Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets

Eulenberg-Gustavus, Claudia; Bähring, Sylvia; Maass, Philipp G.; Luft, Friedrich C.; Kettritz, Ralph

doi:10.1084/jem.20161093

Cited by 43 publications

(40 citation statements)

References 55 publications

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“…Epigenetic mechanisms control the CD177 allelesilencing process and one of two CD177 alleles is silenced during neutrophil differentiation, which may cause monoallelic HNA-2 expression in mature neutrophils. 19 In neutrophils from 787A-1291G/787A-1291A (AG/AA) heterozygous donors, neutrophils epigenetically silenced for HNA-2 expression on both chromosomes will appear as the HNA-2-negative population. Since the 787A-1291A (AA) haplotype allele results in much lower HNA-2 expression than 787A-1291G (AG) allele (Figs.…”

Section: Discussionmentioning

confidence: 99%

The nonconservative CD177 single‐nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen‐2 atypical/low expression and deficiency

Schuller

et al. 2019

Transfusion

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BACKGROUND Human neutrophil antigen‐2 (HNA‐2) is exclusively expressed on neutrophils. HNA‐2–deficient individuals (HNA‐2 null) are susceptible to produce isoantibodies. The nonsense CD177 coding single‐nucleotide polymorphism (SNP) c.787A>T has been demonstrated as the primary genetic mechanism for HNA‐2 deficiency. We hypothesized that the other genetic variants also contribute to HNA‐2 expression variation and deficiency. STUDY DESIGN AND METHODS The deficiency, density, and percentage of HNA‐2 antigen on neutrophils from 292 healthy blood donors were determined in flow cytometry. CD177 genotypes were determined by genomic DNA sequence analyses. The full‐length CD177 cDNAs were amplified and sequenced. Additionally, the whole CD177 genomic sequence in eight HNA‐2–null immunized women and four HNA‐2–positive donors were analyzed with next‐generation sequencing. The associations of CD177 SNP genotypes with HNA‐2 expression variation were statistically analyzed. RESULTS A functional CD177 SNP c.1291G>A was identified in the current study. Atypical (trimodal) HNA‐2 expression phenotype was consistently observed in donors carrying the heterozygous c.1291G/A genotype. Phenotype‐genotype analyses of SNP c.787A>T and SNP c.1291G>A revealed that all homozygous 787T‐1291G (TG/TG) genotype donors were HNA‐2 null in healthy blood donors. On the other hand, five of eight HNA‐2–immunized females were homozygous for the 787T‐1291G (TG/TG) genotype while the other three HNA‐2–immunized females had the 787T‐1291G/787A‐1291A (TG/AA) genotype and the lowest HNA‐2 expression was observed in healthy subjects with the 787T‐1291G/787A‐1291A (TG/AA) and 787A‐1291A/787A‐1291A (AA/AA) genotype. CONCLUSION The CD177 SNP c.1291G>A is a genetic determinant for the atypical and low HNA‐2 expression, which also contributes to HNA‐2 deficiency phenotype.

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Section: Discussionmentioning

confidence: 99%

The nonconservative CD177 single‐nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen‐2 atypical/low expression and deficiency

Schuller

et al. 2019

Transfusion

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“…Humans Several publications have reported that, in healthy individuals, 45-65% of circulating neutrophils are CD177 + [5,6,8,14], with variability of CD177 expression reflecting control by epigenetic mechanisms [15] (Figure 1). CD177 (also known as human neutrophil antigen NB1) is a glycoprotein Neutrophils are the primary responders to infections and tissue damage, but a growing body of evidence suggests that distinct subpopulations of these cells are immunoregulatory and are associated with cancer and other inflammatory diseases.…”

Section: Neutrophil Diversity and Heterogeneity Under Homeostatic Conmentioning

confidence: 99%

Neutrophil Diversity in Health and Disease

Silvestre-Roig

Fridlender

Glogauer

et al. 2019

Trends in Immunology

357

335

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“…A dose effect of the wild-type CD177*787A or heterozygosity for both *787A and *787T has been correlated with the proportion of HNA-2-positive neutrophils [10,59]. Recently, gene silencing and a novel monoallelic expression pattern caused by disparate CpG and histone methylation have been described as basis for distinct neutrophil subsets thus introducing epigenetic mechanisms [70]. …”

Section: Hna-2mentioning

confidence: 99%

Molecular Genetics of the Human Neutrophil Antigens

Flesch

Reil²

2018

Transfus Med Hemother

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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.

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Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets

Cited by 43 publications

References 55 publications

The nonconservative CD177 single‐nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen‐2 atypical/low expression and deficiency

The nonconservative CD177 single‐nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen‐2 atypical/low expression and deficiency

Neutrophil Diversity in Health and Disease

Molecular Genetics of the Human Neutrophil Antigens

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