MicroRNA 497 modulates interleukin 1 signalling via the MAPK/ERK pathway

AbstractThe MAPK/ERK signalling pathway has been described to mediate IL-1 induction of target genes and is known to be regulated by microRNAs (miRNA). We describe a novel miRNA regulating the expression of the MEK1 gene and how it impacts IL-1 induced IL-6 transcription. miR-497 was predicted to target MEK1 3′UTR using bioinformatic tools. Transfection of miR-497 into HeLa cells inhibited MEK1 protein expression by 50%. In transient transfection experiments, the luciferase activity of a MEK1 3′UTR luciferase reporter construct was reduced in the presence of miR-497, and mutation of the predicted miR-497 binding site restored activity. miR-497 also decreased protein levels of RAF1 and ERK1 but not ERK2. Addition of miR-497 was further shown to inhibit IL-1 induced IL-6 gene transcription

CD8+ T Cell Phenotype and Function in Childhood and Adult-Onset Connective Tissue Disease

CD8+ T cells are cytotoxic lymphocytes that destroy pathogen infected and malignant cells through release of cytolytic molecules and proinflammatory cytokines. Although the role of CD8+ T cells in connective tissue diseases (CTDs) has not been explored as thoroughly as that of other immune cells, research focusing on this key component of the immune system has recently gained momentum. Aberrations in cytotoxic cell function may have implications in triggering autoimmunity and may promote tissue damage leading to exacerbation of disease. In this comprehensive review of current literature, we examine the role of CD8+ T cells in systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, polymyositis, and dermatomyositis with specific focus on comparing what is known about CD8+ T cell peripheral blood phenotypes, CD8+ T cell function, and CD8+ T cell organ-specific profiles in adult and juvenile forms of these disorders. Although, the precise role of CD8+ T cells in the initiation of autoimmunity and disease progression remains to be elucidated, increasing evidence indicates that CD8+ T cells are emerging as an attractive target for therapy in CTDs

Survey on green roofs in Poland

The aim of this paper is to present the results of a survey on green roofs among potential real estate developers and users, concerning knowledge about, awareness of the benefits of, and interest in green roofs. The survey sample consisted of 151 persons – potential owner-builders from Poland. This is not a large number, but it is significant. The research sample was purposive and statistically insignificant, and the study was an initial part of a larger project. Greenery in urban settings positively affects human quality of life and health and contact with nature improves well-being and reduces stress. Roofs covered with greenery are also a sign of growing environmental awareness. In Poland, green roofs are usually a feature of public and commercial buildings. The low popularity of this solution in single-family housing has its source in potential owner-builders being unaware of the benefits of the roofs’ application, funding opportunities, and benefits in the form of a greater amount of biologically active surfaces. Currently, the technology of covering roofs with greenery is highly developed, and there are many experienced contractors who operate on the Polish market. However, there is a deficiency in knowledge about green roofs among real estate developers and prospective owner-builders, which constitutes a demand barrier. Many people are anxious about using a green roof out of fear of high construction costs and necessary greenery maintenance. This is due to misinformation, as it is possible to use an extensive, low-maintenance roof type. In the case of an intensive roof, the maintenance largely resembles that of a traditional domestic garden. The costs of creating a roof garden are higher than in the case of traditional roofing materials, but a smaller plot could be bought as a result, as a greater amount of biologically active surfaces can be obtained to meet zoning regulations. In Poland, there are currently no legal regulations that obligate or incentivise the use of green roofs. The popularity of this solution is growing, which gives hope for making cities greener. In an era of progressing climate change, building additional green spaces, including those on roofs, is a crucial remedy for the severe consequences of unsustainable urbanisation

Differential impact of sex steroid hormones on B cell class switching, dependant upon sex chromosomal complement

Cis-gender females mount stronger humoral immune responses than cis-gender males in response to infection/vaccination, but are more likely to develop B-cell-driven autoimmune disorders. Murine work suggests a complex interplay between sex chromosomes and hormones creates this sex-bias. Oestrogen has been shown to enhance class-switch recombination(CSR)- the process by which B-cells ‘switch’ to IgG/A/E immunoglobulin isotypes. This study utilises a unique in vivo human model, with samples from both cis-gender and trans-gender age-matched young healthy volunteers, to investigate the impact of sex-chromosomal complement and hormonal milieu on CSR. Peripheral blood samples were collected from cis-male(n=43) and -female(n=62) volunteers(14-31yrs), and trans-male(n=25) and trans-female(n=23) volunteers(15-19yrs) on GnRH-analogue(“puberty blockers”), +/- testosterone or oestrogen treatment, respectively. PBMC/serum phenotyping was performed using flow cytometry and LEGENDplex™ immunoassay. Sorted CD19+ cells from a representative subset(n=22) were sent for RNAseq analysis. Post-pubertal cis-males had lower percentages of class-switched(IgD-CD27+) B-cells than cis-females(p=0.002), specifically pertaining to decreased IgG+ B-cells(p=0.009). Whilst IgG subclasses 1-3 are implicated in infection responses and the bulk of pathogenic autoantibodies, IgG4 is purported to be immunoregulatory. Cis-males demonstrated a higher IgG4:IgG1 serum antibody ratio than cis-females(p=0.003). Oestrogen blockade on an XX background in trans-males resulted in a reduced proportion of class-switched B-cells compared to cis-females(p=0.005), in-line with the cis-male profile. The ratio of IgG1:IgG4 subclasses was unaffected. Interestingly, oestrogen treatment on the XY background of trans-females demonstrated no overall effect on class-switching(p=0.250) but IgG4:IgG1 ratios were decreased significantly(p=0.015). Preliminary mechanistic analysis showed that AICDA(Activation-induced cytidine deaminase, an enzyme essential for CSR DNA mutations) expression was decreased in cis-males(p=0.038), and that oestrogen blockade in trans-males(p=0.125) was associated with a potential reduction, compared to cis-females. No differences were observed following oestrogen treatment in trans-females compared to cis-males(p=0.230). Oestrogen differentially affected B-cell CSR on XX and XY chromosomal backgrounds. Further work is implicated to establish the mechanisms behind this

