Background A central facet of the immunopathogenesis of systemic lupus erythematosus (SLE) is the activation of interferon (IFN) signalling. In SLE patients, several types of IFNs are upregulated as well as the genes that are stimulated by IFNs. Sustained expression of interferon-stimulated genes (ISGs) may have adverse effects including altered T cell function, tissue inflammation and organ damage. The distinct association of the IFN gene signature to SLE disease activity is still uncertain.
Methods Peripheral blood samples from 34 SLE patients and 15 healthy controls were collected in PAXgene tubes. RNA from peripheral blood cells (PBCs) was extracted using the PAXgene Blood RNA Kit. The mRNA transcripts of 105 ISGs were measured using the multiplexed Nanostring nCounter Gene Expression platform. Bioinformatics and statistical analysis were performed using nSolver and SPSS.
Results We found that SLE patients had significantly higher expression levels of a wide range of ISGs, as compared to healthy controls. The 5 most upregulated ISGs in PBCs were IFI27, IFI44L, USP18, RSAD2 and ISG15. Using principal component analysis we identified two subsets of ISGs of which one included the mentioned top-five expressed ISGs; this gene cluster consisted of ISGs with predominantly antiviral functions and STAT1/STAT2, and did not associate with clinical disease activity or history of nephritis in SLE patients. Instead these genes associated with anti-SSA/SSB antibodies and PBC expression of PDCD1 and LAG3, which are markers of CD8 T cell exhaustion. The second group of ISGs associated with clinical disease activity, STAT3 and NFKB expression.
Conclusions Our results indicate the presence of ISG subsets that are differentially associated to clinical, serological and immunological features of SLE. Thus, the IFN gene signature in SLE may consist of a highly complex network of ISGs that can be clustered, and each in their way contribute to the pathogenesis of SLE. Also, this challenges the construction IFN gene signatures and scores with respect to what purpose they are intended for.
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