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

Annieck M. Diks, Cristina Teodosio, Bas de Mooij, Rick J. Groenland, Brigitta A. E. Naber, Inge F. de Laat, Sandra A. Vloemans, Susan Rohde, Marien I. de Jonge, Linda Lorenz, Debbie Horsten, Jacques J. M. van Dongen, Magdalena A. Berkowska, Henne Holstege

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Article number25
Pages (from-to)25
Issue number1
Publication statusPublished - Dec 2023

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