Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus.
Ontology highlight
ABSTRACT:
SUBMITTER: Buang N
PROVIDER: S-EPMC8012390 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-? antibodies, anti-IFN-? receptor antibodies, and IFN-?-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.
| S-EPMC6769759 | biostudies-literature
Project description:Endothelial cell (EC) dysfunction is a hallmark of Systemic Lupus Erythematosus (SLE) and Tie2 is a receptor essential for vascular stability. Inflammatory processes promote inhibition of Tie2 homeostatic activation, driving vascular dysfunction. In this work we determined whether type I Interferons (IFN) induce Tie2 signalling-mediated endothelial dysfunction in patients with SLE. Serum levels of Angiopoietin (Ang)-1, Ang-2 and soluble (s)Tie1 in patients with SLE and healthy controls were measured by ELISA. Monocytes from patients with SLE and Human Umbilical Vein EC (HUVEC) were stimulated with IFN-α, IFN-β (1000 I.U.) or SLE serum (20%). mRNA and protein expression, phosphorylation and translocation were determined by quantitative PCR, ELISA, Western Blot, flow cytometry and confocal microscopy. Viability and angiogenic capacity were determined by calcein and tube formation assays. We found that sTie1 and Ang-2 serum levels were increased and Ang-1 decreased in patients with SLE and were associated with clinical characteristics. Type I IFN significantly decreased Ang-1 and increased Ang-2 in monocytes from patients with SLE. Type I IFN increased sTie1 and Ang-2 secretion and reduced Tie2 activation in HUVEC. Functionally, type I IFN significantly reduced EC viability and impaired angiogenesis in a Tie2 signalling-dependent manner. Finally, SLE serum increased Ang-2 and sTie1 secretion and significantly decreased tube formation. Importantly, Tie1 and IFNAR1 knockdown reversed these effects in tube formation. Overall, type I IFN play an important role in the stability of EC by inhibiting Tie2 signalling, suggesting that these processes may be implicated in the cardiovascular events observed in patients with SLE.
| S-EPMC10756137 | biostudies-literature
Project description:ObjectivesPlasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL-3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL-3 and IFN levels, and a whole blood 'IL-3 gene signature', in human SLE.MethodsSerum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL-3-regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL-3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors.ResultsSerum IL-3 levels correlated with IFNα (r = 0.612, 95% CI 0.455-0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406-0.720, P < 0.0001). IL-3 stimulation of WBC in vitro altered 794 genes (-1 ≥ logFC ≥ 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an 'IL-3 gene signature'. There was strong correlation between the IL-3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898-0.964, P < 0.0001).ConclusionA dual IL-3/IFN gene signature is a feature of SLE. An association between IL-3 and IFN raises the possibility that dual blockade of IL-3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature.
| S-EPMC6928763 | biostudies-literature
Project description:The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid ? oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.
| S-EPMC3378560 | biostudies-literature
Project description:Metabolic fingerprints in serum characterize diverse diseases for diagnostics and biomarker discovery. The identification of systemic lupus erythematosus (SLE) by serum metabolic fingerprints (SMFs) will facilitate precision medicine in SLE in an early and designed manner. Here, a discovery cohort of 731 individuals including 357 SLE patients and 374 healthy controls (HCs), and a validation cohort of 184 individuals (SLE/HC, 91/93) are constructed. Each SMF is directly recorded by nano-assisted laser desorption/ionization mass spectrometry (LDI MS) within 1 minute using 1 µL of native serum, which contains 908 mass to charge features. Sparse learning of SMFs achieves the SLE identification with sensitivity/specificity and area-under-the-curve (AUC) up to 86.0%/92.0% and 0.950 for the discovery cohort. For the independent validation cohort, it exhibits no performance loss by affording the sensitivity/specificity and AUC of 89.0%/100.0% and 0.992. Notably, a metabolic biomarker panel is screened out from the SMFs, demonstrating the unique metabolic pattern of SLE patients different from both HCs and rheumatoid arthritis patients. In conclusion, SMFs characterize SLE by revealing its unique metabolic pattern. Different regulation of small molecule metabolites contributes to the precise diagnosis of autoimmune disease and further exploration of the pathogenic mechanisms.
| S-EPMC10787061 | biostudies-literature
Project description:A hallmark of systemic lupus erythematosus (SLE) is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies; however, the antibody-independent features of the B-cell compartment in SLE are less understood. In this study, we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients. We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients. Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner, which can be recapitulated by direct IFN-α treatment. Furthermore, the effect of IFN-α on enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax. Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6, which was also linked to the overactivated type I IFN pathway. In addition, the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients, and these cells were significantly reduced after short-term standard therapies. Thus, the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients, which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.
| S-EPMC6461980 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease associated with multiple immunologic abnormalities. Prominent among these is upregulation of type I interferon (IFN)?a powerful immune adjuvant. IFN is, in part, produced in SLE in response to autoantigens in the form of self-nucleic acids and their associated nuclear proteins. Sources of these autoantigens include apoptotic and necrotic cells as well as neutrophils undergoing a specific form of cell death called NETosis. Although plasmacytoid dendritic cells are the main producers of IFN-a, other cells are important regulators of this process. Both genetic and environmental risk factors play a role in the development and pathogenesis of SLE. Further highlighting the importance of IFN, candidate gene and genome-wide association studies have identified a number of genes involved in type I IFN pathways associated with SLE. In this review, 3 monogenic deficiencies that result in lupus-like phenotypes and several polygenic variants that have been consistently associated with SLE are highlighted, and the relationship of these genes to IFN-a production is discussed. Clinical associations of the type I IFN pathway and the use of IFN-blocking agents as therapeutic agents in SLE are also reviewed.
| S-EPMC3216059 | biostudies-literature
Project description:Background and aimInterferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE). We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features.MethodsFour hundred ninety-seven well-characterized SLE patients and 322 population controls were included. Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM). Functional type I IFN activity was estimated by a WISH reporter cell assay. Levels of IFN-γ were estimated by MSD 30-plex assay. IFN-α and IFN-λ1 were measured by ELISA. Values above the third quartile of patients' measurements were defined as high. Associations among high IFN results and SLE features were investigated by nominal regression analysis.ResultsAll IFN measurements were higher in SLE patients than in controls. High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations. Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies. Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE.ConclusionsHigh functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs. High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile. IFN-λ1 in isolation is associated with milder disease. Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways.
| S-EPMC6489203 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-06-03 | E-GEOD-46923 | biostudies-arrayexpress
Project description:A role for interferon (IFN) in systemic lupus erythematosus (SLE) pathogenesis is inferred from the prominent IFN gene signature (IGS), but the major IFN species and its relationship to disease activity are unknown. A bioinformatic approach employing individual IFN species gene signatures to interrogate SLE microarray datasets demonstrates a putative role for numerous IFN species, with prominent expression of IFNB1 and IFNW signatures. In contrast with other SLE-affected organs, the IGS is less prominent in lupus nephritis. SLE patients with active and inactive disease have readily detectable IGS and the IGS changes synchronously with a monocyte signature but not disease activity, and is significantly related to monocyte transcripts. Monocyte over-expression of three times as many IGS transcripts as T and B cells and IGS retention in monocytes, but not T and B cells from inactive SLE patients contribute to the lack of correlation between the IGS and SLE disease activity.
| S-EPMC6478921 | biostudies-literature