Genetic association with articular damage in patients with juvenile idiopathic arthritis (JIA)

n/

ReCOMmendations for management of Preschool ASthma for General Practitioners : COMPAS GP

Asthma is a chronic, inflammatory, heterogenic disease of the bronchi. It is characterised by bronchial obstruction in the form of wheezing, coughing, shortness of breath and breathing difficulty, showing variable intensity and resolving after medication, or sometimes spontaneously. Making the diagnosis of asthma in children under 5 years of age is based on clinical criteria – the presence of symptoms of bronchial constriction, confirmation of its reversibility and lack of symptoms suggestive of other clinical diagnosis. The criterion for diagnosis are usually three episodes of bronchial obstruction, or a single episode of severe intensity. A detailed history and physical examination allows in most cases to rule out other diseases with similar clinical course. Frequent recurrence of symptoms is an indication for the initial differential diagnosis in primary health care, including a chest X-ray, blood count, often an ENT and/or allergological consultation. However severe, frequent and not responding to treatment episodes of bronchoconstriction indicate the need for diagnostics in specialist hospital wards. Chronic treatment of asthma is based on the administration of anti-inflammatory drugs, inhaled therapy is the treatment of choice in most patients. The assessment of the severity of asthma exacerbation determines the range of treatment, on an outpatient basis consisting of bronchodilators, corticosteroids and oxygen therapy. An important element of treatment is appropriate patient education, with particular attention to the exacerbation risk factors and correct inhalation technique. Children suffering from asthma should be vaccinated against pneumococcal disease and against influenza annually

Genetic association with articular damage in patients with juvenile idiopathic arthritis (JIA)

n/

Sex and Pubertal Differences in the Type 1 Interferon Pathway Associate With Both X Chromosome Number and Serum Sex Hormone Concentration

Type 1 interferons (IFN) are an antiviral cytokine family, important in juvenile onset systemic lupus erythematosus (jSLE) which is more common in females, around puberty. We report that plasmacytoid dendritic cells (pDC) from healthy females produced more type 1 IFN after toll like receptor (TLR) 7 signaling than males, even before puberty, but that puberty itself associated with increased production of type 1 IFN. A unique human model allows us to show that this was related to X chromosome number, and serum testosterone concentration, in a manner which differed depending on the number of X chromosomes present. In addition, we have showed that pDC were more activated in females overall, and immune cell TLR7 gene expression was higher in females after puberty. Therefore, sex hormones and X chromosome number were associated individually and interactively with the type 1 IFN response, which contributes to our understanding of why females are more likely to develop an IFN mediated disease like jSLE after puberty

Investigating cytotoxic cell phenotype and function in juvenile systemic lupus erythematosus

Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults. It is a complex, systemic disease, characterized by autoantibody production against nuclear antigens. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells and natural killer (NK) cells contribute to disease pathology and studies exploring cytotoxicity in JSLE are very rare. To address this, this work examined cytotoxic cell immunophenotype in the peripheral blood of a large cohort of JSLE patients and age and sex-matched controls. The results revealed a reduction in CD8+ T cells expressing the cytotoxic mediators, perforin and CD107a, and effector cytokines IFN-γ and TNF-α in JSLE compared to controls. This reduction was present regardless of treatment or disease activity, suggesting it was an underlying feature of disease. Transcriptomic analysis identified potential metabolic disturbances, including mitochondrial dysfunction, as a possible mechanism underpinning these observations. The results also revealed that NK cells as a whole and perforin and granzyme A producing NK cells were markedly reduced in JSLE versus controls, which was associated with a decrease in NK functionality. Unlike CD8+ T cells, the reduction in overall NK cell frequencies was associated with increasing disease activity, with transcriptomic analysis revealing upregulation of IFN-α responses and apoptotic pathways in active JSLE. Notably, both JSLE CD8+ T cell and NK cell apoptosis was markedly increased in the presence of IFN-α suggesting the numerical deficiency in cytotoxic cell frequencies could be attributed, at least in part, to increased apoptosis. Altogether these results identify a global deficiency in cytotoxicity in JSLE. However further characterization of the role of cytotoxic cells is necessary to understand the contribution of cytotoxic cells to disease pathology enabling the development of new therapeutic avenues