SLE Patients Carrying a Disease-Associated PTPN22 R620W Variant Show Reduced Interferon-Inducing Capacity

Yaya Wang¹, David Ewart², Ami Yamamoto², Emily C. Baechler¹, Parastoo Fazeli³ and Erik J. Peterson², ¹Medicine, University of Minnesota, Minneapolis, MN, ²University of Minnesota, Minneapolis, MN, ³Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Functional Genomics, innate immunity, interferons, systemic lupus erythematosus (SLE) and toll-like receptors

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis II: Pathogenic Targets, Genetic Variants and Apoptosis

Session Type: Abstract Submissions (ACR)

Background/Purpose

Type 1 interferons (IFN) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Increased expression of IFN-regulated genes, termed the IFN-signature, correlates with autoantibodies and disease activity in SLE. Likely sources of type 1 IFN in SLE include plasmacytoid dendritic cells (pDC), which produce IFNα following Toll-like receptor 7 (TLR7) activation. A coding variant in the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with SLE. PTPN22 encodes lymphoid tyrosine phosphatase (Lyp). We showed previously that Lyp is required for TLR-driven type 1 IFN production in myeloid cells. Variant PTPN22 encodes an R620W bearing protein (“LypW”). We recently established that LypW is associated with impaired TLR-driven type 1 IFN production and type 1 IFN-dependent immunity. However, the functional consequences of LypW carriage in human SLE patients remain unclear. The current study was designed to address the effect of LypW carriage on interferogenic TLR signaling in SLE patients.

Methods

Caucasian SLE patients satisfying 1987 ARA diagnostic criteria were genotyped for PTPN22 LypW variant carriage. Plasma IFNα concentrations in 15 LypW carriers and 21 non-carriers were determined by ELISA. IFN gene signature in whole blood was also determined by quantitative PCR (qPCR). PBMC were stimulated with R848, a TLR7/8 agonist, and IFNα2 and TNFα expression in pDC (Lin^–HLA-DR⁺CD123⁺) were detected by FACS. We measured IFNα protein levels in the supernatant from R848-stimulated SLE PBMC by ELISA. We compared STAT1 activation in SLE PBMC from carriers and non-carriers by phospho-flow.

Results

In both LypW carrier and non-carrier SLE patients, we observed comparable IFNα protein in plasma and type 1 IFN gene “signatures” in whole blood. We found that the percentage of pDC that produce IFNα2 after R848 simulation was significantly reduced in LypW carrier SLE patients, while the percentage of pDC producing TNFα was comparable to that observed in non-carrier patients. Further, we observed that IFNα2 expression in pDC was decreased in LypW carriers. Supernatant IFNα protein levels from R848-stimulated PBMC were significantly reduced in LypW carriers. Moreover, activation of type 1 IFN-driven STAT1 was impaired in LypW carrier PBMC after R848 stimulation.

Conclusion

LypW carrier SLE patients have reduced capacity for TLR-induced type 1 IFN production, even as they exhibit elevated whole blood type 1 IFN signatures similar to those observed in non-carrier patients. The findings suggest that LypW carriage may identify a subset of SLE patients who harbor defects in type 1 IFN-dependent host defense or anti-inflammatory functions.

Disclosure:

Y. Wang,
None;

D. Ewart,
None;

A. Yamamoto,
None;

E. C. Baechler,
None;

P. Fazeli,
None;

E. J. Peterson,
None.

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/sle-patients-carrying-a-disease-associated-ptpn22-r620w-variant-show-reduced-interferon-inducing-capacity/