title: Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Melissa E
authors.identifier: http://orcid.org/0000-0002-6933-9745
authors.initials: ME
authors.lastname: Munroe
authors.affiliation: Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Rufei
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Yan D
authors.initials: YD
authors.lastname: Zhao
authors.affiliation: Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Fife
authors.affiliation: Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Robertson
authors.affiliation: Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Timothy B
authors.identifier: http://orcid.org/0000-0003-3532-6660
authors.initials: TB
authors.lastname: Niewold
authors.affiliation: Department of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.affiliation: Department of Rheumatology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keith
authors.affiliation: Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D053264:B-Cell Activating Factor / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000097:blood*; D016898:Interferon-alpha / Q000097:blood; D007371:Interferon-gamma / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D008297:Male; D015999:Multivariate Analysis; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007370:Interferon Type I; D016898:Interferon-alpha; D007371:Interferon-gamma
keywords: Autoantibodies; Autoimmunity; Chemokines; Cytokines; Systemic Lupus Erythematosus