Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system.
Flow cytometry
Functional studies
Healthy aging
Immunosenescence
PLCG2 rs72824905
PLCγ2 p.P522R
Phospholipase C gamma 2
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
20 04 2023
20 04 2023
Historique:
received:
08
08
2022
accepted:
14
02
2023
medline:
24
4
2023
pubmed:
21
4
2023
entrez:
20
04
2023
Statut:
epublish
Résumé
The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.
Sections du résumé
BACKGROUND
The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells.
METHODS
We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination.
RESULTS
In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination.
CONCLUSION
The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.
Identifiants
pubmed: 37081539
doi: 10.1186/s13024-023-00604-9
pii: 10.1186/s13024-023-00604-9
pmc: PMC10116473
doi:
Substances chimiques
COVID-19 Vaccines
0
Phospholipase C gamma
EC 3.1.4.3
PLCG2 protein, human
EC 3.1.4.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
25Informations de copyright
© 2023. The Author(s).
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