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B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Cellular & Molecular Immunology volume 20, pages 881–894 (2023)Cite this article

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Abstract

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

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Acknowledgements

We thank Dr. Kwok Wah Chan, Dr. Xi Yang, and Mr. King-Hung Ko for their kind help in the renal histopathological assessment and technical assistance. We also thank the service of the Medical Faculty Core Facility and Laboratory Animal Unit, The University of Hong Kong.

Funding

This work was supported by funding for Chongqing International Institute for Immunology (2020YJC10), National Natural Science Foundation of China (81901635, 82171782, 82260326, 81971464), Shenzhen Science and Technology Program (CYJ20210324114602008), Hong Kong Research Grants Council Theme-Based Research Scheme (T12-703/19 R) and the Centre for Oncology and Immunology under the Health@InnoHK Initiative by the Innovation and Technology Commission, Hong Kong, China.

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Authors and Affiliations

  1. Centre for Infection and Immunity Studies, School of Medicine, The Sun Yat-sen University, Shenzhen, 518107, Guangdong, China

    Kongyang Ma & Rencai Qin

  2. Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, 999077, China

    Kongyang Ma, Wenhan Du, Shiyun Wang, Fan Xiao & Liwei Lu

  3. Department of Rheumatology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China

    Kongyang Ma & Dongzhou Liu

  4. Chongqing International Institute for Immunology, Chongqing, 400038, China

    Wenhan Du & Liwei Lu

  5. Department of Rheumatology and Immunology, Southwest Hospital, The First Hospital Affiliated to Army Medical University, Chongqing, 400038, China

    Jingyi Li

  6. Department of Laboratory Medicine, Affiliated Hospital and Institute of Medical Immunology, Jiangsu University, Zhenjiang, China

    Jie Tian & Ke Rui

  7. Department of Rheumatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China

    Yida Xing & Xiaodan Kong

  8. Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China

    Xiaoxia Zhu & Hejian Zou

  9. Department of Rheumatology and Immunology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Jing Wang & Lan He

  10. Department of Rheumatology and Immunology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China

    Cainan Luo & Lijun Wu

  11. Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Haijing Wu & Qianjin Lu

  12. Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Yun Zhang & Chengping Wen

  13. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China

    Liwei Lu

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Contributions

KM, WD, SW, and JT designed and performed the mouse experiments and statistical analysis. JL, YX, XZ, JW, CL, HW, and FX performed the experiments with human samples. XK, KR, RQ, HZ, YZ, CW, DL, and LH participated in the data analysis. LL, QL, and LW supervised the study, and KM wrote the manuscript.

Corresponding authors

Correspondence to Qianjin Lu, Lijun Wu or Liwei Lu.

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The authors declare no competing interests.

Ethical approval

All human experiments were approved by the Institutional Medical Ethics Committee of Third Military Medical University (Reference Number: 2016-77-tmmu) and Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong Western Cluster (HKU/HA HKW IRB) (Reference Number: UW 16-342). Written permission was obtained from all subjects who participated in the study. All animal experiments were approved by the Committee on the Use of Live Animals in Teaching and Research (CULATR, No: 3392-14) at the University of Hong Kong.

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Ma, K., Du, W., Wang, S. et al. B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation. Cell Mol Immunol 20, 881–894 (2023). https://doi.org/10.1038/s41423-023-01049-2

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