Abstract
BackgroundActivation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNβ therapy is often beneficial in MS, implying different immunoregulatory roles for these IFNs. This study was aimed to investigate potential diversification of IFNα-and IFNβ-mediated response programs in autoimmune diseases.MethodsPeripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in 54 healthy controls (HCs), 69 SLE (47 test, 22 validation), 149 IFNβ-treated MS (71 test, 78 validation), 160 untreated MS, 78 IIM and 76 RA patients. Patients with a type I IFN signature were selected for analysis.ResultsWe identified IFNα- and IFNβ-specific response programs (GC-A and GC-B, respectively) in SLE and IFNβ-treated MS patients. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNβ-treated MS patients, which was confirmed in additional cohorts. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in untreated MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero.ConclusionsOur findings show diversification of the type I IFN response in autoimmune diseases, suggesting different pathogenic roles of the type I IFNs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0946-9) contains supplementary material, which is available to authorized users.
Highlights
Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA)
Differential expression of interferon response gene (IRG) in SLE versus IFNβ-treated MS patients In order to explore in vivo differences in the composition of type I IFN signatures in autoimmune diseases, we studied IRG expression profiles of a prototype IFNαdriven disease, i.e., SLE, and those of MS patients who were treated with IFNβ for 3 months
To ensure that the observed IFN signature was induced by the IFNβ treatment, MS patients with an IFN signature before start of IFNβ treatment were excluded from analysis
Summary
Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). Type I IFNs achieve their biological effects by binding to multi-subunit receptors, IFNAR1 and IFNAR2, on the cell surface. This leads to receptor dimerization and activation of the JAK-STAT pathway, a complex cascade of intracellular secondary messengers that emerge in transcriptional activation of genes containing IFN-stimulated response elements (ISRE) and/or IFN gamma-activated sequences (GAS) [1,2,3,4]. The antiviral activity involves suppression of viral replication, induction of apoptosis in virally infected cells, stimulation of T cell and B cell responses, natural killer cell-mediated and CD8+ T cell-mediated cytotoxicity and activation of dendritic cells [6]
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