P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

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. © 2021 He et al.

Citation

Yuke He, Antonia E Gallman, Chengmei Xie, Qian Shen, Jianyang Ma, Finn D Wolfreys, Moriah Sandy, Todor Arsov, Xiaoqian Wu, Yuting Qin, Pingjing Zhang, Simon Jiang, Maurice Stanley, Philip Wu, Jingjing Tan, Huihua Ding, Haiyan Xue, Wei Chen, Jinping Xu, Lindsey A Criswell, Joanne Nititham, Marcin Adamski, A Richard Kitching, Matthew C Cook, Lanfang Cao, Nan Shen, Jason G Cyster, Carola G Vinuesa. P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. The Journal of experimental medicine. 2022 Jan 03;219(1)

Mesh Tags

Substances

PMID: 34889940

search → result