Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1γ can result in experimental myositis

2021 ◽  
pp. annrheumdis-2020-218661
Author(s):  
Naoko Okiyama ◽  
Yuki Ichimura ◽  
Miwako Shobo ◽  
Ryota Tanaka ◽  
Noriko Kubota ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Kinase Inhibitor ◽  
Inflammatory Myopathy ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Interferon Α ◽  
Muscle Fibres ◽  
Type I ◽  
Wild Type

ObjectivesTo investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy.MethodsWild-type, β2-microglobulin-null, perforin-null, Igμ‐null and interferon α/β receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8+ or CD4+ T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib.ResultsImmunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in β₂-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igμ‐null mice developed myositis normally. Adoptive transfer of CD8+ T cells induced myositis in recipients, while transfer of CD4+ T cells or IgG did not. Treatment with tofacitinib inhibited TIF1γ-induced myositis.ConclusionsHere we show that TIF1γ is immunogenic enough to cause experimental myositis, in which CD8+ T cells and type I interferons, but not CD4+ T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.

scholarly journals Targeting JAK/STAT pathway in Takayasu’s arteritis

2020 ◽  
Vol 79 (7) ◽  
pp. 951-959 ◽  
Author(s):  
Paul Régnier ◽  
Alexandre Le Joncour ◽  
Anna Maciejewski-Duval ◽  
Anne-Claire Desbois ◽  
Cloé Comarmond ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Takayasu’S Arteritis ◽  
Signalling Pathway ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Takayasu's Arteritis

ObjectiveTakayasu’s arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK.MethodsWe analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK.ResultsTranscriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients.ConclusionsJAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.

scholarly journals JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Lucas Walz ◽  
Avi J. Cohen ◽  
Andre P. Rebaza ◽  
James Vanchieri ◽  
Martin D. Slade ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Type I Interferon ◽  
Meta Analysis ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Janus Kinase Inhibitor ◽  
Janus Kinase Inhibitors

Abstract Background The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 17 million. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and due to direct antiviral ability against viruses including coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate the effect of Janus kinase-inhibitors and Type I interferons and their ability to produce positive patient outcomes in COVID-19 patients. Methods A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30 th 2020, including any study type that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. Results Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03 – 0.39, p<0.001) and ICU admission (OR, 0.05; 95% CI, 0.01 – 0.26, p<0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68 – 48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04 – 0.85, p<0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00 – 3.59, p=0.05). Conclusions Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

scholarly journals STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

2019 ◽  
Author(s):  
Natacha Zanin ◽  
Cédric M. Blouin ◽  
Christine Viaris de Lesegno ◽  
Daniela Chmiest ◽  
Ludger Johannes ◽  
...  
Keyword(s):  
Early Endosome ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Endosomal Sorting ◽  
Early Endosomes ◽  
Stat Signaling ◽  
Molecular Machinery ◽  
Β Receptor

ABSTRACTActivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-α/β receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-α/β-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN-α stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-β stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN-α and IFN-β.SummaryThe spatiotemporal activation of JAK/STAT signaling by IFN-α is controlled by STAM association with Hrs at the early endosome.

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.

scholarly journals Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarfaraz A. Hasni ◽  
Sarthak Gupta ◽  
Michael Davis ◽  
Elaine Poncio ◽  
Yenealem Temesgen-Oyelakin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Controlled Clinical Trial ◽  
Type I ◽  
Systemic Lupus ◽  
Double Blind ◽  
Premature Cardiovascular Disease ◽  
Increased Risk

AbstractIncreased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity (p = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.

Multiple effects of immunostimulatory DNA on T cells and the role of type I interferons

2001 ◽  
pp. 77-84 ◽  
Author(s):  
Siquan Sun ◽  
Xiaohong Zhang ◽  
David Tough ◽  
Jonathan Sprent
Keyword(s):  
T Cells ◽  
Type I Interferons ◽  
Type I ◽  
Immunostimulatory Dna

scholarly journals The activation of bystander CD8+ T cells and their roles in viral infection

2019 ◽  
Vol 51 (12) ◽  
pp. 1-9 ◽  
Author(s):  
Tae-Shin Kim ◽  
Eui-Cheol Shin
Keyword(s):  
T Cells ◽  
Viral Infections ◽  
Hepatitis A Virus ◽  
Tissue Injury ◽  
Strong Association ◽  
Killer Cell ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Bystander Activation

AbstractDuring viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as “bystander activation.” Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.

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