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      T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target

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          Abstract

          Background

          Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN

          Methods

          We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells’ participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations.

          Results

          We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients.

          Conclusions

          T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.

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          Most cited references 87

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          The regulation of IgA class switching.

          IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-cell-dependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.
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            Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond.

             M Mohty (2007)
            The success of allogeneic stem cell transplantation and solid-organ transplantation owes much to improvements in the immunosuppressive regimens that prevent graft-versus-host disease (GVHD) or suppress allograft rejection. A better understanding of the immune mechanisms underlying induction of immunological tolerance is the key to successful transplantation. Polyclonal antibodies such as antithymocyte globulins (ATG) have been used for decades. The common belief is that ATG efficacy relies on its capacity to deplete T lymphocytes. The aim of this review is to offer an overview of the recent findings that have been demonstrated in ATG's immunomodulatory activity. The polyclonal nature of ATG is reflected in its diverse effects on the immune system: (1) T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; (2) modulation of key cell surface molecules that mediate leukocyte/endothelium interactions; (3) induction of apoptosis in B-cell lineages; (4) interference with dendritic cell functional properties; and (5) induction of regulatory T and natural killer T cells. As a consequence, ATG provides multifaceted immunomodulation paving the way for future applications and suggesting that the use of ATG should be included in the immunosuppression therapeutic armamentarium to help reduce the incidence of organ rejection and GVHD.
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              Glucocorticoids in T cell development and function*.

              Glucocorticoids are small lipophilic compounds that mediate their many biological effects by binding an intracellular receptor (GR) that, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription. Perhaps the most recognized biologic effect of glucocorticoids on peripheral T cells is immunosuppression, which is due to inhibition of expression of a wide variety of activationinduced gene products. Glucocorticoids have also been implicated in Th lineage development (favoring the generation of Th2 cells) and, by virtue of their downregulation of fasL expression, the inhibition of activation-induced T cell apoptosis. Glucocorticoids are also potent inducers of apoptosis, and even glucocorticoid concentrations achieved during a stress response can cause the death of CD4(+)CD8(+ )thymocytes. Perhaps surprisingly, thymic epithelial cells produce glucocorticoids, and based upon in vitro and in vivo studies of T cell development it has been proposed that these locally produced glucocorticoids participate in antigen-specific thymocyte development by inhibiting activation-induced gene transcription and thus increasing the TCR signaling thresholds required to promote positive and negative selection. It is anticipated that studies in animals with tissue-specific GR-deficiency will further elucide how glucocorticoids affect T cell development and function.
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                Author and article information

                Contributors
                +48 58 349 15 12 , jakub.ruszkowski@gumed.edu.pl
                Journal
                Clin Exp Nephrol
                Clin. Exp. Nephrol
                Clinical and Experimental Nephrology
                Springer Singapore (Singapore )
                1342-1751
                1437-7799
                7 November 2018
                7 November 2018
                2019
                : 23
                : 3
                : 291-303
                Affiliations
                [1 ]ISNI 0000 0001 0531 3426, GRID grid.11451.30, Department of Pathophysiology, Faculty of Medicine, , Medical University of Gdańsk, ; Dębinki 7, 80-211 Gdańsk, Poland
                [2 ]ISNI 0000 0001 0531 3426, GRID grid.11451.30, Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, , Medical University of Gdańsk, ; Gdańsk, Poland
                Article
                1665
                10.1007/s10157-018-1665-0
                6394565
                30406499
                © The Author(s) 2018

                Open AccessThis 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.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004569, Ministerstwo Nauki i Szkolnictwa Wyższego;
                Award ID: 02-0058/07/262
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © Japanese Society of Nephrology 2019

                Nephrology

                glomerulonephritis, iga nephropathy, t lymphocytes

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