Metabolic regulation of organelle homeostasis in lupus T cells

Department of Medicine, State University of New York Upstate Medical University, Syracuse, 13210, USA.
Clinical Immunology (Impact Factor: 3.67). 07/2012; 144(3):200-13. DOI: 10.1016/j.clim.2012.07.001
Source: PubMed


Abnormal T-cell signaling and activation are characteristic features in systemic lupus erythematosus (SLE). Lupus T cells are shifted toward an over-activated state, important signaling pathways are rewired, and signaling molecules are replaced. Disturbances in metabolic and organelle homeostasis, importantly within the mitochondrial, endosomal, and autophagosomal compartments, underlie the changes in signal transduction. Mitochondrial hyperpolarization, enhanced endosomal recycling, and dysregulated autophagy are hallmarks of pathologic organelle homeostasis in SLE. This review is focused on the metabolic checkpoints of endosomal traffic that control immunological synapse formation and mitophagy and may thus serve as targets for treatment in SLE.

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Available from: Gergely Talaber, Jun 19, 2015
    • "Neutrophils also suppress human T-cell proliferation during endotoxin-induced acute systemic inflammation by releasing H 2 O 2 (Pillay et al., 2012). A large body of evidence suggests that alterations of the T-cell redox homeostasis, might be involved in the pathogenesis of immune-related diseases such as AIDS (Staal et al., 1992; Herzenberg et al., 1997; Gil et al., 2003), viral infections (Chrobot et al., 2000; Kesarwani et al., 2013), cancer (Kovacic and Jacintho, 2001; Valko et al., 2007), intestinal inflammation (Reyes et al., 2005), systemic lupus erythematosus (Caza et al., 2012; Perl, 2013; Doherty et al., 2014; Kato and Perl, 2014), and other autoimmune diseases (Hultqvist et al., 2009; Kesarwani et al., 2013; Padgett et al., 2013; Ortona et al., 2014). "
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    ABSTRACT: T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over the past years, it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from being elucidated. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.
    No preview · Article · Mar 2015 · Biological Chemistry
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    • "Mutations of ATG5 that inhibit early steps in autophagy were identified in SLE patients [74], while restoration of autophagy through mTOR blockade with rapamycin reduced disease activity [75]. Multiple SLE therapies modulate autophagy [76], suggesting that autophagy defects are pathogenic. "
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    ABSTRACT: Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of systemic lupus erythematosus (SLE). Infections may serve as initial trigger to the development of autoimmunity and carry an overall greater risk of morbidity and mortality than the general population. Initial presentation of SLE can mimic infections, and in turn infections can mimic disease flares in established SLE. Infections due to predisposition by commonly used immunosuppressive therapies are a significant cause of morbidity and mortality. In this review, viral, bacterial, fungal, and parasitic infections that contribute to the etiology of SLE, potentially mimic or precipitate flares, create diagnostic dilemmas, complicate treatment, or protect against disease, are discussed. Infection risks of current immunosuppressive therapies used in the treatment of SLE are outlined. Strategies to prevent infection, including vaccines, prophylactic antibiotic therapies, toll-like receptor antagonism, and antioxidant treatment that may decrease disease burden and improve quality of life in lupus patients will be discussed.
    Full-text · Article · Jan 2014 · International Reviews Of Immunology
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    • "Also T cell activation results to be impaired by defects in the autophagic process. Mice knockout for Atg3 [69] and Atg7 [70] were unable to eliminate damaged ER causing the persistence of such damaged organelles and a defective calcium (Ca 2+ ) release from the ER, which is essential for T cell activation [63] [71]. "
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    ABSTRACT: The incidence of autoimmune pathologies is increasing worldwide. This has stimulated interest on their etiopathogenesis, caused by a complex interaction of genetic and environmental factors. With the advent of genome-wide linkage, candidate gene and genome wide association studies, risk polymorphisms in autophagy-related genes were discovered in several autoimmune conditions suggesting the possible contribution of autophagy to their etiopathogenesis. Autophagy represents the principal catabolic process mediated by lysosomes used by eukaryotic cells and is strictly regulated by proteins belonging to the Atg family. The function of autophagy has been well characterized in various tissues and systems, but its role in the regulation of innate and adaptive immune systems has been only recently discovered. It plays a fundamental role in the modulation of thymocyte selection and in the generation of T lymphocyte repertoire by participating to the intracellular antigen presentation on MHC class-II molecules by thymic epithelial cells. Furthermore, the generation of mice knockout for specific autophagy-related genes induced several immunological alterations, including defects in B and T cell compartments and in T cell activation. In this review we report recent evidence on the role of authophagy in autoimmunity and discuss its relevance to the pathogenesis of these diseases. We finally highlight that future research may disclose potential new therapeutic targets for the treatment of this category of disorders by modulating the autophagic pathway.
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