Type I interferon gene signature test-low and -high patients with systemic lupus erythematosus have distinct gene expression signatures

Lupus. 2019 Nov;28(13):1524-1533. doi: 10.1177/0961203319885447. Epub 2019 Oct 29.


Objectives: Type I interferon (IFN) is implicated in systemic lupus erythematosus (SLE) pathogenesis. We aimed to identify type I IFN signaling-dependent and -independent molecular pathways in a large population of patients with SLE.

Methods: Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were profiled using whole transcriptome array analyses. Type I IFN gene signature (IFNGS) test status (high or low) was determined using a validated qualitative polymerase chain reaction-based test. IFN-type-specific signatures were developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or pooled IFN-α. These, and multiple literature-derived cell type and cytokine pathway signatures, were evaluated in individual and pooled study populations. A Fisher's exact test was used for associations, adjusted for false discovery rate.

Results: Whole blood samples from IFNGS test-high patients were enriched versus IFNGS test-low patients for CD40L signaling (Q < 0.001), CXC cytokine (Q < 0.001), TLR8-mediated monocyte activation (Q < 0.001), IgG (Q < 0.001), major histocompatibility complex class I (Q < 0.001), and plasma cell (Q < 0.001) gene expression signatures. IFNGS test-low patients had significant enrichment of eosinophil (Q < 0.001), IFN-γ-specific (Q = 0.005), and T-cell or B-cell (Q < 0.001) signatures. Similar enrichment profiles were demonstrated in patients with primary Sjögren's syndrome, systemic sclerosis, and dermatomyositis.

Conclusions: IFNGS test-high patients overexpressed many gene signatures associated with SLE pathogenesis compared with IFNGS test-low patients, reflecting broad immune activation. These results provide new insights into the molecular heterogeneity underlying SLE pathogenesis, highlighting shared mechanisms beyond type I IFN, across several autoimmune diseases.

Trial registration: Clinicaltrials.gov: NCT01438489 and NCT01283139.

Keywords: Anifrolumab; disease pathogenesis; systemic lupus erythematosus; transcriptomics; type I IFN.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Cytokines / immunology*
  • Dermatomyositis / genetics
  • Dermatomyositis / immunology
  • Double-Blind Method
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • Interferon Type I / genetics*
  • Interferon Type I / immunology
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / physiopathology*
  • Male
  • Middle Aged
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / immunology
  • Severity of Illness Index
  • Sjogren's Syndrome / genetics
  • Sjogren's Syndrome / immunology


  • Cytokines
  • Interferon Type I

Associated data

  • ClinicalTrials.gov/NCT01438489
  • ClinicalTrials.gov/NCT01283139