title: PTPN22 Variant R620W Is Associated With Reduced Toll-like Receptor 7-Induced Type I Interferon in Systemic Lupus Erythematosus.
abstract: OBJECTIVE
  Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is associated with an increased risk of systemic lupus erythematosus (SLE). PTPN22 encodes Lyp, and a disease-associated coding variant bears an R620W substitution (LypW). LypW carriage is associated with impaired production of type I interferon (IFN) by myeloid cells following Toll-like receptor (TLR) engagement. The aim of this study was to investigate the effects of LypW carriage on TLR signaling in patients with SLE.
  
  
  METHODS
  Plasma IFNα concentrations and whole-blood IFN gene scores were compared in SLE patients who were LypW carriers and those who were noncarriers. TLR-7 agonist R848-stimulated IFNα and tumor necrosis factor levels, IFN-dependent gene expression, and STAT-1 activation were determined in peripheral blood mononuclear cells (PBMCs) and/or plasmacytoid dendritic cells (PDCs) obtained from these patients. The effect of LypW expression on the systemic type I IFN response to R848 stimulation in vivo was assessed in transgenic mice.
  
  
  RESULTS
  Plasma IFNα levels and whole-blood IFN gene signatures were comparable in SLE patients who were LypW carriers and those who were noncarriers. However, PBMCs from LypW carriers produced less IFNα and showed reduced IFN-dependent gene up-regulation and STAT-1 activation after R848 stimulation. The frequency of PDCs producing IFNα2 and the per-cell IFNα2 levels were significantly reduced in LypW carriers. LypW-transgenic mice displayed reduced TLR-7-induced circulating type I IFN responses.
  
  
  CONCLUSIONS
  PDCs from SLE patients carrying the disease-associated PTPN22 variant LypW showed a reduced capacity for TLR-7 agonist-induced type I IFN production, even though LypW carriers displayed systemic type I IFN activation comparable with that observed in noncarriers. LypW carriage identifies SLE patients who may harbor defects in TLR- and PDC-dependent host defense or antiinflammatory functions.
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: David
authors.initials: D
authors.lastname: Ewart
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Juliet N
authors.initials: JN
authors.lastname: Crabtree
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Ami
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Baechler
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Fazeli
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Peterson
mesh_terms: D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007370:Interferon Type I / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000276:immunology*; D008822:Mice, Transgenic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D007093:Imidazoles; D007370:Interferon Type I; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C402365:resiquimod