Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification

Ann Rheum Dis. 2016 Nov;75(11):2014-2021. doi: 10.1136/annrheumdis-2015-208140. Epub 2016 Jan 25.


Objectives: The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE.

Methods: Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models.

Results: In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification).

Conclusions: Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.

Keywords: Autoantibodies; Autoimmunity; Chemokines; Cytokines; Systemic Lupus Erythematosus.

MeSH terms

  • Adult
  • Autoantibodies / blood*
  • B-Cell Activating Factor / blood
  • Case-Control Studies
  • Female
  • Humans
  • Interferon Type I / blood*
  • Interferon-alpha / blood
  • Interferon-gamma / blood*
  • Lupus Erythematosus, Systemic / blood*
  • Lupus Erythematosus, Systemic / diagnosis
  • Lupus Erythematosus, Systemic / immunology
  • Male
  • Multivariate Analysis
  • Time Factors


  • Autoantibodies
  • B-Cell Activating Factor
  • Interferon Type I
  • Interferon-alpha
  • Interferon-gamma