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      The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis

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          Abstract

          Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease characterized by the destruction of insulin-secreting pancreatic β cells. In humans with T1D and in nonobese diabetic (NOD) mice (a murine model for human T1D), autoreactive T cells cause β-cell destruction, as transfer or deletion of these cells induces or prevents disease, respectively. CD4 + and CD8 + T cells use distinct effector mechanisms and act at different stages throughout T1D to fuel pancreatic β-cell destruction and disease pathogenesis. While these adaptive immune cells employ distinct mechanisms for β-cell destruction, one central means for enhancing their autoreactivity is by the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-1. In addition to their production by diabetogenic T cells, proinflammatory cytokines are induced by reactive oxygen species (ROS) via redox-dependent signaling pathways. Highly reactive molecules, proinflammatory cytokines are produced upon lymphocyte infiltration into pancreatic islets and induce disease pathogenicity by directly killing β cells, which characteristically possess low levels of antioxidant defense enzymes. In addition to β-cell destruction, proinflammatory cytokines are necessary for efficient adaptive immune maturation, and in the context of T1D they exacerbate autoimmunity by intensifying adaptive immune responses. The first half of this review discusses the mechanisms by which autoreactive T cells induce T1D pathogenesis and the importance of ROS for efficient adaptive immune activation, which, in the context of T1D, exacerbates autoimmunity. The second half provides a comprehensive and detailed analysis of (1) the mechanisms by which cytokines such as IL-1 and IFN-γ influence islet insulin secretion and apoptosis and (2) the key free radicals and transcription factors that control these processes.

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          Innate immunity.

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            CD28/B7 system of T cell costimulation.

            T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional research that will unravel this important, yet complex, signaling pathway.
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              Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.

              Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
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                Author and article information

                Journal
                Ann N Y Acad Sci
                Ann. N. Y. Acad. Sci
                nyas
                Annals of the New York Academy of Sciences
                Blackwell Publishing Ltd
                0077-8923
                1749-6632
                April 2013
                16 January 2013
                : 1281
                : 1
                : 16-35
                Affiliations
                [1 ]Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham Birmingham, Alabama
                [2 ]Department of Biochemistry, The Medical College of Wisconsin Milwaukee, Wisconsin
                Author notes
                Address for correspondence: Hubert M. Tse, Ph.D., Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Shelby 1202, 1825 University Boulevard, Birmingham, AL, 35294. htse@ 123456uab.edu
                Article
                10.1111/j.1749-6632.2012.06826.x
                3715103
                23323860
                bd414577-2958-416c-9d01-81b950f976ba
                © 2013 The New York Academy of Sciences

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

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                Uncategorized
                cytokines,reactive oxygen species,type 1 diabetes
                Uncategorized
                cytokines, reactive oxygen species, type 1 diabetes

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