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

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

doi:10.1084/jem.20211004

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

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. CriswellJoanne Nititham, Marcin Adamski, A. Richard Kitching, Matthew C. Cook, Lanfang Cao, Nan Shen^*, Jason G. Cyster^*, Carola G. Vinuesa^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

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.

Original language	English
Article number	e20211004
Journal	Journal of Experimental Medicine
Volume	219
Issue number	1
DOIs	https://doi.org/10.1084/jem.20211004
Publication status	Published - 10 Dec 2021

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10.1084/jem.20211004

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He, Y., Gallman, A. E., Xie, C., Shen, Q., Ma, J., Wolfreys, F. D., Sandy, M., Arsov, T., Wu, X., Qin, Y., Zhang, P., Jiang, S., Stanley, M., Wu, P., Tan, J., Ding, H., Xue, H., Chen, W., Xu, J., ... Vinuesa, C. G. (2021). P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. Journal of Experimental Medicine, 219(1), Article e20211004. https://doi.org/10.1084/jem.20211004

@article{a889978453ff4eb08ff76227f41b2c14,

title = "P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance",

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.",

author = "Yuke He and Gallman, {Antonia E.} and Chengmei Xie and Qian Shen and Jianyang Ma and Wolfreys, {Finn D.} and Moriah Sandy and Todor Arsov and Xiaoqian Wu and Yuting Qin and Pingjing Zhang and Simon Jiang and Maurice Stanley and Philip Wu and Jingjing Tan and Huihua Ding and Haiyan Xue and Wei Chen and Jinping Xu and Criswell, {Lindsey A.} and Joanne Nititham and Marcin Adamski and Kitching, {A. Richard} and Cook, {Matthew C.} and Lanfang Cao and Nan Shen and Cyster, {Jason G.} and Vinuesa, {Carola G.}",

year = "2021",

month = dec,

day = "10",

doi = "10.1084/jem.20211004",

language = "English",

volume = "219",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

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He, Y, Gallman, AE, Xie, C, Shen, Q, Ma, J, Wolfreys, FD, Sandy, M, Arsov, T, Wu, X, Qin, Y, Zhang, P, Jiang, S , Stanley, M, Wu, P, Tan, J, Ding, H, Xue, H, Chen, W, Xu, J, Criswell, LA, Nititham, J, Adamski, M, Kitching, AR, Cook, MC, Cao, L, Shen, N, Cyster, JG & Vinuesa, CG 2021, 'P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance', Journal of Experimental Medicine, vol. 219, no. 1, e20211004. https://doi.org/10.1084/jem.20211004

TY - JOUR

T1 - P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance

AU - He, Yuke

AU - Gallman, Antonia E.

AU - Xie, Chengmei

AU - Shen, Qian

AU - Ma, Jianyang

AU - Wolfreys, Finn D.

AU - Sandy, Moriah

AU - Arsov, Todor

AU - Wu, Xiaoqian

AU - Qin, Yuting

AU - Zhang, Pingjing

AU - Jiang, Simon

AU - Stanley, Maurice

AU - Wu, Philip

AU - Tan, Jingjing

AU - Ding, Huihua

AU - Xue, Haiyan

AU - Chen, Wei

AU - Xu, Jinping

AU - Criswell, Lindsey A.

AU - Nititham, Joanne

AU - Adamski, Marcin

AU - Kitching, A. Richard

AU - Cook, Matthew C.

AU - Cao, Lanfang

AU - Shen, Nan

AU - Cyster, Jason G.

AU - Vinuesa, Carola G.

PY - 2021/12/10

Y1 - 2021/12/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85122699620&partnerID=8YFLogxK

U2 - 10.1084/jem.20211004

DO - 10.1084/jem.20211004

M3 - Article

SN - 0022-1007

VL - 219

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 1

M1 - e20211004

ER -

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

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