Abstract
Type I interferons (IFN) are central players in the pathogenesis of systemic lupus erythematosus (SLE) and the up-regulation of interferon-stimulated genes (ISGs) in SLE patients is subjected to increasing scrutiny as for its use in diagnosis, stratification and monitoring of SLE patients. Determinants of this immunological phenomenon are yet to be fully charted. The purpose of this systematic review was to characterize expressions of ISGs in blood of SLE patients and to analyze if they associated with core demographic and clinical features of SLE. Twenty cross-sectional, case-control studies comprising 1033 SLE patients and 602 study controls could be included. ISG fold-change expression values (SLE vs controls), demographic and clinical data were extracted from the published material and analyzed by hierarchical cluster analysis and generalized linear modelling. ISG expression varied substantially within each study with IFI27, IFI44, IFI44L, IFIT4 and RSAD2, being the top-five upregulated ISGs. Analysis of inter-study variation showed that IFI27, IFI44, IFI44L, IFIT1, PRKR and RSAD2 expression clustered with the fraction of SLE cases having African ancestry or lupus nephritis. Generalized linear models adjusted for prevalence of lupus nephritis and usage of hydroxychloroquine confirmed the observed association between African ancestry and IFI27, IFI44L, IFIT1, PRKR and RSAD2, whereas disease activity was associated with expression of IFI27 and RNASE2. In conclusion, this systematic review revealed that expression of ISGs often used for deriving an IFN signature in SLE patients were influenced by African ancestry rather than disease activity. This underscores the necessity of taking ancestry into account when employing the IFN signature for clinical research in SLE.
Highlights
Systemic lupus erythematosus (SLE) is a clinically and immunologically heterogeneous autoimmune disease that is characterized by chronic activation of the interferon (IFN) system
Using the Newcastle-Ottawa Scale (NOS) to systematically describe basic features of the quality of the included studies, we found that the median NOS score was 6, ranging from 4 to 8, Table I
This systematic review provides an overview of IFN-stimulated genes (ISG) expressions in full blood and peripheral blood mononuclear cells (PBMCs) from SLE study populations and shows how these ISGs are associated with clinical and demographic characteristics in these populations
Summary
Systemic lupus erythematosus (SLE) is a clinically and immunologically heterogeneous autoimmune disease that is characterized by chronic activation of the interferon (IFN) system. Due to the systemic nature of SLE, any organ may be involved with varying severity. Renal involvement (lupus nephritis) is a common and severe disease phenotype that may progress to renal end-stage disease with non-Caucasian patients, especially those of African ancestry, having the highest risk hereof.[1,2,3]. Resulting in a breach of self-tolerance, the pathogenesis of SLE involves a complex interplay of genetic susceptibility, epigenetic factors and environmental triggers.[4] Sustained production of various types of IFNs plays a key role in this process. The finding of a type II IFN response preceding a type I IFN response in early SLE indicates differentiated roles of these 2 types of responses in SLE pathogenesis.[8]
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