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      IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjögren’s syndrome

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          Abstract

          <p class="first" id="Par1">Increased numbers of T follicular helper (Tfh) cells have been implicated in the development of autoimmune diseases including primary Sjögren’s syndrome (pSS), but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear. Here, we first found negative correlations between IL-10 <sup>+</sup> regulatory B (Breg) cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren’s syndrome (ESS). Moreover, we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice. In culture, IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation. By using an adoptive transfer approach and two-photon live imaging, we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2−/− mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2−/− mice transferred with wild-type B cells. In ESS mice, CD19 <sup>+</sup>CD1d <sup>hi</sup>CD5 <sup>+</sup> Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation. Consistently, CD19 <sup>+</sup>CD24 <sup>+</sup>CD38 <sup>hi</sup> Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion. Furthermore, the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice. Together, these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development. </p>

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          Structure and Dynamics of the M3 Muscarinic Acetylcholine Receptor

          Acetylcholine (ACh), the first neurotransmitter to be identified 1 , exerts many of its physiological actions via activation of a family of G protein-coupled receptors (GPCRs) known as muscarinic ACh receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G protein coupling preference and the physiological responses they mediate. 2–4 Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. 5–6 We describe here the structure of the Gq/11-coupled M3 mAChR bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the Gi/o-coupled M2 receptor, offers new possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows the first structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and raise additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer new insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.
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            Transcription factor Achaete-Scute homologue 2 initiates T follicular helper cell development

            In immune responses, activated T cells migrate to B cell follicles and develop to T follicular helper (Tfh) cells, a new subset of CD4+ T cells specialized in providing help to B lymphocytes in the induction of germinal centers 1,2 . Although Bcl6 has been shown to be essential in Tfh cell function, it may not regulate the initial migration of T cells 3 or the induction of Tfh program as exampled by C-X-C chemokine receptor type 5 (CXCR5) upregulation 4 . Here, we show that Achaete-Scute homologue 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor 5 , is selectively upregulated in its expression in Tfh cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6 and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro and accelerates T cell migration to the follicles and Tfh cell development in vivo. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes while inhibits expression of Th1 and Th17 genes. Acute deletion of Ascl2 as well as blockade of its function with the Id3 protein in CD4+ T cells results in impaired Tfh cell development and the germinal center response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh cell generation. Thus, Ascl2 directly initiates Tfh cell development.
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              Advances in understanding the pathogenesis of primary Sjögren's syndrome.

              Primary Sjögren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications.
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                Author and article information

                Journal
                Cellular & Molecular Immunology
                Cell Mol Immunol
                Springer Nature
                1672-7681
                2042-0226
                April 4 2019
                Article
                10.1038/s41423-019-0227-z
                6884445
                30948793
                0730302e-4ac6-4031-9626-e5b107be7879
                © 2019

                http://www.springer.com/tdm

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