BackgroundIdiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF; therefore, microRNAs may reveal novel pathogenic pathways.ObjectivesWe sought to determine the regulatory role of microRNA (miR)-155 in the profibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts, and its contribution to experimental pulmonary fibrosis.MethodsBleomycin-induced lung fibrosis in wild-type and miR-155−/− mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors.ResultsmiR-155−/− mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-β production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of IPF and miR-155−/− fibroblasts.ConclusionsWe describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.

The B7-like protein family members play critical immunomodulatory roles and constitute attractive targets for the development of novel therapies for human diseases. We identified Ig-like domain-containing receptor (ILDR)2 as a novel B7-like protein with robust T cell inhibitory activity, expressed in immune cells and in immune-privileged and inflamed tissues. A fusion protein, consisting of ILDR2 extracellular domain with an Fc fragment, that binds to a putative counterpart on activated T cells showed a beneficial effect in the collagen-induced arthritis model and abrogated the production of proinflammatory cytokines and chemokines in autologous synovial-like cocultures of macrophages and cytokine-stimulated T cells. Collectively, these findings point to ILDR2 as a novel negative regulator for T cells, with potential roles in the development of immune-related diseases, including autoimmunity and cancer.

SummaryDes-amino-D-arginine vasopressin (DDAVP) stimulates the release of factor VIII and plasminogen activator from the vascular endothelium. An infusion of exogenous factor VIII given to haemophiliacs causes an increase in platelet activation. This activation does not occur after stimulating a rise in the patient's own factor VIII level caused by DDAVP infusion. We hypothesised therefore that DDAVP could also cause the endothelial release of prostacyclin (PGI2), a potent anti-platelet agent which would counteract the aggregating effect of factor VIII. To examine this possibility we studied the effect of DDAVP on prostacyclin release, as measured by its stable metabolite 6-oxo-PGFla, in vitro and in vivo. Rabbit aortic rings were incubated with different concentrations of DDAVP using saline as control. The supernatant was assayed for 6-oxo-PGFlct by radioimmunoassay. All concentrations of DDAVP gave a significant release of 6-oxo-PGF1α. Vasopressin was much less potent. When DDAVP was infused into haemophilic patients there was a significant increase in circulating 6-oxo-PGF1α levels immediately after the infusion. The facial flushing observed as a side-effect of DDAVP could therefore be prostacyclin-mediated. We confirmed this by abolishing the DDAVP induced flushing seen in normal subjects by prior treatment with aspirin which inhibits PGI2 formation.

The contribution of antigen-driven B-cell adaptive immune responses within the inflamed muscle of inflammatory myopathies (IMs) is largely unknown. In this study, we investigated the immunoglobulin V H gene repertoire, somatic hypermutation, clonal diversification, and selection of infiltrating B cells in muscle biopsies from IM patients (dermatomyositis and polymyositis), to determine whether B cells and/or plasma cells contribute to the associated pathologies of these diseases. The data reveal that Ig V H gene repertoires of muscle-infiltrating B cells deviate from the normal V H gene repertoire in individual patients, and differ between different types of IMs. Analysis of somatic mutations revealed clonal diversification of muscle-infiltrating B cells and evidence for a chronic B-cell response within the inflamed muscle. We conclude that muscle-infiltrating B cells undergo selection, somatic hypermutation and clonal diversification in situ during antigen-driven immune responses in patients with IMs, providing insight into the contribution of B cells to the pathological mechanisms of these disorders.Keywords: B cell r Clonal diversification r Myositis r Somatic hypermutation r V-gene repertoire Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInflammatory myopathies (IMs) are a group of autoimmune diseases, associated with inflammatory cell infiltration to the muscle and muscle weakness; this can vary from mild to severe or, in some cases, absence of muscle weakness (amyopathic dermatomyositis (DM)). IMs are composed of three principal subsets: DM, polymyositis (PM) and inclusion body myositis (IBM), each with distinct clinical and pathological features. In DM, inflammation is predominately perivascular and/or perimysial around the PM and IBM are characterised by scattered necrotic and regenerating muscle fibres and endomysial inflammation with invasion and destruction of non-necrotic muscle fibres [1,2]. Inflammatory infiltrates in both disorders mostly consist of CD8 + T cells and macrophages [3,4] which invade MHC class I antigen expressing muscle fibres [5] leading to fibre necrosis. In contrast to DM, B cells are few or absent within the inflammatory infiltrates of PM and IBM. However, various autoantibodies are associated with * These authors share co-authorship. * * These authors share senior co-authorship. + , CD20 + proliferating B cells. Initially, sections at intervals of between 40 and 80 μm were stained for CD20 + B cells and plasma cells to determine the presence of these phenotypes (n = 3-7 depending on the tissue availability). Serial sections surrounding areas of B-cell and/or plasma cell infiltration were used to establish the infiltration of the other cell phenotypes (n ≥ 3). Original objective lens magnification for images A-D: 40×; E: 63×. (E) Scale bar is 15 μm.DM and PM, and in some cases IBM [6][7][8], suggesting that a loss of B-cell tolerance may contribute to disease pathogenesis in all IMs.Generation of B c...

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