IFN- γ Mediates the Development of Systemic Lupus Erythematosus

Abstract

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs in the body. It is characterized by overexpression of antibodies against autoantigen. Although previous bioinformatics analyses have identified several genetic factors underlying SLE, they did not discriminate between naive and individuals exposed to anti-SLE drugs. Here, we evaluated specific genes and pathways in active and recently diagnosed SLE population.

Methods: GSE46907 matrix downloaded from Gene Expression Omnibus (GEO) was analyzed using R, Metascape, STRING, and Cytoscape to identify differentially expressed genes (DEGs), enrichment pathways, protein-protein interaction (PPI), and hub genes between naive SLE individuals and healthy controls.

Results: A total of 134 DEGs were identified, in which 29 were downregulated, whereas 105 were upregulated in active and newly diagnosed SLE cases. GO term analysis revealed that transcriptional induction of the DEGs was particularly enhanced in response to secretion of interferon-γ and interferon-α and regulation of cytokine production innate immune responses among others. KEGG pathway analysis showed that the expression of DEGs was particularly enhanced in interferon signaling, IFN antiviral responses by activated genes, class I major histocompatibility complex (MHC-I) mediated antigen processing and presentation, and amyloid fiber formation. STAT1, IRF7, MX1, OASL, ISG15, IFIT3, IFIH1, IFIT1, OAS2, and GBP1 were the top 10 DEGs.

Conclusions: Our findings suggest that interferon-related gene expression and pathways are common features for SLE pathogenesis, and IFN-γ and IFN-γ-inducible GBP1 gene in naive SLE were emphasized. Together, the identified genes and cellular pathways have expanded our understanding on the mechanism underlying development of SLE. They have also opened a new frontier on potential biomarkers for diagnosis, biotherapy, and prognosis for SLE.

Figure 1

Heat map of hierarchical clustering analysis for the DEGs between SLE and healthy controls. Each row represents a gene, and each column represents a sample. Color indicates the level of gene expression. Red represents high expression, and green represents low expression. The top is the sample cluster tree, and the left is the gene cluster tree.

Figure 2

The volcano plots of genes in SLE and healthy control. The vertical lines represent |log2.0 fold change| of SLE/healthy control up and down, respectively, and the horizontal line represents adj. P value of 0.05. And in the plot, red and blue points represent magnitude change of DGEs for SLE and healthy control, respectively.

Figure 3

Top 20 enriched terms of function enrichment analysis of the DEGs identified in SLE, analyzed by Metascape.

Figure 4

Protein-protein interaction (PPI) network of DEGs constructed using the STRING online database and Cytoscape 3.7.2, with 90 nodes and 973 edges. Red represents upregulated genes, while green represents downregulated genes.

Figure 5

Top 10 hub genes and cointeraction in the PPI network, constructed by cytoHubba of Cytoscape based on a degree score. Color scale represents highly of degree scores.