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TLR4+CXCR4+ plasma cells drive nephritis development in systemic lupus erythematosus
  1. Kongyang Ma1,
  2. Jingyi Li2,
  3. Xiaohui Wang1,
  4. Xiang Lin1,
  5. Wenhan Du1,
  6. Xi Yang1,
  7. Fangxiang Mou2,
  8. Yongfei Fang2,
  9. Yanbin Zhao3,
  10. Xiaoping Hong3,
  11. Kwok Wah Chan1,
  12. Xiaoming Zhang4,
  13. Dongzhou Liu3,
  14. Lingyun Sun5,
  15. Liwei Lu1
  1. 1 Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
  2. 2 Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing, China
  3. 3 Department of Rheumatology and Immunology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
  4. 4 Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
  5. 5 Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
  1. Correspondence to Prof Dongzhou Liu, Department of Rheumatology and Immunology Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University Shenzhen China ; liu_dz2001{at}sina.com, Prof Lingyun Sun, Department of Rheumatology and Immunology Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing China ; lingyunsun{at}nju.edu.cn and Professor Liwei Lu, Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China ; liweilu{at}hku.hk

Abstract

Objectives In patients with systemic lupus erythematosus (SLE), immune tolerance breakdown leads to autoantibody production and immune-complex glomerulonephritis. This study aimed to identify pathogenic plasma cells (PC) in the development of lupus nephritis.

Methods PC subsets in peripheral blood and renal tissue of patients with SLE and lupus mice were examined by flow cytometry and confocal microscopy, respectively. Sorting-purified PCs from lupus mice were adoptively transferred into Rag2-deficient recipients, in which immune-complex deposition and renal pathology were investigated. In culture, PCs from lupus mice and patients with SLE were treated with a TLR4 inhibitor and examined for autoantibody secretion by enzyme-linked immunospot assay (ELISPOT). Moreover, lupus mice were treated with a TLR4 inhibitor, followed by the assessment of serum autoantibody levels and glomerulonephritis activity.

Results The frequencies of TLR4+CXCR4+ PCs in peripheral blood and renal tissue were found significantly increased with the potent production of anti-dsDNA IgG, which were associated with severe renal damages in patients with SLE and mice with experimental lupus. Adoptive transfer of TLR4+CXCR4+ PCs from lupus mice led to autoantibody production and glomerulonephritis development in Rag2-deficient recipients. In culture, TLR4+CXCR4+ PCs from both lupus mice and patients with SLE showed markedly reduced anti-dsDNA IgG secretion on TLR4 blockade. Moreover, in vivo treatment with TLR4 inhibitor significantly attenuated autoantibody production and renal damages in lupus mice.

Conclusions These findings demonstrate a pathogenic role of TLR4+CXCR4+ PCs in the development of lupus nephritis and may provide new therapeutic strategies for the treatment of SLE.

  • autoimmune diseases
  • autoantibodies
  • systemic lupus erythematosus
  • lupus nephritis
  • B cells

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Footnotes

  • KM and JL contributed equally.

  • Handling editor Josef S Smolen

  • Contributors KM, XW, XL, WD and XY designed and performed mouse experiments and statistical analysis. JL, FM, YF and YZ performed experiments with human samples. KWC, XH, DL, XZ and LS participated in the design of the study and helped in analysing data. KM, LS and LL supervised the study and wrote the manuscript.

  • Funding This work was supported by grants from the National Basic Research Program of China (No 2014CB541904), National Natural Science Foundation of China (No 81771761, 81771735), Sanming Project of Medicine in Shenzhen (SZSM201512019), Hong Kong Croucher Foundation (260960116) and the General Research Fund, Hong Kong Research Grants Council (No 17114515) and Interdisciplinary Innovation Team and External Cooperation Program (No. GJHZ201312), Chinese Academy of Sciences.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval All protocols using human samples were approved by Ethics Committee of the Second Affiliated Hospital of Jinan University, Ethics Committee of the First Hospital Affiliated to Army Medical University and Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong Western Cluster (HKU/HA HKW IRB). All protocols involving live animals were approved by the Committee on the Use of Live Animals in Teaching and Research (CULATR) at The University of Hong Kong.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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