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Human SLE variant NCF1-R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages
  1. Linyu Geng1,2,
  2. Jian Zhao1,
  3. Yun Deng1,
  4. Ivan Molano1,
  5. Xue Xu1,
  6. Lingxiao Xu1,
  7. Phillip Ruiz3,
  8. Quanzhen Li4,
  9. Xuebing Feng2,
  10. Miaojia Zhang5,
  11. Wenfeng Tan5,
  12. Diane L Kamen1,
  13. Sang-Cheol Bae6,
  14. Gary S Gilkeson1,7,
  15. Lingyun Sun2,
  16. Betty P Tsao1
  1. 1 Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  2. 2 Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
  3. 3 Department of Surgery, University of Miami School of Medicine, Miami, Florida, USA
  4. 4 Department of Immunology and Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
  5. 5 Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  6. 6 Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases and Hanyang University Institute for Rheumatology, Seoul, The Republic of Korea
  7. 7 Ralph H Johnson VA Medical Center, Medical University of South Carolina, Charleston, South Carolina, USA
  1. Correspondence to Dr. Betty P Tsao, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; tsaob{at}; Dr. Lingyun Sun, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China; lingyunsun{at}


Objectives We previously identified a hypomorphic variant, p.Arg90His (p.R90H) of neutrophil cytosolic factor 1 (NCF1, a regulatory subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex), as an putative causal variant for systemic lupus erythematosus (SLE), and established a knock-in (KI) H90 variant in the C57BL/6 background to study how this variant promotes lupus development.

Methods Wild type (WT) and KI littermates were assessed for immune profiles and lupus-like features. Disease activity and renal damage of patients with SLE were assessed by systemic lupus erythematosus disease activity index (SLEDAI) and renal items of systemic lupus international collaborating clinics (SLICC), respectively.

Results Compared with WT littermates, 5-week-old homozygous KI mice had reduced oxidative burst, splenomegaly, elevated type I interferon (IFN-I) scores, increased ratios of splenic follicular T helper 2 (Tfh2) to either T follicular regulatory (Tfr) or Tfh1 cells, increased ANA+ follicular, germinal centre and plasma cells without spontaneous kidney disease up to 1 year of age. Pristane treatment exacerbated the immune dysregulation and induced IFN-I-dependent kidney disease in 36-week-old H90 KI female mice. Decreased efferocytosis of macrophages derived from KI mice and patients with homozygous H90 SLE promoted elevated ratios of Tfh2/Tfr and Tfh2/Tfh1 as well as dysregulated humoral responses due to reduced voltage-gated proton channel 1 (Hv1)-dependent acidification of phagosome pH to neutralise the decreased electrogenic effect of the H90 variant, resulting in impaired maturation and phagosome proteolysis, and increased autoantibody production and kidney damage in mice and patients with SLE of multiple ancestries.

Conclusions A lupus causal variant, NCF1-H90, reduces macrophage efferocytosis, enhances Tfh2 responses and promotes autoantibody production and kidney damage in both mice and patients with SLE.

  • lupus erythematosus
  • systemic
  • T-lymphocyte subsets
  • autoimmunity
  • efferocytosis

Data availability statement

All data relevant to the study are included in the article.

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Data availability statement

All data relevant to the study are included in the article.

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  • Handling editor Josef S Smolen

  • Contributors BPT and GG designed the study; LS provided the kidney biopsy section of patients with lupus. XF, MZ, WT and LX provided the DNA samples of patients with lupus. DLK, GG and S-CB provided renal damage scoring and DNA samples of patients with lupus; IM, LG, JZ, YD and XX conducted experiments and association studies of patients with lupus; LG and JZ analysed data and performed statistical analyses; PR performed renal score assessment of mice; Q-ZL conducted the autoantigen array; BPT and LG drafted the manuscript; all authors edited and reviewed the manuscript.

  • Funding This work was supported by Lupus Research Alliance (grant to BPT), NRF-2017M3A9B4050335 and NRF-2021R1A6A1A03038899 (grant to S-CB).

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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