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.
Highlights
Systemic lupus erythematosus (SLE) is a chronic-inflammatory autoimmune disease that affects multiple organs and is characterised by the production of autoantibodies to nuclear antigens and immune complex formation
We focused on the contribution of CD4+ T cells, CD162 monocytes and CD16+ monocytes to the IFN signature observed in patients with SLE and compared these results to the pure virus-induced signatures detected in healthy individuals immunised with the yellow fever vaccine (YFV)
Detection of cell-specific IFN signatures in SLE and viral infection To discriminate between the type I IFN responses induced in active SLE patients from those induced in ND after viral infection, we compared the gene expression profiles of sorted peripheral blood CD4+ T cells, CD162 inflammatory monocytes and CD16+ resident monocytes from 8 SLE patients and 4 ND 7 days after yellow fever vaccination
Summary
Systemic lupus erythematosus (SLE) is a chronic-inflammatory autoimmune disease that affects multiple organs and is characterised by the production of autoantibodies to nuclear antigens and immune complex formation. Previous results from microarray studies that investigated the gene expression profiles of peripheral blood mononuclear cells (PBMCs) from patients with SLE have consistently shown an upregulation of IFN-inducible genes, such as IFI44, IFI44L, ISG15, RSAD2, IFIT1, IFIT3, OAS1, OAS2, OASL, MX1, STAT1 and LY6E, when compared with healthy donors (ND). The differential expression of IFN-inducible genes is known as an ‘‘IFN signature’’ and can be used to distinguish the transcriptomes of SLE patients from ND [3]. This signature is of potential interest for use as a surrogate IFN biomarker in diagnostic applications.
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