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He Y, Gallman AE, Xie C, et al. P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. J Exp Med. 2021;219(1)doi: 10.1084/jem.20211004.
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., Criswell, L. A., Nititham, J., Adamski, M., Kitching, A. R., Cook, M. C., Cao, L., Shen, N., Cyster, J. G., & Vinuesa, C. G. (2022). P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. The Journal of experimental medicine, 219(1), . https://doi.org/10.1084/jem.20211004
He, Yuke, et al. "P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance." The Journal of experimental medicine vol. 219,1 (2022). doi: https://doi.org/10.1084/jem.20211004
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. P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. J Exp Med. 2022 Jan 03;219(1). doi: 10.1084/jem.20211004. Epub 2021 Dec 10. PMID: 34889940.
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J Exp Med. 2022 Jan 03;219(1). doi: 10.1084/jem.20211004. Epub 2021 Dec 10.

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

The Journal of experimental medicine

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

Affiliations

  1. Centre for Personalised Immunology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  2. Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA.
  3. Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia.
  4. Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  5. Department of Pediatrics, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
  6. Russell/Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA.
  7. Centre for Personalised Immunology, Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.
  8. Francis Crick Institute, London, UK.

PMID: 34889940 DOI: 10.1084/jem.20211004

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.

© 2021 He et al.

Conflict of interest statement

Disclosures:  J.G. Cyster reported "other" from Be BioPharma and MiroBio outside the submitted work. No other disclosures were reported.

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