scholarly journals Levels of type I interferon in patients with systemic lupus erythematosus

2021 ◽  
pp. 16-20
Author(s):  
C. Erramuspe ◽  
M. Racca ◽  
M. Siemsen ◽  
M. Pelosso ◽  
M. Quaglia ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Organ Damage ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Dsdna Antibodies ◽  
Different Levels

Introduction: type I interferon (IFN) is a cytokine that plays a fundamental role in the pathogenesis of Systemic Lupus Erythematosus (SLE). Different levels of this cytokine could explain the heterogeneity of this pathology and be useful to evaluate its activity. Objectives: to determine the serum type I IFN levels in patients with SLE and evaluate its usefulness as a biomarker of activity. Material and Method: 16 patients with SLE (ACR 1997) and 16 controls. Methods: Disease activity (SLEDAI-2K), organ damage (SLICC), type I IFN (HEK-Blue- IFNα/β), anti-dsDNA antibodies (Indirect Immunofluorescence), anti-ENA antibodies (ELISA), C3-C4 (Immunoturbidimetry). Statistics: InfoStat/Instat/MedCalc. P values <0.05 were statistically significant. Results: an increase in IFN concentration was observed in the SLE group respect to the control (p <0.05). Patients with IFN values above the cut-off point were associated with the presence of anti-dsDNA antibodies (OR: 13.33; p<0.05). Hypocomplementemic patients and those with a SLEDAI-2K score greater than 8 had higher IFN levels compared to patients with normal complement and a lower index score, respectively (p<0.05). Conclusions: these results suggest the importance that the determination of IFN type I could have for the monitoring of SLE activity.

scholarly journals Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

2020 ◽  
Author(s):  
Laura Barnabei ◽  
Hicham Lamrini ◽  
Mathieu Castela ◽  
Nadia Jeremiah ◽  
Marie-Claude Stolzenberg ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Early Onset ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Consensus Sequences ◽  
Expression Of Genes

AbstractSystemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets.SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFNα-consensus sequences.

scholarly journals Resolution of the Expert Council «The role of type I interferon inhibitor in the treatment of patients with systemic lupus erythematosus»

2021 ◽  
Vol 15 (4) ◽  
pp. 126-128
Author(s):  
A. M. Lila ◽  
S. K. Soloviev ◽  
T. V. Popkova
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Organ Damage ◽  
Immunosuppressive Drugs ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Key Points

On April 28, 2021, a meeting of the Council of Experts was held with the participation of the leading experts in the field of rheumatic diseases, approaches to the treatment of patients with systemic lupus erythematosus (SLE) were discussed. The issues of medical care for patients with SLE and their routing, key points of Russian and international clinical guidelines for the management of patients with SLE, as well as the role of interferon (IFN) type I in the pathogenesis of the disease were discussed. It is noted that the management of patients with SLE requires a multidisciplinary approach. The basis of therapy is the use of glucocorticoids (GC), immunosuppressive drugs and their combinations. But long-term use of GC in patients with SLE leads to severe complications. Early prescription of biological disease-modifying antirheumatic drugs (bDMARDs) allows to achieve the greatest effect and prevent the development of irreversible organ damage associated with SLE. Currently data from three clinical trials on the efficacy and safety of the type I IFN inhibitor anifrolumab are available. During the discussion, experts defined the clinical profile of a patient with SLE, for whom administration of bDMARD therapy is indicated. According to experts, the use of a type I IFN inhibitor in routine clinical practice can improve disease outcomes in both short and long term.

Type I interferon gene signature test–low and –high patients with systemic lupus erythematosus have distinct gene expression signatures

Lupus ◽  
2019 ◽  
Vol 28 (13) ◽  
pp. 1524-1533 ◽  
Author(s):  
PZ Brohawn ◽  
K Streicher ◽  
B W Higgs ◽  
C Morehouse ◽  
H Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Gene Signature ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Blood Samples ◽  
Ifn Γ

