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- W4225808743 abstract "B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a de novo variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis." @default.
- W4225808743 created "2022-05-05" @default.
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- W4225808743 date "2021-12-10" @default.
- W4225808743 modified "2023-10-18" @default.
- W4225808743 title "P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance" @default.
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- W4225808743 doi "https://doi.org/10.1084/jem.20211004" @default.
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- W4225808743 hasPublicationYear "2021" @default.
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