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Rheumatoid Arthritis: Molecular Mechanisms and Immunotherapy

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Guest Editor
Department of Molecular Biology, Immunology and Medical Genetics, Trakia University, 6000 Stara Zagora, Bulgaria
Interests: autoantibodies; autoimmune disorders; clinical immunology; cytokines; cytokine gene polymorphisms; rheumatoid arthritis

Special Issue Information

Dear  Colleagues,

Rheumatoid arthritis (RA) is a progressive autoimmune disorder that displays genetic, pathophysiological and clinical heterogeneity. The pathogenesis of RA is primarily due to the activation of both innate and adaptive immune systems and the overproduction of a plethora of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-8, IL-12, IL-17, IL-18 and IL-23. The dysregulated interaction of various cell types, cytokines and mediators leads to a constant pro-inflammatory background that promotes the propensity to break autotolerance and develop chronic synovial inflammation, bone erosion and cartilage destruction.

The advent of novel therapeutic avenues such as biological disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), including Janus kinase inhibitors, has made a breakthrough in RA treatment, but many unmet demands remain. The benefit from bDMARDs and tsDMARDs is often accompanied by severe adverse effects. In addition, personalized responsiveness to inflammatory cytokine inhibitors is observed. These facts further emphasize the need to develop novel treatment strategies for RA.

This Special Issue aims to provide a platform for the latest research clarifying the molecular and immune mechanisms underlying pathological events related to the clinical presentation and different treatment outcomes of RA. Understanding the individual variations in RA pathogenesis at the molecular level will considerably improve patient management and outcomes. Original articles and reviews revealing the inflammatory pathways, the variations in molecular mechanisms in RA pathogenesis and potential new immune-based therapy that targets specific molecular pathways involved in RA inflammation are welcome.

Prof. Dr. Irena Manolova
Guest Editor

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Keywords

  • rheumatoid arthritis
  • pathogenesis
  • innate immunity
  • adaptive immunity
  • inflammation
  • cytokines
  • autoantibodies
  • immunotherapy
  • clinical outcome

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Published Papers (1 paper)

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Research

22 pages, 4205 KiB  
Article
Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S
by Devy Zisman, Hala Sabtan, Maya M. Rahat, Elina Simanovich, Amir Haddad, Tal Gazitt, Joy Feld, Gleb Slobodin, Adi Kibari, Muna Elias and Michal A. Rahat
Int. J. Mol. Sci. 2024, 25(13), 7267; https://doi.org/10.3390/ijms25137267 - 2 Jul 2024
Viewed by 1056
Abstract
Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) [...] Read more.
Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin’ s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S. Full article
(This article belongs to the Special Issue Rheumatoid Arthritis: Molecular Mechanisms and Immunotherapy)
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