mTOR Activation Underlies Enhanced B Cell Proliferation and Autoimmunity in PrkcdG510S/G510S Mice
Copyright © 2023 by The American Association of Immunologists, Inc..
Autosomal recessive PRKCD deficiency has previously been associated with the development of systemic lupus erythematosus in human patients, but the mechanisms underlying autoimmunity remain poorly understood. We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of systemic lupus erythematosus in the mouse genome, using CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulated the human phenotype and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell-autonomous role of Prkcd. A detailed analysis of B cell activation in PrkcdG510S/G510S mice shows an upregulation of the PI3K/mTOR pathway after the engagement of the BCR in these cells, leading to lymphoproliferation. Treatment of mice with rapamycin, an mTORC1 inhibitor, significantly improves autoimmune symptoms, demonstrating in vivo the deleterious effect of mTOR pathway activation in PrkcdG510S/G510S mice. Additional defects in PrkcdG510S/G510S mice include a decrease in peripheral mature NK cells that might contribute to the known susceptibility to viral infections of patients with PRKCD mutations.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:210 |
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| Enthalten in: |
Journal of immunology (Baltimore, Md. : 1950) - 210(2023), 9 vom: 01. Mai, Seite 1209-1221 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moreews, Marion [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.7.1.1 |
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| Anmerkungen: |
Date Completed 19.04.2023 Date Revised 21.06.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.4049/jimmunol.2200818 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354665855 |
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| 245 | 1 | 0 | |a mTOR Activation Underlies Enhanced B Cell Proliferation and Autoimmunity in PrkcdG510S/G510S Mice |
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| 520 | |a Copyright © 2023 by The American Association of Immunologists, Inc. | ||
| 520 | |a Autosomal recessive PRKCD deficiency has previously been associated with the development of systemic lupus erythematosus in human patients, but the mechanisms underlying autoimmunity remain poorly understood. We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of systemic lupus erythematosus in the mouse genome, using CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulated the human phenotype and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell-autonomous role of Prkcd. A detailed analysis of B cell activation in PrkcdG510S/G510S mice shows an upregulation of the PI3K/mTOR pathway after the engagement of the BCR in these cells, leading to lymphoproliferation. Treatment of mice with rapamycin, an mTORC1 inhibitor, significantly improves autoimmune symptoms, demonstrating in vivo the deleterious effect of mTOR pathway activation in PrkcdG510S/G510S mice. Additional defects in PrkcdG510S/G510S mice include a decrease in peripheral mature NK cells that might contribute to the known susceptibility to viral infections of patients with PRKCD mutations | ||
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| 700 | 1 | |a Reuschlé, Quentin |e verfasserin |4 aut | |
| 700 | 1 | |a Drouillard, Annabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Dessay, Pénélope |e verfasserin |4 aut | |
| 700 | 1 | |a Meignien, Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jiang |e verfasserin |4 aut | |
| 700 | 1 | |a Fallone, Lucie |e verfasserin |4 aut | |
| 700 | 1 | |a Rousseaux, Noëmi |e verfasserin |4 aut | |
| 700 | 1 | |a Ainouze, Michelle |e verfasserin |4 aut | |
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