STAT5 molecules are key components of the IL-2 signaling pathway, the deficiency of which often results in autoimmune pathology due to a reduced number of CD4+CD25+ naturally occurring regulatory T (Treg) cells. One of the consequences of the IL-2-STAT5 signaling axis is up-regulation of FOXP3, a master control gene for naturally occurring Treg cells. However, the roles of STAT5 in other Treg subsets have not yet been elucidated. We recently demonstrated that IL-2 enhanced IL-10 production through STAT5 activation. This occurred in two types of human Treg cells: a novel type of umbilical cord blood-derived Treg cell, termed HOZOT, and Tr1-like Treg cells, IL-10-Treg. In this study, we examined the regulatory mechanisms of IL-10 production in these Treg cells, focusing specifically on the roles of STAT5. By performing bioinformatic analysis on the IL-10 locus, we identified one STAT-responsive element within intron 4, designated I-SRE-4, as an interspecies-conserved sequence. We found that I-SRE-4 acted as an enhancer element, and clustered CpGs around the I-SRE-4 were hypomethylated in IL-10-producing Treg cells, but not in other T cells. A gel-shift analysis using a nuclear extract from IL-2-stimulated HOZOT confirmed that CpG DNA methylation around I-SRE-4 reduced STAT5 binding to the element. Chromatin immunoprecipitation analysis revealed the in situ binding of IL-2-activated STAT5 to I-SRE-4. Thus, we provide molecular evidence for the involvement of an IL-2-STAT5 signaling axis in the expression of IL-10 by human Treg cells, an axis that is regulated by the intronic enhancer, I-SRE-4, and epigenetic modification of this element.
We mainly refer to the acute setting of meningococcemia. Meningococcemia is an infection caused by Neisseria meningitidis, which has 13 clinically significant serogroups that are distinguishable by the structure of their capsular polysaccharides. N. meningitidis, also called meningococcus, is a Gram-negative, aerobic, diplococcus bacterium. The various consequences of severe meningococcal sepsis include hypotension, disseminated intravascular coagulation (DIC), multiple organ failure, and osteonecrosis due to DIC. The gold standard for the identification of meningococcal infection is the bacteriologic isolation of N. meningitidis from body fluids such as blood, cerebrospinal fluid (CSF), synovial fluid, and pleural fluid. Blood, CSF, and skin biopsy cultures are used for diagnosis. Meningococcal infection is a medical emergency that requires antibiotic therapy and intensive supportive care. Management of the systemic circulation, respiration, and intracranial pressure is vital for improving the prognosis, which has dramatically improved since the wide availability of antibiotics. This review of the literature provides an overview of current concepts on meningococcemia due to N. meningitidis infection.
We previously established a novel cell line, termed HOZOT, derived from umbilical cord blood mononuclear cells that is characterized as a human cytotoxic regulatory T (Treg) cell line with a FOXP3(+)CD4(+)CD8(+)CD25(+) phenotype. Here, we describe a new property of HOZOT cells: they actively penetrate into a variety of human cancer cell lines, but not into normal cell lines, and form apparent cell-in-cell structures. In the process of cell penetration, we observed that HOZOT cells adhered to target cells seemed to first insert their nuclei into the cytoplasm of target cells, distinct from the process of phagocytosis. In addition, blocking experiments showed that major histocompatibility complex class I is one of the target cell recognition molecules for HOZOT cells. Furthermore, we propose that cell-in-cell structures between HOZOT cells and target cancer cells could be one of the cytotoxic mechanisms of HOZOT cells.
IMPORTANCE Extracorporeal cardiopulmonary resuscitation (ECPR) is expected to improve the neurological outcomes of patients with refractory cardiac arrest; however, it is invasive, expensive, and requires substantial human resources. The ability to predict neurological outcomes would assist in patient selection for ECPR. OBJECTIVE To develop and validate a prediction model for neurological outcomes of patients with out-of-hospital cardiac arrest with shockable rhythm treated with ECPR. DESIGN, SETTING, AND PARTICIPANTS This prognostic study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest registry, a multi-institutional nationwide cohort study that included 87 emergency departments in Japan. All adult patients with out-of-hospital cardiac arrest and shockable rhythm who were treated with ECPR between June 2014 and December 2017 were included. Patients were randomly assigned to the development and validation cohorts based on the institutions. The analysis was conducted between November 2019 and August 2020. EXPOSURES Age (<65 years), time from call to hospital arrival (Յ25 minutes), initial cardiac rhythm on hospital arrival (shockable), and initial pH value (Ն7.0). MAIN OUTCOMES AND MEASURES The primary outcome was 1-month survival with favorable neurological outcome, defined by Cerebral Performance Category 1 or 2. In the development cohort, a simple scoring system was developed to predict this outcome using a logistic regression model. The diagnostic ability and calibration of the scoring system were assessed in the validation cohort. RESULTS A total of 916 patients were included, 458 in the development cohort (median [interquartile range {IQR}] age, 61 [47-69] years, 377 [82.3%] men) and 458 in the validation cohort (median [IQR] age, 60 [49-68] years; 393 [85.8%] men). The cohorts had the same proportion of favorable neurological outcome (57 patients [12.4%]). The prediction scoring system was developed, attributing a score of 1 for each clinical predictor. Patients were divided into 4 groups, corresponding to their scores on the prediction model, as follows: very low probability (score 0), low probability (score 1), middle probability (score 2), and high probability (score 3-4) of good neurological outcome. The mean predicted probabilities in the groups stratified by score were as follows: very low, 1.6% (95% CI, 1.6%-1.6%); low, 4.4% (95% CI, 4.2%-4.6%); middle, 12.5% (95% CI, 12.1%-12.8%); and high, 30.8% (95% CI, 29.1%-32.5%). In the validation cohort, the C statistic of the scoring system was (continued) Key Points Question Can the neurological outcome of patients with out-ofhospital cardiac arrest and shockable rhythm who are treated with extracorporeal cardiopulmonary resuscitation (ECPR) be predicted using accessible information? Findings In this prognostic study of 916 patients, a model using time to hospital arrival, pH in initial blood gas assessment, shockable rhythm on hospital arrival, and being younger than 65 years was developed to predict survival ...
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