Objectives Type I interferon (IFN) is implicated in systemic lupus erythematosus (SLE) pathogenesis. We aimed to identify type I IFN signaling-dependent and -independent molecular pathways in a large population of patients with SLE. Methods Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were profiled using whole transcriptome array analyses. Type I IFN gene signature (IFNGS) test status (high or low) was determined using a validated qualitative polymerase chain reaction–based test. IFN-type-specific signatures were developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or pooled IFN-α. These, and multiple literature-derived cell type and cytokine pathway signatures, were evaluated in individual and pooled study populations. A Fisher’s exact test was used for associations, adjusted for false discovery rate. Results Whole blood samples from IFNGS test–high patients were enriched versus IFNGS test–low patients for CD40L signaling ( Q < 0.001), CXC cytokine ( Q < 0.001), TLR8-mediated monocyte activation ( Q < 0.001), IgG ( Q < 0.001), major histocompatibility complex class I ( Q < 0.001), and plasma cell ( Q < 0.001) gene expression signatures. IFNGS test–low patients had significant enrichment of eosinophil ( Q < 0.001), IFN-γ-specific ( Q = 0.005), and T-cell or B-cell ( Q < 0.001) signatures. Similar enrichment profiles were demonstrated in patients with primary Sjögren’s syndrome, systemic sclerosis, and dermatomyositis. Conclusions IFNGS test–high patients overexpressed many gene signatures associated with SLE pathogenesis compared with IFNGS test–low patients, reflecting broad immune activation. These results provide new insights into the molecular heterogeneity underlying SLE pathogenesis, highlighting shared mechanisms beyond type I IFN, across several autoimmune diseases. Trial registration Clinicaltrials.gov: NCT01438489 and NCT01283139.

scholarly journals Activation of Type I Interferon Pathway in Systemic Lupus Erythematosus: Association with Distinct Clinical Phenotypes

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Theophanis P. Karageorgas ◽  
Dimitrios D. Tseronis ◽  
Clio P. Mavragani
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Clinical Manifestations ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Genetic Studies ◽  
Interferon Pathway

Growing evidence over the last few years suggests a central role of type I IFN pathway in the pathogenesis of systemic autoimmune disorders. Data from clinical and genetic studies in patients with systemic lupus erythematosus (SLE) and lupus-prone mouse models, indicates that the type I interferon system may play a pivotal role in the pathogenesis of several lupus and associated clinical features, such as nephritis, neuropsychiatric and cutaneous lupus, premature atherosclerosis as well as lupus-specific autoantibodies particularly against ribonucleoproteins. In the current paper, our aim is to summarize the latest findings supporting the association of type I IFN pathway with specific clinical manifestations in the setting of SLE providing insights on the potential use of type I IFN as a therapeutic target.

Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1951-1957 ◽  
Author(s):  
Christian Lood ◽  
Stefan Amisten ◽  
Birgitta Gullstrand ◽  
Andreas Jönsen ◽  
Maria Allhorn ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Protein Expression ◽  
Vascular Disease ◽  
Platelet Activation ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Increased Risk

AbstractPatients with systemic lupus erythematosus (SLE) have a markedly increased risk to develop cardiovascular disease, and traditional cardiovascular risk factors fail to account for this increased risk. We used microarray to probe the platelet transcriptome in patients with SLE and healthy controls, and the gene and protein expression of a subset of differentially expressed genes was further investigated and correlated to platelet activation status. Real-time PCR was used to confirm a type I interferon (IFN) gene signature in patients with SLE, and the IFN-regulated proteins PRKRA, IFITM1 and CD69 (P < .0001) were found to be up-regulated in platelets from SLE patients compared with healthy volunteers. Notably, patients with a history of vascular disease had increased expression of type I IFN-regulated proteins as well as more activated platelets compared with patients without vascular disease. We suggest that interferogenic immune complexes stimulate production of IFNα that up-regulates the megakaryocytic type I IFN-regulated genes and proteins. This could affect platelet activation and contribute to development of vascular disease in SLE. In addition, platelets with type I IFN signature could be a novel marker for vascular disease in SLE.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus

2020 ◽  
Author(s):  
Kerry A Casey ◽  
Michael A Smith ◽  
Dominic Sinibaldi ◽  
Nickie L Seto ◽  
Martin P Playford ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Cardiometabolic Disease ◽  
Type I ◽  
Systemic Lupus ◽  
Disease Markers
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