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      Pathways leading to an immunological disease: systemic lupus erythematosus

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          Abstract

          SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE.

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          Most cited references117

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          Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

          Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
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            Systemic lupus erythematosus

            Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.
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              Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.

              Dendritic cells (DCs) are important in regulating both immunity and tolerance. Hence, we hypothesized that systemic lupus erythematosus (SLE), an autoimmune disease characterized by autoreactive B and T cells, may be caused by alterations in the functions of DCs. Consistent with this, monocytes from SLE patients' blood were found to function as antigen-presenting cells, in vitro. Furthermore, serum from SLE patients induced normal monocytes to differentiate into DCs. These DCs could capture antigens from dying cells and present them to CD4-positive T cells. The capacity of SLE patients' serum to induce DC differentiation correlated with disease activity and depended on the actions of interferon-alpha (IFN-alpha). Thus, unabated induction of DCs by IFN-alpha may drive the autoimmune response in SLE.
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                Author and article information

                Journal
                Rheumatology (Oxford)
                Rheumatology (Oxford)
                brheum
                Rheumatology (Oxford, England)
                Oxford University Press
                1462-0324
                1462-0332
                April 2017
                27 March 2017
                27 March 2017
                : 56
                : Suppl 1 , TITLE: SLE review series: working for a better standard of care
                : i55-i66
                Affiliations
                [1 ]Singapore Immunology Network, 8A Biomedical Grove, Immunos
                [2 ]School of Biological Sciences, Nanyang Technological University, Singapore
                [3 ]Department of Neurology and Neurotherapeutics
                [4 ]Department of Immunology
                [5 ]The Rheumatic Diseases Division, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, TX, USA
                Author notes
                [*]

                Anne B. Satterthwaite, Anna-Marie Fairhurst and Laurie S. Davis contributed equally to this study

                Correspondence to: Laurie S. Davis, The Rheumatic Diseases Division, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, TX 75390-8884, USA. E-mail: laurie.davis@ 123456utsouthwestern.edu
                Article
                kew427
                10.1093/rheumatology/kew427
                5410978
                28375453
                baae38c6-65c2-45e0-b52a-79983049bef3
                © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 29 July 2016
                : 20 October 2016
                Page count
                Pages: 12
                Funding
                Funded by: National Institutes of Health (NIH)
                Award ID: AR067625, AI122720
                Funded by: Alliance for Lupus Research (ALR)
                Award ID: 257549
                Funded by: ALR
                Award ID: 257549
                Funded by: NIH
                Award ID: AR067625
                Award ID: AI122720
                Categories
                Reviews

                Rheumatology
                systemic lupus erythematosus,sle,sle pathogenesis,autoantibodies,immunology,tolerance,inflammation,tissue destruction

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