PTPN22 Variant R620W Is Associated With Reduced Toll‐like Receptor 7–Induced Type I Interferon in Systemic Lupus Erythematosus
Copyright policy )PTPN22 Variant R620W Is Associated With Reduced Toll‐like Receptor 7–Induced Type I Interferon in Systemic Lupus Erythematosus
ObjectiveProtein 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.MethodsPlasma 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.ResultsPlasma 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.ConclusionPDCs 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.
- University of Minnesota United States
- University of Minnesota Morris United States
- University of Minnesota System United States
Adult, Membrane Glycoproteins, Gene Expression Profiling, Imidazoles, Interferon-alpha, Mice, Transgenic, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Dendritic Cells, Middle Aged, Polymorphism, Single Nucleotide, STAT1 Transcription Factor, Gene Expression Regulation, Toll-Like Receptor 7, Case-Control Studies, Interferon Type I, Leukocytes, Mononuclear, Animals, Humans, Lupus Erythematosus, Systemic, Female
Adult, Membrane Glycoproteins, Gene Expression Profiling, Imidazoles, Interferon-alpha, Mice, Transgenic, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Dendritic Cells, Middle Aged, Polymorphism, Single Nucleotide, STAT1 Transcription Factor, Gene Expression Regulation, Toll-Like Receptor 7, Case-Control Studies, Interferon Type I, Leukocytes, Mononuclear, Animals, Humans, Lupus Erythematosus, Systemic, Female
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