 amino acids and is approximately 9.5 kb. CD177 is not expressed on all circulating neutrophils and the percentage of CD177+ cells can vary between individuals.Exact molecular mechanisms underlying either the deficiency or differential expression are still not clearly understood. HNA-2 has no described antigenic diversity although polymorphisms have been described in exons 1, 2 and 4 through 9. Numerous SNPs have been attributed to the high and low expression of HNA-2 antigens but not officially approved yet.
Details on extensive annotation of HNA class II alleles can be found in the file provided below.
Class III HNAs
Although first described in 1964, the location of HNA-3 was not elucidated until 2010 when HNA-3 specific antibodies were shown to recognize choline transporter-like protein-2 (CTL2) peptides. CLT-2 is a transmembrane protein and is widely expressed on both haematopoietic cells, for example neutrophils, lymphocytes, platelets and tissue endothelial cells, for example lung, liver, colon and inner ear. CLT2 is a member of the soluble carrier family 44 (SLC44A2) and has two transcript variants known as TV-1 and TV-2, although the variant TV-1 is not expressed on neutrophils. SLC44A2 is encoded on chromosome 19 at position 19p13.2, has 22 exons, 706 amino acids, is approximately 42 kb and has multiple reported splice variants. Details on extensive annotation of HNA class III alleles can be found in the file provided below.
Class IV & V HNAs
HNA-4a was first described in 1986 and is located on the integrin alpha M chain (ITGAM) or CD11b. CD11b is located on chromosome 16 at position 16p11.2, consists of 30 exons, 1,152 amino acids and is approximately 73 kb. The CD11b/CD18 dimer, also known as the macrophage receptor 1 (MAC-1), has multiple transcript variants encoding different isoforms (NCBI). MAC-1 is the most abundantly expressed integrin on neutrophils but is also expressed on natural killer cells, fibrocytes, mast cells and cytotoxic T cells. The incidence of HNA-4a-negative individuals has been reported as approximately 1/50 in English Caucasian blood donors and not observed in a study of Thai blood donors. The HNA-4b polymorphism (rs1143679) has been associated with an increased risk of systemic lupus erythematosus.
HNA-5 was described in 1979 and is located on the integrin subunit alpha L chain (ITGAL) or CD11a. CD11a is located on chromosome 16 at position 16p11.2, has 31 exons, 1,170 amino acids and is approximately 50.5 kb. The CD11a/CD18 dimer, also known as lymphocyte-activating factor 1 (LAF-1), has two known transcript variants that result in multiple isoforms. LAF-1 is expressed on all leucocytes but is predominately expressed on lymphocytes. The incidence of HNA-5a-negative blood donors is reported as approximately 7/100 of English Caucasians and up to 3/25 Thai. The HNA-5b polymorphism has been linked with increased vaccine-induced immunity to hepatitis B and reduced instance of ophthalmopathy resulting from Graves’ disease.
Details on extensive annotation of HNA class IV and V alleles can be found in the file provided below.