PTPN22 Variant R620W Is Associated With Reduced Toll-like Receptor 7-Induced Type I Interferon in Systemic Lupus Erythematosus.
Arthritis Rheumatol
; 67(9): 2403-14, 2015 Sep.
Article
en En
| MEDLINE
| ID: mdl-26018863
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.CONCLUSION:
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Glicoproteínas de Membrana
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Interferón-alfa
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Receptor Toll-Like 7
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Proteína Tirosina Fosfatasa no Receptora Tipo 22
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Lupus Eritematoso Sistémico
Tipo de estudio:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Adult
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Animals
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
Arthritis Rheumatol
Año:
2015
Tipo del documento:
Article