ObjectiveIdentifying components of immuneparesis, a hallmark of chronic liver failure, is crucial for our understanding of complications in cirrhosis. Various suppressor CD4+ T cells have been established as potent inhibitors of systemic immune activation. Here, we establish the presence, regulation and mechanism of action of a suppressive CD4+ T cell subset expressing human leucocyte antigen G (HLA-G) in patients with acute decompensation of cirrhosis (AD).DesignFlow cytometry was used to determine the proportion and immunophenotype of CD4+HLA-G+ T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4+HLA-G+ cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways.ResultsPatients with AD were distinguished by an expansion of a CD4+HLA-G+CTLA-4+IL-35+ immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G+ phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines.ConclusionWe have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.

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This paper presents original research of a model of water–water ejector whose aim is to mix a quantity of water of the return network with the water of the supply network of a central heating system. The water of the supply network at a certain pressure passes through the ejector nozzle, where the pressure energy in the nozzle is converted into kinetic energy, and consequently in the space around the nozzle vacuum gauge pressure is created which enables the absorption of a quantity of water from the network return, which is mixed with the water of the supply network. This water regulates the temperature of the water at the entrance of the central heating radiator. For the model ejector, characteristic equation was written and was analyzed in terms of pressure and mixing coefficient. The analysis was tested using nozzles of different sizes. To analyze the role of the diffuser as a part of the ejector, the ejector characteristics were analyzed without a diffuser. The characteristics of diffuser and non-diffuser ejectors are presented in the same diagram for comparative analysis of the pressure difference and mixing coefficients achieved by the ejector for different ratios f3/fr1.

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