Abstract
A role for interferon (IFN) in systemic lupus erythematosus (SLE) pathogenesis is inferred from the prominent IFN gene signature (IGS), but the major IFN species and its relationship to disease activity are unknown. A bioinformatic approach employing individual IFN species gene signatures to interrogate SLE microarray datasets demonstrates a putative role for numerous IFN species, with prominent expression of IFNB1 and IFNW signatures. In contrast with other SLE-affected organs, the IGS is less prominent in lupus nephritis. SLE patients with active and inactive disease have readily detectable IGS and the IGS changes synchronously with a monocyte signature but not disease activity, and is significantly related to monocyte transcripts. Monocyte over-expression of three times as many IGS transcripts as T and B cells and IGS retention in monocytes, but not T and B cells from inactive SLE patients contribute to the lack of correlation between the IGS and SLE disease activity.
Highlights
A role for interferon (IFN) in systemic lupus erythematosus (SLE) pathogenesis is inferred from the prominent IFN gene signature (IGS), but the major IFN species and its relationship to disease activity are unknown
Microarray data derived from publicly available datasets and collaborators was used to define the subtype of IFN in SLE patients (Supplementary Data 1)
Genes induced by the in vitro stimulation of normal human peripheral blood mononuclear cells (PBMC) with IFNA2, IFNB1, IFNW1 or IFNG, and as controls the signatures induced by TNF or IL1239 were employed as reference modules
Summary
A role for interferon (IFN) in systemic lupus erythematosus (SLE) pathogenesis is inferred from the prominent IFN gene signature (IGS), but the major IFN species and its relationship to disease activity are unknown. A phase 2 trial using the antibody anifrolumab which blocks binding of all type I IFNs to the shared IFN receptor provided clinically meaningful benefit in subjects with SLE and with high IGS scores[27]. These trials raised the important question of whether IFNA is the predominant IFN acting in SLE. Some correlation between module 5.12 with SLE flares was noted and characterization of the module using the IFN database, the Interferome[37], was done in an attempt to classify the species of IFN38
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