PTPN22 Variant R620W Is Associated With Reduced Toll-like Receptor 7-Induced Type I Interferon in Systemic Lupus Erythematosus.

Autor: Wang Y; University of Minnesota, Minneapolis., Ewart D; University of Minnesota, Minneapolis., Crabtree JN; University of Minnesota, Minneapolis., Yamamoto A; University of Minnesota, Minneapolis., Baechler EC; University of Minnesota, Minneapolis., Fazeli P; University of Minnesota, Minneapolis., Peterson EJ; University of Minnesota, Minneapolis.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2015 Sep; Vol. 67 (9), pp. 2403-14.
DOI: 10.1002/art.39211
Abstrakt: 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.
(© 2015, American College of Rheumatology.)
Databáze: MEDLINE
Externí odkaz: