Overview of the biology of type I interferons

Type I interferons are pleiotropic cytokines with antiviral, antitumor and immunoregulatory functions. An aspect of their complex biology is the paradox that, depending on context, type I interferons can be anti-inflammatory and tissue protective or can be proinflammatory and promote autoimmunity. Along these lines, the activation of type I interferon pathways is effective in suppressing disease activity in patients with multiple sclerosis and in animal models of arthritis and colitis, while there is an expectation that blockade of the same pathways will be beneficial in the treatment of patients with systemic lupus erythematosus

Use of RNA sequencing to evaluate rheumatic disease patients

Studying the factors that control gene expression is of substantial importance for rheumatic diseases with poorly understood etiopathogenesis. In the past, gene expression microarrays have been used to measure transcript abundance on a genome-wide scale in a particular cell, tissue or organ. Microarray analysis has led to gene signatures that differentiate rheumatic diseases, and stages of a disease, as well as response to treatments. Nowadays, however, with the advent of next-generation sequencing methods, massive parallel sequencing of RNA tends to be the technology of choice for gene expression profiling, due to several advantages over microarrays, as well as for the detection of non-coding transcripts and alternative splicing events. In this review, we describe how RNA sequencing enables unbiased interrogation of the abundance and complexity of the transcriptome, and present a typical experimental workflow and bioinformatics tools that are often used for RNA sequencing analysis. We also discuss different uses of this next-generation sequencing technology to evaluate rheumatic disease patients and investigate the pathogenesis of rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis and Sjögren\u27s syndrome

IFN-g Induces Histone 3 Lysine 27 Trimethylation in a Small Subset of Promoters to Stably Silence Gene Expression in Human Macrophages

The mechanisms by which IFN-g activates expression of interferon-stimulated genes that have inflammatory and host defense functions are well understood. In contrast, little is known about how IFN-g represses gene expression. By using transcriptomic and epigenomic analysis, we found that stable repression of a small group of genes by IFN-g is associated with recruitment of the histone methyltransferase EZH2 and deposition of the negative mark histone 3 lysine 27 trimethylation (H3K27me3) at their promoters. Repressed genes included MERTK, PPARG, and RANK, which have anti-inflammatory functions and promote osteoclast differentiation. Gene repression and H3K27me3 persisted after IFN-g signaling was terminated, and these silenced genes were no longer responsive to glucocorticoids, IL-4, and M-CSF. These results identify cytokineinduced H3K27 trimethylation as a mechanism that stabilizes gene silencing in macrophages. IFN-ginduced macrophage activation is thus reinforced by a chromatin-based mechanism that blocks antiinflammatory and opposing pathways