Dataset Information

Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms.

ABSTRACT:

Background

The human neutrophil antigen 2 (HNA-2), which is expressed on CD177, is undetectable in 3-5% of the normal population. Exposure of these HNA-2_null individuals to HNA-2-positive cells can cause immunization and pro-duction of HNA-2 antibodies, which can induce immune neutropenia and transfusion-related acute lung injury. In HNA-2-positive individuals, neutrophils are divided into a CD177^pos. and a CD177^neg. subpopulation. The molecular background of HNA-2 deficiency and the bimodal expression pattern, however, are not completely decoded.

Study design

An international collaboration was conducted on the genetic analysis of HNA-2-phenotyped blood samples, including HNA-2-deficient individuals, mothers, and the respective children with neonatal immune neutropenia and regular blood donors.

Results

From a total of 54 HNA-2_null individuals, 43 were homozygous for the CD177 *787A>T substitution. Six carried the CD177 *c.1291G>A single nucleotide polymorphism. All HNA-2-positive samples with >40% CD177^pos. neutrophils carried the *787A wild-type allele, whereas a lower rate of CD177^pos. neutrophils was preferentially associated with *c.787AT heterozygosity. Interestingly, only the *c.787A allele sequence was detected in complementary DNA (cDNA) sequence analysis carried out on all *c.787AT heterozygous individuals. However, cDNA analysis after sorting of CD177^pos. and CD177^neg. neutrophil subsets from HNA-2-positive individuals showed identical sequences, which makes regulatory elements within the promoter unlikely to affect CD177 gene transcription in different CD177 neutrophil subsets.

Conclusion

This comprehensive study clearly demonstrates the impact of single nucleotide polymorphisms on the expression of HNA-2 on the neutrophil surface but challenges the hypothesis of regulatory epigenetic effects being implicated in the bimodal CD177 expression pattern.

SUBMITTER: Flesch BK

PROVIDER: S-EPMC7590758 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms.

Flesch Brigitte K BK Reil Angelika A Nogués Núria N Canals Carme C Bugert Peter P Schulze Torsten J TJ Huiskes Elly E Porcelijn Leendert L Höglund Petter P Ratcliffe Paul P Schönbacher Marlies M Kerchrom Hans H Kellershohn Josina J Bayat Behnaz B

Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 20200122 5

<h4>Background</h4>The human neutrophil antigen 2 (HNA-2), which is expressed on CD177, is undetectable in 3-5% of the normal population. Exposure of these HNA-2<sub>null</sub> individuals to HNA-2-positive cells can cause immunization and pro-duction of HNA-2 antibodies, which can induce immune neutropenia and transfusion-related acute lung injury. In HNA-2-positive individuals, neutrophils are divided into a CD177<sup>pos.</sup> and a CD177<sup>neg.</sup> subpopulation. The molecular backgroun ...[more]

PMID: 33173457

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Project description:Aims/hypothesisGlucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels.MethodsCRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca2+ using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes GPR142 and CASR were knocked out to evaluate roles in amino acid sensing.ResultsRNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including FFAR1, GPBAR1, GPR119, CASR and GPR142. Glucose induced action potential firing and cytosolic Ca2+ elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1/2 (SGLT1/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While CASR knockout blunted intracellular Ca2+ responses, a CASR/GPR142 double knockout was needed to reduce GIP secretory responses to aromatic amino acids.Conclusions/interpretationThe newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity.

Dataset Information

Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms.

Background

Study design

Results

Conclusion

Publications

Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms.

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