TY - JOUR
T1 - Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system
AU - Diks, Annieck M.
AU - Teodosio, Cristina
AU - de Mooij, Bas
AU - Groenland, Rick J.
AU - Naber, Brigitta A. E.
AU - de Laat, Inge F.
AU - Vloemans, Sandra A.
AU - Rohde, Susan
AU - de Jonge, Marien I.
AU - Lorenz, Linda
AU - Horsten, Debbie
AU - van Dongen, Jacques J. M.
AU - Berkowska, Magdalena A.
AU - Holstege, Henne
N1 - Funding Information: This work was supported by the HorstingStuit Foundation, the Hans und Ilse Breuer Foundation and Stichting VUmc Fund; and by the ABOARD project, Project number: ZonMW (#73305095007 and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). Funding Information: CT is the recipient of a USAL4EXCELLENCE fellowship, funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101034371. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Flow cytometry
KW - Functional studies
KW - Healthy aging
KW - Immunosenescence
KW - PLCG2 rs72824905
KW - PLCγ2 p.P522R
KW - Phospholipase C gamma 2
UR - http://www.scopus.com/inward/record.url?scp=85153434201&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13024-023-00604-9
DO - https://doi.org/10.1186/s13024-023-00604-9
M3 - Article
C2 - 37081539
SN - 1750-1326
VL - 18
SP - 25
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 25
ER -