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
- T-lymphocyte subsets
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.
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