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      Cause and consequences of the activated type I interferon system in SLE

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          Abstract

          Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN)-regulated genes (an IFN signature), which is caused by an ongoing production of type I IFNs by plasmacytoid dendritic cells (pDCs). The reasons behind the continuous IFN production in SLE are the presence of self-derived IFN inducers and a lack of negative feed-back signals that downregulate the IFN response. In addition, several cells in the immune system promote the IFN production by pDCs and gene variants in the type I IFN signaling pathway contribute to the IFN signature. The type I IFNs act as an immune adjuvant and stimulate T cells, B cells, and monocytes, which all play an important role in the loss of tolerance and persistent autoimmune reaction in SLE. Consequently, new treatments aiming to inhibit the activated type I IFN system in SLE are now being developed and investigated in clinical trials.

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          Most cited references46

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          Interferons and viruses: an evolutionary arms race of molecular interactions.

          Over half a century has passed since interferons (IFNs) were discovered and shown to inhibit virus infection in cultured cells. Since then, researchers have steadily brought to light the molecular details of IFN signaling, catalogued their pleiotropic effects on cells, and harnessed their therapeutic potential for a variety of maladies. While advances have been plentiful, several fundamental questions have yet to be answered and much complexity remains to be unraveled. We explore the current knowledge surrounding four main questions: are type I IFN subtypes differentially produced in response to distinct pathogens? How are IFN subtypes distinguished by cells? What are the mechanisms and consequences of viral antagonism? Lastly, how can the IFN response be harnessed to improve vaccine efficacy?
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            B cells responses and cytokine production are regulated by their immune microenvironment.

            The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naïve T cells produce multiple cytokines upon activation while naïve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-α, IFN-β, IFN-γ. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response.
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              A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients.

              Recent research in systemic lupus erythematosus (SLE) yielded new antigens and antibodies in SLE patients. We describe the various autoantibodies that can be detected in patients with SLE. A literature review, using the terms “autoantibody” and “systemic lupus erythematosus”, was conducted to search for articles on autoantibodies in SLE, their target antigens, association with disease activity and other clinical manifestations. One hundred and eighty autoantibodies were so far described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of an autoantibody, the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 180 autoantibodies. SLE is so far the autoimmune disease with the largest number of detectable autoantibodies. Their production could be antigen-driven, the result of a polyclonal B cell activation, impaired apoptotic pathways, or the outcome of an idiotypic network dysregulation.
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                Author and article information

                Contributors
                +46 18 6115398 , lars.ronnblom@medsci.uu.se
                Journal
                J Mol Med (Berl)
                J. Mol. Med
                Journal of Molecular Medicine (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0946-2716
                1432-1440
                20 April 2016
                20 April 2016
                2016
                : 94
                : 10
                : 1103-1110
                Affiliations
                Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                Article
                1421
                10.1007/s00109-016-1421-4
                5052287
                27094810
                b4619c57-2963-4fcc-b593-99c5ea77a951
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 1 March 2016
                : 31 March 2016
                : 11 April 2016
                Funding
                Funded by: The Swedish Research Council
                Funded by: The Swedish Rheumatism Foundation
                Funded by: King Gustaf Vs 80-year Foundation
                Funded by: FundRef http://dx.doi.org/10.13039/501100004063, Knut och Alice Wallenbergs Stiftelse;
                Funded by: AZ Science for Life Lab research collaboration grant
                Categories
                Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2016

                Molecular medicine
                type i interferon,systemic lupus erythematosus,plasmacytoid dendritic cells,etiopathogenesis,immune regulation

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