Interferon Pathway In Systemic Lupus Erythematosus Research Articles

Transposable element dysregulation in systemic lupus erythematosus and regulation by histone conformation and Hsp90

Systemic lupus erythematosus (SLE) represents an autoimmune disease in which activation of the type I interferon pathway leads to dysregulation of tolerance and the generation of autoantibodies directed against nuclear constituents. The mechanisms driving the activation of the interferon pathway in SLE have been the subject of intense investigation but are still incompletely understood. Transposable elements represent an enormous source of RNA that could potentially stimulate the cell intrinsic RNA-recognition pathway, leading to upregulation of interferons. We used RNA-seq to define transposable element families and subfamilies in three cell types in SLE and found diverse effects on transposable element expression in the three cell types and even within a given family of transposable elements. When potential mechanisms were examined, we found that Hsp90 inhibition could drive increased expression of multiple type of transposable elements. Both direct inhibition and the delivery of a heat shock itself, which redirects heat shock regulators (including Hsp90) off of basal expression promoters and onto heat shock-responsive promoters, led to increased transposable element expression. This effect was amplified by the concurrent delivery of a histone deacetylase inhibitor. We conclude that transposable elements are dysregulated in SLE and there are tissue-specific effects and locus-specific effects. The magnitude of RNAs attributable to transposable elements makes their dysregulation of critical interest in SLE where transposable element RNA complexed with proteins has been shown to drive interferon expression.

Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies.

Could 2′5′-oligoadenylate synthetase isoforms be biomarkers to differentiate between disease flare and infection in lupus patients? A pilot study

2'5'-Oligoadenylate synthetase (OAS) was shown to be related to systemic lupus erythematosus (SLE) 20 years ago, and was rediscovered to be involved in type I interferon pathway in SLE by several microarray gene expression studies recently. The goal of this study was to investigate OAS isoform expressions in lupus patients, to evaluate whether they could become biomarkers to differentiate between disease flare and infection. Fifty-four SLE patients presented with fever or systemic inflammatory syndrome, or both, were enrolled. Gene expressions of OAS1, OAS2, and OASL were studied by using real time PCR in active SLE (SLEDAI >or=9, n=29) and in those complicated with infections (n=25). The latter group was composed of 19 patients with invasive bacterial infections, and six patients with viral infections. C reactive protein (CRP) and other clinical parameters were also measured. Twenty-nine healthy individuals made up a normal control group. The mRNA expressions of OAS1, OAS2, and OASL were higher in patients with lupus flares than those with infections (p<0.03), or normal controls (p<0.001). SLE complicated with infections have higher OAS1 expression level (P=0.002), lower OASL (P=0.004), and equivalent OAS2 (P=0.135), when compared with those of normal controls. OASL expression level was negatively correlated with infection in lupus by logistic regression analysis (p=0.008). Area under the receiver operating characteristic curve for the prediction of infection was 0.92 (p<0.0001) for OASL, and 0.77 (p=0.007) for CRP. Therefore, our preliminary data suggest that the pattern of OAS isoform expressions, OASL in particular, may provide useful information in differentiating disease flares from certain infections in SLE.