SLE Peripheral Blood B Cell, T Cell and Myeloid Cell Transcriptomes Display Unique Profiles and Each Subset Contributes to the Interferon Signature (original) (raw)
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Arthritis & Rheumatism, 2006
Methods. WISH epithelial cell line cells were cultured with medium, with recombinant IFN␣, IFN, or IFN␥, or with 50% plasma from SLE patients (n ؍ 73), rheumatoid arthritis (RA) patients (n ؍ 19), or healthy donors (n ؍ 30). Real-time quantitative polymerase chain reaction was used to determine WISH cell expression of IFN target genes, including PRKR, IFIT1, IFI44, MX1, and C1orf29 (preferentially induced by IFN␣) and CXCL9 (Mig) (preferentially induced by IFN␥).
Leucocyte subset-specific type 1 interferon signatures in SLE and other immune-mediated diseases
RMD Open, 2016
Objectives: Type 1 interferons (IFN-1) are implicated in the pathogenesis of systemic lupus erythematosus (SLE), but most studies have only reported the effect of IFN-1 on mixed cell populations. We aimed to define modules of IFN-1-associated genes in purified leucocyte populations and use these as a basis for a detailed comparative analysis. Methods: CD4+ and CD8+ T cells, monocytes and neutrophils were purified from patients with SLE, other immune-mediated diseases and healthy volunteers and gene expression then determined by microarray. Modules of IFN-1-associated genes were defined using weighted gene coexpression network analysis. The composition and expression of these modules was analysed. Results: 1150 of 1288 IFN-1-associated genes were specific to myeloid subsets, compared with 11 genes unique to T cells. IFN-1 genes were more highly expressed in myeloid subsets compared with T cells. A subset of neutrophil samples from healthy volunteers (HV) and conditions not classically associated with IFN-1 signatures displayed increased IFN-1 gene expression, whereas upregulation of IFN-1-associated genes in T cells was restricted to SLE. Conclusions: Given the broad upregulation of IFN-1 genes in neutrophils including in some HV, investigators reporting IFN-1 signatures on the basis of whole blood samples should be cautious about interpreting this as evidence of bona fide IFN-1mediated pathology. Instead, specific upregulation of IFN-1-associated genes in T cells may be a useful biomarker and a further mechanism by which elevated IFN-1 contributes to autoimmunity in SLE.
Proceedings of the National Academy of Sciences, 2003
Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression ''signature'' served as a marker for more severe disease involving the kidneys, hematopoetic cells, and͞or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
Arthritis research & therapy, 2018
Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients. The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs). Innate immune receptor expression was determined by RT-PCR and flow cytometry. To clarify the contribution of RNA-binding RIG-like receptors (RLRs) and DNA-binding receptors (DBRs) to IFN-I activation, peripheral blood mononuclear cells (PBMCs) from patients were treated with BX795, a TANK-binding kinase 1 (TBK1) inhibitor blocking RLR ...
Clinical and Experimental Immunology, 1997
SUMMARY Transient expression of IFN-γ and IL-2 mRNA and its control by post-transcriptional and suppressive mechanisms were analysed in phytohaemagglutinin-induced peripheral blood mononuclear cells (PBMC) from 47 patients with SLE and 31 age-matched normal donors, using quantitative hybridization with antisense RNA probes. In SLE, basal levels of gene expression did not deviate from those of normal donors, but strongly aberrant patterns were obtained upon induction. The ratio of subjects exhibiting highly inducible IFN-γ gene expression in their PBMC to those showing moderate or low inducibility was increased five-fold in SLE (P = 0.003). High inducibility was observed for 43% of SLE patients and was equally pronounced in partial remission, mild or active disease. Inducibility of IL-2 mRNA, by contrast, remained similar to that for normal donors. However, regulation of IFN-γ gene expression differed for mild SLE. Patients with mild disease showing high inducibility of IFN-γ mRNA in...
Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus
Lupus, 2009
Cross-sectional studies of patients with systemic lupus erythematosus (SLE) have demonstrated an association between activation of type I interferon (IFN) pathway and disease activity. This study examined longitudinal changes in IFN-regulated gene expression in peripheral blood using microarrays. A cross-section of 66 patients from the Autoimmune Biomarkers Collaborative Network SLE archive was evaluated. We also examined paired samples from a 15 patient subset collected during a period of low disease activity (Baseline) and at a subsequent flare event, and baseline scores of 29 patients who maintained low disease activity. IFN response (IFNr) scores were calculated from three IFN-regulated genes. Overall, higher IFNr scores were associated with increased disease activity. However, IFNr scores were not significantly different between the paired Baseline and Flare samples. An extended longitudinal analysis in 11 patients indicated little change in IFNr scores over time, even during d...
Journal of immunology (Baltimore, Md. : 1950), 2016
The loss of tolerance and the presence of circulating autoantibodies directed against nuclear Ags is the hallmark of systemic lupus erythematosus (SLE). Many of these Ags are complexed with short, noncoding RNAs, such as U1 and Y1. The amount of U1 and Y1 RNA complexed with SLE patient Abs and immune complexes was measured in a cross-section of 228 SLE patients to evaluate the role of these RNA molecules within the known biochemical framework of SLE. The study revealed that SLE patients had significantly elevated levels of circulating U1 and/or Y1 RNA compared with healthy volunteers. In addition, the blood-borne RNA molecules were correlated with SLE disease activity and increased expression of IFN-inducible genes. To our knowledge, this study provides the first systematic examination of the role of circulating RNA in a large group of SLE patients and provides an important link with IFN dysregulation.
Coordinate overexpression of interferon-?-induced genes in systemic lupus erythematosus
Arthritis & Rheumatism, 2004
Results. Expression of IFN␣-inducible genes was significantly higher in SLE PBMCs than in those from disease controls or healthy donors. The level of expression of all IFIGs in PBMCs from SLE patients with IFN␣ pathway activation correlated highly with the inherent responsiveness of those genes to IFN␣, suggesting coordinate activation of that cytokine pathway.