Molecular Genetics of the Human Neutrophil Antigens

Abstract

Background and Objective: Antibodies to human neutrophil antigens (HNAs) have been implicated in transfusion-related acute lung injury and allo- and autoimmune neutropenia. To date, five HNA systems are assigned, and during the last decades enormous efforts have been undertaken to identify the underlying genes and to characterize the antigens. This review of the literature will provide the current genetic, molecular and functional information on HNAs. Recent Findings: New information on alleles and antigens has been added to nearly each of the five HNA systems. HNA-1d has been added as the antithetical epitope to HNA-1c that is located on the glycoprotein encoded by FCGR3B*02 but not by FCGR3B. FCGR3B*04 and *05 now are included as new alleles. A CD177*787A>T substitution was demonstrated as the main reason for the HNA-2-negative phenotype on neutrophils. The target glycoprotein of HNA-3 antibodies could be identified as choline transporter-like protein 2 (CTL2) encoded by SLC44A2. The conformation sensitive epitope discriminates between arginine and glutamine at position 152 resulting in HNA-3a and HNA-3b. An additional Leu151Phe substitution can impair HNA-3a antibody binding. Recently an alloantibody against HNA-4b which discriminates from HNA-4a by an Arg61His exchange of the glycoprotein encoded by the ITGAM gene was reported in neonatal alloimmune neutropenia. An update of the current HNA nomenclature based on the new findings was provided in 2016 by the ISBT Granulocyte Immunobiology Working Party nomenclature subcommittee. Conclusions: The molecular basis of each of the five HNA antigen systems has been decoded during the past decades. This enables reliable molecular typing strategies, antibody detection and specification as well as development of new assays based on recombinant antigens. However, research on HNA alleles, antigens, and antibodies is not finally terminated and also in the future will add new findings.

Neonatal alloimmune neutropaenia: Experience from an Australian paediatric health service

“…The Fc γ-receptor IIIb glycoprotein (FcγRIIIb; also CD16b) comprises the HNA-1a, -1b, -1c and -1d alloantigens and is important in immune complex clearance and phagocytosis of opsonised microorganisms. 25 The majority of NAIN cases have demonstrated alloantibodies against HNA-1a, -1b and -2a. 5,6 However, alloantigens HNA-1c, -1d, -3a, -3b, -4a, -4b and -5a and their respective antibodies have also been reported in NAIN.…”

Targeted exome sequencing designed for blood group, platelet, and neutrophil antigen investigations: Proof‐of‐principle study for a customized single‐test system

“…The sample set included gene CNVs from zero up to four copy samples for HNA-1. 43 HNA-2 phenotypes were determined for five (four positive, one negative) samples by flow cytometry 22 using an APC-labeled mem166 clone (Santa Cruz Biosciences).…”

A novel nonsense mutation found in the CD177 gene of Thai individuals with the HNA‐2 null phenotype

“…The frequency of the HNA‐2 null phenotype has been reported to be approximately 0.5% to 5% among Thai and other populations . HNA‐2 isoantibodies produced by HNA‐2 null individuals are implicated in transfusion‐related acute lung injury (TRALI) and immune neutropenia …”

“…9,10 HNA-2 isoantibodies produced by HNA-2 null individuals are implicated in transfusion-related acute lung injury (TRALI) and immune neutropenia. 3,5 To date, different mutations of HNA-2 antigen expression have been reported in varying populations. 1,8,14 A recent study in a Chinese population identified two polymorphisms associated with the HNA-2 null phenotype in exons 7 and 8 of the CD177 gene (c.787A>T and c.955delG, respectively).…”