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Cited by 14Immune responses and vaccinationsImmunodeficiency and Autoimmune DisordersT-cell and B-cell Immunology

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

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Diks, Annieck M., Teodosio, Cristina, de Mooij, Bas, Groenland, Rick J., Naber, Brigitta A. E., de Laat, Inge F., Vloemans, Sandra A., Rohde, Susan +6 more·2023·Molecular Neurodegeneration
DOI 10.1186/s13024-023-00604-9PMC PMC10116473

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Abstract

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.

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  • The mildly hypermorphic PLCG2P522R variant is associated with increased longevity, improved clearance of Aβ, and protection against AD.

    “With respect to AD, the mildly hypermorphic PLCG2P522R variant is associated with increased longevity, improved clearance of Aβ, and protection against AD.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [23]

    The Background links p.P522R to increased likelihood of extreme longevity and lower Alzheimer’s disease risk, and the Discussion describes it as a slight gain-of-function variant. The paper does not report improved Aβ clearance: its Discussion instead reports slightly reduced phagocytosis in carriers’ myeloid cells and only speculates about more efficient clearance of brain tissue damage and debris. No page numbers are available in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The GOF P522R variant of PLCG2 confers protection in AD and the M28L variant confers risk.

    “the GOF P522R variant of PLCG2 confers protection in AD and the M28L variant confers risk”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [23]

  • Recent genetic studies have revealed genetic variants in PLCG2 that divergently impact AD risk.

    “recent genetic studies have revealed genetic variants in PLCG2 that divergently impact AD risk. 11 , 22 , 23 , 24 , 25 , 26 , 27 , 29”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [23]

  • The PLCG2-P522R variant enhances immune responsiveness.

    “Also, it was recently demonstrated that the PLCG2-P522R variant enhances immune responsiveness [35].”

    From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [35]

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References 63 · Cited by 14

Research works printed but not linked: 45

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Authors
Diks, A. M., Teodosio, C., de Mooij, B., Groenland, R. J., Naber, B. A. E., de Laat, I. F., Vloemans, S. A., Rohde, S., de Jonge, M. I., Lorenz, L., Horsten, D., van Dongen, J. J. M., Berkowska, M. A., & Holstege, H.
Affiliations
  • Leiden University Medical Center (NL)
  • Amsterdam University Medical Centers (NL)
Corresponding author
Holstege, Henne
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2023-04-20
Volume
18
Issue
1
Pages
25-25
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-023-00604-9
PMC
PMC10116473
OpenAlex
W4366550133
Cited by
14
References
63
Citations by year
2026: 5 · 2025: 4 · 2024: 1 · 2023: 4
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Pure Amsterdam UMC (acceptedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Lirias (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • ZonMw (#73305095007)
  • Health Holland (#LSHM20106)
  • HorstingStuit Foundation, the Hans und Ilse Breuer Foundation and Stichting VUmc Fund
  • H2020 Marie Skłodowska-Curie Actions (101034371)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
PLCγ2, immune cell function, B cell response, naive B cells, memory B cells, myeloid cells, reactive oxygen species, classical monocytes, FcεRI, longevity, calcium signaling
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, Animals, Humans, Immune System, Phospholipase C gamma

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