title: Expression of Cyclic GMP-AMP Synthase in Patients With Systemic Lupus Erythematosus.
abstract: Type I interferon (IFN) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and interferonopathies such as Aicardi-Goutières syndrome. A recently discovered DNA-activated type I IFN pathway, cyclic GMP-AMP synthase (cGAS), has been linked to Aicardi-Goutières syndrome and mouse models of lupus. The aim of this study was to determine whether the cGAS pathway contributes to type I IFN production in patients with SLE.
  
  
  
  SLE disease activity was measured by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index. Expression of messenger RNA for cGAS and IFN-stimulated genes (ISGs) was determined by quantitative polymerase chain reaction analysis. Cyclic GMP-AMP (cGAMP) levels were examined by multiple reaction monitoring with ultra-performance liquid chromatography tandem mass spectrometry.
  
  
  
  Expression of cGAS in peripheral blood mononuclear cells (PBMCs) was significantly higher in SLE patients than in normal controls (n = 51 and n = 20 respectively; P < 0.01). There was a positive correlation between cGAS expression and the IFN score (P < 0.001). The expression of cGAS in PBMCs showed a dose response to type I IFN stimulation in vitro, consistent with it being an ISG. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients (7 of 48) but none of the normal (0 of 19) or rheumatoid arthritis (0 of 22) controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP.
  
  
  
  Increased cGAS expression and cGAMP in a proportion of SLE patients indicates that the cGAS pathway should be considered as a contributor to type I IFN production. Whereas higher cGAS expression may be a consequence of exposure to type I IFN, detection of cGAMP in patients with increased disease activity indicates potential involvement of this pathway in disease expression.
authors.affiliation: University of Washington, Seattle.
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.affiliation: University of Washington, Seattle.
authors.forename: Laura
authors.initials: L
authors.lastname: Durcan
authors.affiliation: University of Washington, Seattle.
authors.forename: Reynold M
authors.initials: RM
authors.lastname: Karr
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Briggs
authors.affiliation: St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust and Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: University of Washington, Seattle.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Teal
authors.affiliation: University of Washington, Seattle.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Woodward
authors.affiliation: University of Washington, Seattle.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology*; D008297:Male; D009712:Nucleotides, Cyclic / Q000097:blood; D009713:Nucleotidyltransferases / Q000096:biosynthesis*; D015398:Signal Transduction; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase