Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system

Molecular Neurodegeneration

卷:18

Research Article

Henne Holstege¹  Linda Lorenz¹  Debbie Horsten¹  Susan Rohde¹  Sandra A. Vloemans²  Magdalena A. Berkowska²  Brigitta A. E. Naber²  Inge F. de Laat²  Bas de Mooij²  Rick J. Groenland²  Annieck M. Diks³  Jacques J. M. van Dongen⁴  Cristina Teodosio⁴  Marien I. de Jonge⁵ 

[1] Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands;

[2] Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333, Leiden, ZA, the Netherlands;

[3] Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333, Leiden, ZA, the Netherlands;Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands;

[4] Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333, Leiden, ZA, the Netherlands;Translational and Clinical Research Program, Cancer Research Center (IBMCC; University of Salamanca - CSIC), Salamanca, Spain;Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain;

[5] Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands;

关键词: Phospholipase C gamma 2;    PLCγ2 p.P522R;    PLCG2 rs72824905;    Healthy aging;    Immunosenescence;    Flow cytometry;    Functional studies;   

DOI  :  10.1186/s13024-023-00604-9

 received in 2022-08-08, accepted in 2023-02-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsWe 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.ResultsIn 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.ConclusionThe immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.

【 授权许可】

CC BY   
© The Author(s) 2023

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