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      Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future

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          Abstract

          Janus-kinase (JAK) and signal transduction activator of transcription (STAT) signal transduction pathway is involved in a wide range of physiological and pathological processes, including in the pathogenesis of several autoimmune diseases. Data supporting the role of JAK/STAT in the development of vasculitis are limited and mostly focused on large vessel vasculitis and Behçet’s disease. In this review, we provide a thorough picture of currently available evidence on the topic, gathered from in vitro experiments, animal models and human real-life data, analyzing the rationale for the use of JAK inhibitors for the management of vasculitis. Overall, despite a very strong biological and pathogenic basis, data are too few to recommend this therapeutic approach, beyond very severe and refractory forms of vasculitis. However, for the same reasons, a strong scientific effort in this direction is indeed worthwhile.

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          Most cited references35

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          2018 update of the EULAR recommendations for the management of Behçet’s syndrome

          Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.
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            Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.

            Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.
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              The emerging role of resident memory T cells in protective immunity and inflammatory disease.

              Over the past decade, it has become clear that there is an important subset of memory T cells that resides in tissues-tissue-resident memory T (TRM) cells. There is an emerging understanding that TRM cells have a role in human tissue-specific immune and inflammatory diseases. Furthermore, the nature of the molecular signals that maintain TRM cells in tissues is the subject of much investigation. In addition, whereas it is logical for TRM cells to be located in barrier tissues at interfaces with the environment, these cells have also been found in brain, kidney, joint and other non-barrier tissues in humans and mice. Given the biology and behavior of these cells, it is likely that they have a role in chronic relapsing and remitting diseases of both barrier and non-barrier tissues. In this Review we discuss recent insights into the biology of TRM cells with a particular focus on their roles in disease, both proven and putative.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                29 March 2021
                2021
                : 12
                : 635663
                Affiliations
                Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
                Author notes

                Edited by: Ilaria Puxeddu, University of Pisa, Italy

                Reviewed by: Roman A. Zinovkin, Lomonosov Moscow State University, Russia

                Cinzia Parolini, University of Milan, Italy

                *Correspondence: Elena Bartoloni, elena.bartolonibocci@ 123456unipg.it
                [†]

                These authors have contributed equally to this work

                This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                635663
                10.3389/fphar.2021.635663
                8039124
                33854436
                f32fde33-e1e8-41c4-a38e-f2bf9f994dab
                Copyright © 2021 Bursi, Cafaro, Perricone, Riccucci, Calvacchi, Gerli and Bartoloni.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 November 2020
                : 19 February 2021
                Categories
                Pharmacology
                Mini Review

                Pharmacology & Pharmaceutical medicine
                jak/stat,vasculitis,giant cell arteritis,takayasu arteritis,behçet’s disease,jak inhibitors

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