title: Association of endogenous anti-interferon-α autoantibodies with decreased interferon-pathway and disease activity in patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  Numerous observations implicate interferon-α (IFNα) in the pathophysiology of systemic lupus erythematosus (SLE); however, the potential impact of endogenous anti-IFNα autoantibodies (AIAAs) on IFN-pathway and disease activity is unclear. The aim of this study was to characterize IFN-pathway activity and the serologic and clinical profiles of AIAA-positive patients with SLE.
  
  
  METHODS
  Sera obtained from patients with SLE (n = 49), patients with rheumatoid arthritis (n = 25), and healthy control subjects (n = 25) were examined for the presence of AIAAs, using a biosensor immunoassay. Serum type I IFN bioactivity and the ability of AIAA-positive sera to neutralize IFNα activity were determined using U937 cells. Levels of IFN-regulated gene expression in peripheral blood were determined by microarray, and serum levels of BAFF, IFN-inducible chemokines, and other autoantibodies were measured using immunoassays.
  
  
  RESULTS
  AIAAs were detected in 27% of the serum samples from patients with SLE, using a biosensor immunoassay. Unsupervised hierarchical clustering analysis identified 2 subgroups of patients, IFN(low) and IFN(high) , that differed in the levels of serum type I IFN bioactivity, IFN-regulated gene expression, BAFF, anti-ribosomal P, and anti-chromatin autoantibodies, and in AIAA status. The majority of AIAA-positive patients had significantly lower levels of serum type I IFN bioactivity, reduced downstream IFN-pathway activity, and lower disease activity compared with the IFN(high) patients. AIAA-positive sera were able to effectively neutralize type I IFN activity in vitro.
  
  
  CONCLUSIONS
  Patients with SLE commonly harbor AIAAs. AIAA-positive patients have lower levels of serum type I IFN bioactivity and evidence for reduced downstream IFN-pathway and disease activity. AIAAs may influence the clinical course in SLE by blunting the effects produced by IFNα.
authors.affiliation: Department of Bioanalytical Research and Development MS-38, Genentech, South San Francisco, California 94080, USA. morimoto@gene.com
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Morimoto
authors.forename: Donna Thibault
authors.initials: DT
authors.lastname: Flesher
authors.forename: Jihong
authors.initials: J
authors.lastname: Yang
authors.forename: Kristen
authors.initials: K
authors.lastname: Wolslegel
authors.forename: Xiangdan
authors.initials: X
authors.lastname: Wang
authors.forename: Ann
authors.initials: A
authors.lastname: Brady
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Abbas
authors.forename: Valerie
authors.initials: V
authors.lastname: Quarmby
authors.forename: Eric
authors.initials: E
authors.lastname: Wakshull
authors.forename: Bruce
authors.initials: B
authors.lastname: Richardson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Townsend
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: D001323:Autoantibodies; D016898:Interferon-alpha