Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases
Reads0
Chats0
TLDR
MTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases, and ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases.Abstract:
Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4(-)CD8(-) (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4(+)CD25(+)FoxP3(+) T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.read more
Citations
More filters
Journal Article
International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome(APS)
Journal ArticleDOI
Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective
Vaishali R. Moulton,Abel Suárez-Fueyo,Esra Meidan,Esra Meidan,Hao Li,Masayuki Mizui,George C. Tsokos +6 more
TL;DR: Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities.
Journal ArticleDOI
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial
Zhi-Wei Lai,Ryan Kelly,Thomas Winans,Ivan Marchena,Ashwini Shadakshari,Julie Yu,Maha Dawood,Ricardo Garcia,Hajra Tily,Lisa Francis,Stephen V. Faraone,Paul E. Phillips,Andras Perl +12 more
TL;DR: A single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications, assessing safety, tolerance, and efficacy in a prospective, biomarker-driven,open-label clinical trial.
Journal ArticleDOI
Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis
TL;DR: It is shown that fibroblast-like synoviocytes in rheumatoid arthritis differ from healthy synovial fibroblasts, not only in their marker expression, proto-oncogene expression, or their epigenetic changes, but also in their intracellular metabolism.
Journal ArticleDOI
Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases.
TL;DR: It is concluded that the loss of redox balance induces alterations in the differentiation and number of CD4+T cell subpopulations, leading to an increase in Th1 and Th17 response.
References
More filters
Journal ArticleDOI
The 1982 revised criteria for the classification of systemic lupus erythematosus
Eng M. Tan,Alan S. Cohen,James F. Fries,Alfonse T. Masi,Dennis J. McShane,Naomi F. Rothfield,Jane G. Schaller,Norman Talal,Robert Winchester +8 more
TL;DR: The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification and showed gains in sensitivity and specificity.
Journal ArticleDOI
Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
TL;DR: In 1992, Piette and colleagues suggested that the ACR revised criteria be reevaluated in light of the above discoveries, and the presence and clinical associations or antiphospholipid antibodies in patients with SLE was suggested.
Journal ArticleDOI
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
Spiros Miyakis,Michael D. Lockshin,Tatsuya Atsumi,D W Branch,Robin L. Brey,Ricard Cervera,R. H. W. M. Derksen,P. G. De Groot,Takao Koike,Pier Luigi Meroni,Guido Reber,Yehuda Shoenfeld,Angela Tincani,Panayiotis G. Vlachoyiannopoulos,Steven A. Krilis +14 more
TL;DR: This document appraise the existing evidence on clinical and laboratory features of APS addressed during the forum and proposes amendments to the Sapporo criteria, including definitions on features ofAPS that were not included in the updated criteria.
Journal ArticleDOI
TSC2 mediates cellular energy response to control cell growth and survival.
TL;DR: It is described that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis.
Journal ArticleDOI
Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.
Michelle Petri,Ana Maria Orbai,Graciela S. Alarcón,Caroline Gordon,Joan T. Merrill,Paul R. Fortin,Ian N. Bruce,David A. Isenberg,Daniel J. Wallace,Ola Nived,Gunnar Sturfelt,Rosalind Ramsey-Goldman,Sang Cheol Bae,John G. Hanly,Jorge Sanchez-Guerrero,Ann E. Clarke,Cynthia Aranow,Susan Manzi,Murray B. Urowitz,Dafna D. Gladman,Kenneth C. Kalunian,Melissa Costner,Victoria P. Werth,Asad Zoma,Sasha Bernatsky,Guillermo Ruiz-Irastorza,Munther A. Khamashta,Søren Jacobsen,Jill P. Buyon,Peter J. Maddison,Mary Anne Dooley,Ronald F van Vollenhoven,Ellen M. Ginzler,Thomas Stoll,Christine A. Peschken,Joseph L. Jorizzo,Jeffrey P. Callen,S. Sam Lim,Barri J. Fessler,Murat Inanc,Diane L. Kamen,Anisur Rahman,Kristjan Steinsson,Andrew G. Franks,Lisa Sigler,Suhail Hameed,Hong Fang,Ngoc Minh Pham,Robin L. Brey,Michael H. Weisman,Gerald McGwin,Laurence S. Magder +51 more
TL;DR: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE.