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. 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.

The multifaceted biology of plasmacytoid dendritic cells

“…Although SLE is generally associated with a type I IFN signature, it has been recently shown that pDC production of type I IFN is impaired in patients carrying a variant of the PTPN22 gene predisposing to SLE 211 . This observation raises the question of whether pDC and type I IFN depletion is a valid strategy for all SLE patients or should be adopted after stratification of the patients for pDC activity.…”

Dendritic cell recruitment and activation in autoimmunity

“…However, even in this clear-cut picture many questions remain open. For example, pDC production of type I IFN is impaired in SLE patients carrying a variant of the PTPN22 gene [256], raising the possibility of a different pathogenic mechanism as well as the hypothesis that pDC targeting should be adopted after patient stratification for pDC activity. It also remains to be established the possible role of these cells in other inflammatory diseases, such as inflammatory bowel diseases.…”

Negative regulation of TLR signaling in myeloid cells—implications for autoimmune diseases

“… showed that Lyp promotes TLR‐induced type I IFN through interactions with TRAF3 resulting in increased TRAF3 K63‐ubiquitinylation and that Lyp620W does not have this function. More recently, this group followed up their findings in primary human plasmacytoid DC from patients with SLE comparing those homozygous for the PTPN22 ‐1858C allele to those carrying one or two copies of the PTPN22 ‐1858T allele . In this study, the authors found that pDCs carrying the PTPN22 ‐1858T allele produced less TLR7‐induced IFNα than PTPN22 ‐1858C/C homozygotes.…”