Cell-Specific Type I IFN Signatures in Autoimmunity and Viral Infection: What Makes the Difference?

Abstract

Gene expression profiling of peripheral blood mononuclear cells (PBMCs) has revealed a crucial role for type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE). However, it is unclear how particular leucocyte subsets contribute to the overall type I IFN signature of PBMCs and whole blood samples.Furthermore, a detailed analysis describing the differences in the IFN signature in autoimmune diseases from that observed after viral infection has not been performed to date. Therefore, in this study, the transcriptional responses in peripheral T helper cells (CD4+) and monocyte subsets (CD16− inflammatory and CD16+ resident monocytes) isolated from patients with SLE, healthy donors (ND) immunised with the yellow fever vaccine YFV-17Dand untreated controls were compared by global gene expression profiling.It was striking that all of the transcripts that were regulated in response to viral exposure were also found to be differentially regulated in SLE, albeit with markedly lower fold-change values. In addition to this common IFN signature, a pathogenic IFN-associated gene signature was detected in the CD4+ T cells and monocytes from the lupus patients. IL-10, IL-9 and IL-15-mediated JAK/STAT signalling was shown to be involved in the pathological amplification of IFN responses observed in SLE. Type I IFN signatures identified were successfully applied for the monitoring of interferon responses in PBMCs of an independent cohort of SLE patients and virus-infected individuals. Moreover, these cell-type specific gene signatures allowed a correct classification of PBMCs independent from their heterogenic cellular composition. In conclusion, our data show for the first time that monocytes and CD4 cells are sensitive biosensors to monitor type I interferon response signatures in autoimmunity and viral infection and how these transriptional responses are modulated in a cell- and disease-specific manner.

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

“…Regardless of the uncertainty whether IFI44L or IFI44 (or both) is the true cis-hub of this trans-eQTL, nearly all of the genes involved in the putative regulatory pathways identified here are interferon-regulated/inducible genes, namely OAS1, OAS2, IFIT1, IFIT3, IFI44, IFI44L, RSAD2, and AGRN (Cheon and Stark 2009;Kyogoku et al 2013). These genes have been previously reported to be co-expressed and/or coregulated in various human cell types, including interferon-exposed fibroblasts and mammary epithelial cell lines (Cheon and Stark 2009), virusinfected airway epithelial cell cultures (Ioannidis et al 2012), and peripheral blood of individuals with acute respiratory infections (Zaas et al 2009), as well as in both normal and cancerous human tissue (Cancer Cell Metabolism Gene DB, https://bioinfo.uth.edu/ccmGDB/).…”

Pathogenese des systemischen Lupus erythematodes

“…IFN-Signatur, zeigte [6]. Im Gegensatz zu viralen Infektionen, bei denen auch eine IFN-Signatur nachweisbar ist, zeigt sich bei SLE z. T. ein erkrankungstypisches Muster [26], das im Krankheitsverlauf chronisch persistiert. Eine Inhibition dieser Genexpression gelingt in vitro mit Anti-IFN-α, aber nicht mit Antikörpern gegen IFN-β oder IFN-γ, sodass IFN-α als das primäre Typ-I-IFN gilt, das mit systemischer Autoimmunität verbunden ist.…”

The Expression of Interferon- Induced Protein with Tetracopeptide Repeats 1 in Monocytes, a Shortcut to the Interferon Signature in Lupus

“…In the present study we have determined mRNA expression levels of 6 ISG in each of the major PBMC from patients with lupus and from healthy subjects, using quantitative PCR. We aimed at replicating in our cohort of patients the up-regulation of some of the ISG showing a robust association to the IFN signature in previous approaches [7][8][9][10]. In addition, we used this strategy as a way to try and find a simpler approach to the IFN signature for clinical purposes.…”

“…Globally, our result point to expression levels of interferon-induced protein with tetracopeptide repeats 1 in monocytes as a biomarker of the IFN signature during active lupus. was studied using high-throughput techniques [7,8]. In both studies, the up-regulation of ISG in the patients was quali-and quantitatively cell-type specific, therefore suggesting that ISG should be better assessed in purified subpopulations.…”