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      Role of Hepatic Deposited Immunoglobulin G in the Pathogenesis of Liver Damage in Systemic Lupus Erythematosus

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          Abstract

          The onset of hepatic disorders in patients with systemic lupus erythematosus (SLE) is frequent; however, the etiology and liver pathogenesis of SLE remain unknown. In the present study, the role of hepatic deposited immunoglobulin G (IgG) in SLE-derived liver damage was investigated. From a retrospective analysis of the medical records of 404 patients with lupus and from experimental studies on mice models, we found that liver dysfunction is common in SLE and liver damage with IgG deposition spontaneously develops in lupus-prone mice. Liver injury was recreated in mice by injecting IgG from lupus serum intrahepatically. The inflammation intensity in the liver decreased with IgG depletion and the lupus IgG-induced liver inflammation in FcγRIII-deficient mice was comparatively low; while, inflammation was increased in FcγRIIb-deficient mice. Macrophages, Kupffer cells, natural killer cells, and their products, but not lymphocytes, are required for the initiation of SLE-associated liver inflammation. Blocking IgG signaling using a spleen tyrosine kinase (Syk) inhibitor suppressed the liver damage. Our findings provided evidence of spontaneously established liver damage in SLE. They also suggested that hepatic-deposited lupus IgG is an important pathological factor in the development of liver injury and that hepatic inflammation is regulated by the Syk signaling pathway. Thus, Syk inhibition might promote the development of a therapeutic strategy to control liver damage in patients with SLE.

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          Most cited references39

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          Fcgamma receptors: old friends and new family members.

          Although cellular receptors for immunoglobulins were first identified nearly 40 years ago, their central role in the immune response was discovered only in the last decade. They are key players in both the afferent and efferent phase of an immune response, setting thresholds for B cell activation, regulating the maturation of dendritic cells, and coupling the exquisite specificity of the antibody response to innate effector pathways, such as phagocytosis, antibody-dependent cellular cytotoxicity, and the recruitment and activation of inflammatory cells. Moreover, because of their general presence as receptor pairs consisting of activating and inhibitory molecules on the same cell, they have become a paradigm for studying the balance of positive and negative signals that ultimately determine the outcome of an immune response. This review will summarize recent results in Fc-receptor biology with an emphasis on data obtained in in vivo model systems.
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            Systemic lupus erythematosus.

            Systemic lupus erythematosus is an autoimmune connective-tissue disorder with a wide range of clinical features, which predominantly affects women, especially from certain ethnic groups. Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. Treatments range from antimalarial agents to corticosteroids and immunosuppressive agents. This Seminar draws attention to advances in the epidemiology, genetics, cardiovascular risks, lupus nephritis, CNS disease, the antiphospholipid syndrome, assessment of disease activity and damage, and pregnancy related and quality of life issues. New therapeutic approaches, such as biological agents and mycophenolate mofetil, will also be discussed.
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              Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo.

              We investigated the differentiation and trafficking of inflammatory monocytes that phagocytosed subcutaneously injected fluorescent microspheres. As expected, most of the monocytes became microsphere+ macrophages, which remained in subcutaneous tissue. However, about 25% of latex+ cells migrated to the T cell area of draining lymph nodes, where they expressed dendritic cell (DC)-restricted markers and high levels of costimulatory molecules. Microsphere-transporting cells were distinct from resident skin DCs, and this transport was reduced by more than 85% in monocyte-deficient osteopetrotic mice. Thus, a substantial minority of inflammatory monocytes carry phagocytosed particles to lymph nodes and differentiate into DCs.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 June 2018
                2018
                : 9
                : 1457
                Affiliations
                [1] 1Key Laboratory of Antibody Technology, National Health and Family Planning Commission, Nanjing Medical University , Nanjing, China
                [2] 2First affiliated Hospital of Nanjing Medical University , Nanjing, China
                [3] 3State Key Laboratory of Reproductive Medicine, Nanjing Medical University , Nanjing, China
                Author notes

                Edited by: J. Michelle Kahlenberg, University of Michigan, United States

                Reviewed by: Alfred Hyoungju Kim, Washington University in St. Louis, United States; Carla Marie Cuda, Northwestern University, United States

                *Correspondence: Guo-Min Deng, gmdeng@ 123456njmu.edu.cn

                Specialty section: This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01457
                6026631
                29988500
                a235796e-f2f8-456e-9959-57d93eeb22be
                Copyright © 2018 Fang, Zaman, Guo, Ding, Xie, Zhang and Deng.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 March 2018
                : 12 June 2018
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 50, Pages: 12, Words: 8603
                Categories
                Immunology
                Original Research

                Immunology
                systemic lupus erythematosus,hepatitis,immunoglobulin g deposition,innate immune cells,spleen tyrosine kinase

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