Cornelia M Weyand1,2, Bowen Wu1, Jörg J Goronzy1,2. 1. Department of Medicine, Stanford University, Stanford. 2. Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California, USA.
Abstract
PURPOSE OF REVIEW: Rheumatoid arthritis (RA) is a prototypic autoimmune disease manifesting as chronic inflammation of the synovium and leading to acceleration of cardiovascular disease and shortening of life expectancy. The basic defect causing autoimmunity has remained elusive, but recent insights have challenged the notion that autoantigen is the core driver. RECENT FINDINGS: Emerging data have added metabolic cues involved in the proper maintenance and activation of immune cells as pathogenic regulators. Specifically, studies have unveiled metabolic pathways that enforce T cell fate decisions promoting tissue inflammation; including T cell tissue invasiveness, T cell cytokine release, T cell-dependent macrophage activation and inflammatory T cell death. At the center of the metabolic abnormalities lies the mitochondria, which is consistently underperforming in RA T cells. The mitochondrial defect results at least partially from insufficient DNA repair and leads to lipid droplet accumulation, formation of invasive membrane ruffles, inflammasome activation and pyroptotic T cell death. SUMMARY: T cells in patients with RA, even naïve T cells never having been involved in inflammatory lesions, have a unique metabolic signature and the changes in intracellular metabolites drive pathogenic T cell behavior. Recognizing the role of metabolic signals in cell fate decisions opens the possibility for immunomodulation long before the end stage synovial inflammation encountered in clinical practice.
PURPOSE OF REVIEW: Rheumatoid arthritis (RA) is a prototypic autoimmune disease manifesting as chronic inflammation of the synovium and leading to acceleration of cardiovascular disease and shortening of life expectancy. The basic defect causing autoimmunity has remained elusive, but recent insights have challenged the notion that autoantigen is the core driver. RECENT FINDINGS: Emerging data have added metabolic cues involved in the proper maintenance and activation of immune cells as pathogenic regulators. Specifically, studies have unveiled metabolic pathways that enforce T cell fate decisions promoting tissue inflammation; including T cell tissue invasiveness, T cell cytokine release, T cell-dependent macrophage activation and inflammatory T cell death. At the center of the metabolic abnormalities lies the mitochondria, which is consistently underperforming in RA T cells. The mitochondrial defect results at least partially from insufficient DNA repair and leads to lipid droplet accumulation, formation of invasive membrane ruffles, inflammasome activation and pyroptotic T cell death. SUMMARY: T cells in patients with RA, even naïve T cells never having been involved in inflammatory lesions, have a unique metabolic signature and the changes in intracellular metabolites drive pathogenic T cell behavior. Recognizing the role of metabolic signals in cell fate decisions opens the possibility for immunomodulation long before the end stage synovial inflammation encountered in clinical practice.
Authors: Stefan O Schönland; Consuelo Lopez; Thomas Widmann; Julia Zimmer; Ewa Bryl; Jörg J Goronzy; Cornelia M Weyand Journal: Proc Natl Acad Sci U S A Date: 2003-10-24 Impact factor: 11.205
Authors: Sung-Jun Park; Oksana Gavrilova; Alexandra L Brown; Jamie E Soto; Shannon Bremner; Jeonghan Kim; Xihui Xu; Shutong Yang; Jee-Hyun Um; Lauren G Koch; Steven L Britton; Richard L Lieber; Andrew Philp; Keith Baar; Steven G Kohama; E Dale Abel; Myung K Kim; Jay H Chung Journal: Cell Metab Date: 2017-08-01 Impact factor: 27.287