TYK2 as a therapeutic target in the treatment of autoimmune and inflammatory diseases

Immunotherapy ◽  
2021 ◽  
Author(s):  
Maciej Gonciarz ◽  
Katarzyna Pawlak-Buś ◽  
Piotr Leszczyński ◽  
Witold Owczarek
Keyword(s):  
Lupus Erythematosus ◽  
Tyrosine Kinases ◽  
Inflammatory Diseases ◽  
Cellular Responses ◽  
Protein Tyrosine Kinases ◽  
Type I Interferons ◽  
Type I ◽  
Intracellular Protein ◽  
Autoimmune And Inflammatory Diseases ◽  
Inflammatory Bowel

JAKs are intracellular protein tyrosine kinases that, through activation of STATs, are responsible for signal transduction pathways that regulate cellular responses to numerous cytokines, growth factors and hormones in many different cells. JAK-STAT signaling plays a key role in regulating immune function, and cytokines – such as IL-23, IL-12 and type I interferons – are central to the pathogenesis of autoimmune diseases, including psoriasis, inflammatory bowel disease and systemic lupus erythematosus. Here the authors review the evidence for targeting TYK2 as a more specific approach to treating these conditions. TYK2 inhibitors are clinically effective in autoimmune and inflammatory diseases and may avoid some of the complications reported with nonselective JAK inhibitors.

scholarly journals Shared development of targeted therapies among autoimmune and inflammatory diseases: a systematic repurposing analysis

2020 ◽  
Vol 12 ◽  
pp. 1759720X2096926
Author(s):  
Arthur Petitdemange ◽  
Julien Blaess ◽  
Jean Sibilia ◽  
Renaud Felten ◽  
Laurent Arnaud
Keyword(s):  
Clinical Trials ◽  
Targeted Therapies ◽  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Drug Repurposing ◽  
Type I ◽  
Tnf Α ◽  
Bowel Diseases ◽  
Autoimmune And Inflammatory Diseases ◽  
Inflammatory Bowel

Background: Pathogenic inflammatory pathways are largely shared between different autoimmune and inflammatory diseases (AIDs). This offers the potential to develop a given targeted therapy in several AIDs. Methods: We analyzed two clinical trials registries (ClinicalTrials.gov and EU Clinical Trials Register) to identify the targeted therapies whose development is shared between at least two of the most common AIDs [rheumatoid arthritis (RA), spondyloarthritis (SpA), cutaneous psoriasis (cPso), inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), giant cell arteritis (GCA), and multiple sclerosis (MS)] using an in-depth repurposing analysis. Results: We identified 142 shared targeted therapies. The four diseases in which shared targeted therapies were the most numerous were RA ( n = 92), cPso ( n = 67), IBD ( n = 58), and SLE ( n = 56). The two clusters of diseases between which the overlap of targeted therapies was the most important were RA and SLE as well as RA, SpA, cPso, and IBD. The targeted therapies which were shared by five diseases or more were abatacept, ustekinumab, rituximab, anakinra, etanercept, infliximab, secukinumab, tofacitinib, alemtuzumab, tocilizumab, adalimumab, apremilast, baricitinib, belimumab, brodalumab, filgotinib, and upadacitinib. The most frequently targeted molecules and pathways were (by descending frequency): JAK-STAT pathways, Th17 axis, TNF-α, IL-6, costimulation molecules, BAFF, CD20, BTK, chemokines and integrins, IL-1, and type I interferon. Conclusion: Many targeted therapies are developed in several AIDs, reflecting the overlap of pathogenic pathways and potential of drug repurposing. This suggests that a revision of the current, clinically based classification of AIDs towards a more mechanistic-based taxonomy might be relevant.

scholarly journals Twist mediates suppression of inflammation by type I IFNs and Axl

2006 ◽  
Vol 203 (8) ◽  
pp. 1891-1901 ◽  
Author(s):  
M. Nusrat Sharif ◽  
Dražen Šošić ◽  
Carla V. Rothlin ◽  
Erin Kelly ◽  
Greg Lemke ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Protein S ◽  
Type I Interferons ◽  
Type I ◽  
Transcriptional Repressors ◽  
Inflammatory Cytokine Production ◽  
Type I Ifns ◽  
Twist Expression ◽  
Autoimmune And Inflammatory Diseases ◽  
Axl Receptor Tyrosine Kinase

Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFα production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFα production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFα production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-κB–dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFα production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.

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.

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials

Lupus ◽  
2020 ◽  
Vol 29 (14) ◽  
pp. 1845-1853
Author(s):  
Jeffery Wei Heng Koh ◽  
Cheng Han Ng ◽  
Sen Hee Tay
Keyword(s):  
Systematic Review ◽  
Herpes Zoster ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Meta Analysis ◽  
Type I Interferons ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Type I Ifn ◽  
Tract Infections

Objective The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. Methods A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Results Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88–7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. Conclusion This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

scholarly journals Interferon-stimulated GTPases in autoimmune and inflammatory diseases: promising role for the guanylate-binding protein (GBP) family

Rheumatology ◽  
2020 ◽  
Author(s):  
Mahamudul Haque ◽  
Ruby J Siegel ◽  
David A Fox ◽  
Salahuddin Ahmed
Keyword(s):  
Inflammatory Diseases ◽  
Parasitic Infections ◽  
Major Protein ◽  
Type I ◽  
Guanosine Triphosphate ◽  
Resistance Proteins ◽  
Growing Body ◽  
Autoimmune And Inflammatory Diseases ◽  
Inducible Genes ◽  
Guanylate Binding Protein

Abstract Human IFNs are secreted cytokines shown to stimulate the expression of over one thousand genes. These IFN-inducible genes primarily encode four major protein families, known as IFN-stimulated GTPases (ISGs), namely myxovirus-resistance proteins, guanylate-binding proteins (GBPs), p47 immunity-related GTPases and very large inducible guanosine triphosphate hydrolases (GTPases). These families respond specifically to type I or II IFNs and are well reported in coordinating immunity against some well known as well as newly discovered viral, bacterial and parasitic infections. A growing body of evidence highlights the potential contributory and regulatory roles of ISGs in dysregulated inflammation and autoimmune diseases. Our focus was to draw attention to studies that demonstrate increased expression of ISGs in the serum and affected tissues of patients with RA, SS, lupus, IBD and psoriasis. In this review, we analysed emerging literature describing the potential roles of ISGs, particularly the GBP family, in the context of autoimmunity. We also highlighted the promise and implications for therapeutically targeting IFNs and GBPs in the treatment of rheumatic diseases.

Type I Interferons in Autoimmune Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 369-393 ◽  
Author(s):  
Mary K. Crow ◽  
Mikhail Olferiev ◽  
Kyriakos A. Kirou
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Pathway Activation ◽  
Interferon Pathway ◽  
Chronic Activation

Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.

scholarly journals Counter-regulation in the IKK family

2011 ◽  
Vol 434 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Luke A. J. O'Neill
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Control Mechanisms ◽  
Biochemical Journal ◽  
Regulatory Feedback Loop

The human IKK [IκB (inhibitor of NF-κB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKα and IKKβ, the so-called canonical members, phosphoryate IκBα, leading to activation of the transcription factor NF-κB (nuclear factor κB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKϵ have a different substrate – IRF3 (interferon regulatory factor 3) – which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKϵ/TBK-1, which occurs via IKKα/IKKβ. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKα/IKKβ. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKϵ/TBK-1 might actually have a pro-inflammatory effect.

scholarly journals Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

2017 ◽  
Vol 23 (33) ◽  
pp. 6137-6146 ◽  
Author(s):  
Morten L Halling ◽  
Jens Kjeldsen ◽  
Torben Knudsen ◽  
Jan Nielsen ◽  
Lars Koch Hansen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Increased Risk ◽  
Autoimmune And Inflammatory Diseases ◽  
Inflammatory Bowel

Anti-inflammatory Activity of Extra Virgin Olive Oil Polyphenols: Which Role in the Prevention and Treatment of Immune-Mediated Inflammatory Diseases?

2017 ◽  
Vol 18 (1) ◽  
pp. 36-50 ◽  
Author(s):  
Carmela Santangelo ◽  
Rosaria Varì ◽  
Beatrice Scazzocchio ◽  
Patrizia De Sancti ◽  
Claudio Giovannini ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Multiple Sclerosis ◽  
Systemic Lupus Erythematosus ◽  
Phenolic Compounds ◽  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Virgin Olive Oil ◽  
Extra Virgin Olive Oil ◽  
Systemic Lupus ◽  
Inflammatory Bowel

Background and Objective: Altered inflammatory response characterizes chronic immunemediated inflammatory diseases (IMID) such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis. Accumulating evidence indicates that regular consumption of extra virgin olive oil (EVOO), the main source of fat in the Mediterranean diet, is associated with a reduced risk of developing chronic degenerative disorders such as cardiovascular diseases, type 2 diabetes and cancer. The beneficial effects on health of EVOO have been attributed, besides to the monounsaturated fats content, to the presence of phenolic compounds that have antioxidant, anti-inflammatory and immunomodulatory properties. The purpose of this review is to provide an overview of the effects of EVOO polyphenols on IMID highlighting the potential mechanisms of action. Methods: Scientific papers were found by searching in PubMed up to May 2017 using the following key words: rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis also in combination with EVOO, phenolic compounds, oleuropein, oleocantal, hydroxytyrosol,tyrosol and oleochantal. Results: In vitro and in vivo studies indicate that EVOO and its polyphenols can improve diseases symptoms in IMID, by acting both at local and systemic levels and by modulating several molecular pathways. Nevertheless, there are not sufficient data to achieve specific nutritional guidelines. Conclusion: Further research is needed to evaluate the real contribution of EVOO and its phenolic compounds in modulating the IMID-associated inflammatory perturbations, in order to develop appropriate nutritional recommendations.

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