Systemic sclerosis & Raynaud's
Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages
Authors' conclusion
Low NCF1 activity increases the risk for the development of dcSSc and lung fibrosis via expanding profibrotic SPP1+MoMs in a CCL2-dependent manner, contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc.
Study context
- Population
- Case-control cohorts of patients with systemic sclerosis (SSc) (Chinese and European Americans) and bleomycin (BLM)-treated mice
- Comparison
- NCF1-H90 hypofunctional variant carriage vs NCF1-R90
- Outcome
- Association of NCF1-H90 allele with lung fibrosis in Chinese patients with SSc; low NCF1 copy number with lung fibrosis in European Americans
Methodological detailscase-control cohorts, Ncf1-H90 knock-in mice vs wildtype littermates, bleomycin-induced lung fibrosis model, longitudinal observation cohort, cytometry by time-of-flight
- Case-control cohorts
- Ncf1-H90 knock-in mice vs wildtype littermates
- Bleomycin-induced lung fibrosis model
- Longitudinal observation cohort
- Cytometry by time-of-flight
Main finding
As reported in the abstract
Odds ratio
2.09
P = 7.96E-10
NCF1-H90 allele · lung fibrosis in Chinese patients with SSc
Odds ratio
4.33
P = 2.60E-2
Low copy number of NCF1 · lung fibrosis in European Americans
Observational data: associations, not effects.
Further findings
Longitudinal SSc cohort: homozygous H90 patients
- Increased ANA titres, anti-topoisomerase seropositivity, anti-centromere seronegativity, increased lung fibrosis incidence and GAP index, elevated modified Rodnan Skin Score (mRSS) and plasma osteopontin (OPN), CCL2, ARG1, TIMP-1 and IL-6 at baseline
- Sustained elevated mRSS during follow-up with decreased survival
Profibrotic CD14+CD68+CD11b+Tim3+ monocytes in SSc peripheral blood mononuclear cell (PBMCs)
- Dose-dependent increases with 0, 1 and 2 copies of H90
- Elevated OPN, CCL2 and ARG1 in monocyte-derived macrophages from H90 patients decreased after anti-CCL2 antibody co-culture
Original publication
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