Objective The interferon (IFN) system is activated in systemic sclerosis (SSc), but the driving mechanisms remain unclear. We asked whether type I and III IFN responses to Toll-like receptor (TLR)-7/8/9 stimulation of leukocytes from patients with SSc differ from healthy individuals, and if the IFN production is associated with clinical features. Methods Peripheral blood mononuclear cells (PBMCs), monocyte-depleted PBMCs, and monocytes were prepared from 45 SSc patients and 47 healthy controls. Cells were stimulated with RNA-containing immune complexes (RNA-IC), an RNA-oligonucleotide (ORN8L), or inactivated herpes simplex virus (HSV) targeting TLR7, TLR8, and TLR9, respectively. IFN-α, -β, -λ1 and -λ2 levels were measured by immunoassays. IFN-α producing cells were analyzed by flow cytometry. Results SSc-PBMCs produced type I and III IFNs in response to all three stimuli, with HSV inducing the strongest response. Compared to controls, SSc-PBMCs produced less IFN-α(p<0.02), while IFN-β levels were higher in HSV-stimulated SSc-monocytes (342 vs. 59.9 pg/ml, p=0.041). Expression of IFN-λ1/2 was lower than type I IFNs. The IFN responses to TLR7/8 stimulation increased in PBMCs in the presence of IFN-α (priming). Strong HSV-induced IFN-α production was associated with diffuse cutaneous SSc, anti-RNA-polymerase III autoantibodies, and interstitial lung disease (ILD).
Adeli et al. (Wed,) studied this question.