Autoimmunity and Inflammation Due to a Gain-of-Function Mutation in Phospholipase Cγ2 that Specifically Increases External Ca2+ Entry
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The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.
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Ali5 mice bear a gain-of-function point mutation resulting in a single amino acid change D993G in PLCγ2, causing spontaneous inflammation.
“Understanding the mechanisms behind the role of PLCγ2 in autoinflammatory diseases was enabled by the identification of the Ali5 mice that bear a gain-of-function point mutation resulting in a single amino acid change (D993G) in PLCγ2 resulting in spontaneous inflammation (106).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [106]
Different degrees of severity have been described for mouse models bearing hypermorphic spontaneous mutations (Ali14 and Ali5).
“Different degrees of severity have also been described for mouse models bearing hypermorphic spontaneous mutations (Ali14 and Ali5 [109, 112])”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [112]
These models recapitulate features of human diseases, including chronic inflammation accompanied by hyperreactive B-cells and expansion of innate inflammatory cells.
“These models seem to recapitulate features of the human diseases, including chronic inflammation accompanied by hyperreactive B-cells and expansion of innate inflammatory cells [102, 112]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [112]
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- Authors
- Yu, P., Constien, R., Dear, N., Katan, M., Hanke, P., Bunney, T. D., Kunder, S., Quintanilla-Martinez, L., Huffstadt, U., Schröder, A., Jones, N. P., Peters, T., Fuchs, H., Hrabe de Angelis, M., Nehls, M., Grosse, J., Wabnitz, P., Meyer, T. P. H., Yasuda, K., Schiemann, M., Schneider-Fresenius, C., Jagla, W., Russ, A., Popp, A., Josephs, M., Marquardt, A., Laufs, J., Schmittwolf, C., Wagner, H., Pfeffer, K., & Mudde, G. C.
- Affiliations
- TUM Klinikum (DE)
- Mary Lyon Centre at MRC Harwell (GB)
- Institute of Cancer Research (GB)
- University of Oxford (GB)
- Corresponding author
- Yu, Philipp
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 22
- Issue
- 4
- Pages
- 451-465
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W1997863210
- Cited by
- 177
- References
- 57
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 14 · 2023: 14 · 2022: 10 · 2021: 17 · 2020: 14 · 2019: 7 · 2018: 5 · 2017: 6 · 2016: 13 · 2015: 8 · 2014: 8 · 2013: 4 · 2012: 4
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- PLCγ2, gain-of-function mutations, autoimmunity, B cells, ENU mutagenesis, mouse mutants
- MeSH terms
- Animals, Arthritis, Experimental, B-Lymphocytes, Base Sequence, Bone Marrow Cells, Calcium, Dermatitis, Inflammation, Male, Molecular Sequence Data, Type C Phospholipases, Autoimmunity, Up-Regulation, Point Mutation, Mice, Phospholipase C gamma
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