Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.

Background: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers.

ERAP1 reduces accumulation of aberrant and disulfide-linked forms of HLA-B27 on the cell surface.

Objective: Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) variants contribute to the risk of ankylosing spondylitis in HLA-B27 positive individuals, implying a disease-related interaction between these gene products. The aim of this study was to determine whether reduced ERAP1 expression would alter the cell surface expression of HLA-B27 and the formation of aberrant disulfide-linked forms that have been implicated in the pathogenesis of spondyloarthritis.

Methods: ERAP1 expression was knocked down in monocytic U937 cells expressing HLA-B27 and endogenous HLA class I.

Identification of Interleukin-1β-Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal-Onset Multisystem Inflammatory Disease.

Objective: Spontaneous inflammatory responses initiated by NLRP3 mutations promote inflammasome-mediated interleukin-1β (IL-1β) processing and release and can induce rapid necrotic cell death. The cells that produce IL-1β in neonatal-onset multisystem inflammatory disease (NOMID) have not been clearly identified, nor have the mechanisms mediating IL-1β release and cell death been completely elucidated.

Methods: Whole blood cells were stimulated with lipopolysaccharide (LPS) in the presence of cathepsin B and caspase 1 inhibitors, followed by ATP treatment.

A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy.

Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen-experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen-specific manner, and mDCs 'lend' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors.

Flt3-L increases CD4+CD25+Foxp3+ICOS+ cells in the lungs of cockroach-sensitized and -challenged mice.

We previously reported in an ovalbumin-induced model of allergic asthma that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c(high)CD8 alpha(high)CD11b(low) dendritic cells in the lung. In this study, we investigated the effect of Flt3-L in a clinically relevant aeroallergen-induced asthma on the phenotypic expression of lung T cells. Balb/c mice were sensitized and challenged with cockroach antigen (CRA), and AHR to methacholine was established.

Flt3-ligand plasmid prevents the development of pathophysiological features of chronic asthma in a mouse model.

Airway inflammation and remodeling are primary characteristics of long-standing asthma. A balance between the T(H)1/T(H)2 cytokines regulates the accumulation and activation of inflammatory cells, including mast cells and eosinophils. Recently, we demonstrated that pUMVC3-hFLex, an active plasmid, mammalian expression vector for the secretion of Flt3-L, reversed established airway hyperresponsiveness (AHR) in a murine model of acute allergic airway inflammation.

Treatment with Flt3 ligand plasmid reverses allergic airway inflammation in ovalbumin-sensitized and -challenged mice.

We have previously reported that fms-like tyrosine kinase 3 ligand (Flt3-L) prevents and reverses established allergic airway inflammation in an ovalbumin (OVA) induced mouse model of asthma. In this study, we investigated the effect of pUMVC3-hFLex, a plasmid, mammalian expression vector for the secretion of Flt3-L on the same mouse model as well as the duration of the effect of the treatment. Allergic airway inflammation to OVA was established in BALB/c mice.

Flt-3 ligand reverses late allergic response and airway hyper-responsiveness in a mouse model of allergic inflammation.

Flt3 ligand (Flt3-L) is a growth factor for dendritic cells and induces type 1 T cell responses. We recently reported that Flt3-L prevented OVA-induced allergic airway inflammation and suppressed late allergic response and airway hyper-responsiveness (AHR). In the present study we examined whether Flt3-L reversed allergic airway inflammation in an established model of asthma.

Novel immunomodulatory oligonucleotides prevent development of allergic airway inflammation and airway hyperresponsiveness in asthma.

Oligodeoxynucleotides containing unmethylated CpG motifs (CpG oligos) have been shown to prevent development of allergic airway inflammation and airway hyperresponsiveness (AHR) in mouse models of asthma. Recently, we reported immunomodulatory oligonucleotides (IMOs) containing novel structures (immunomers) and synthetic immunostimulatory CpR (R=2'-deoxy-7-deazguanosine) motifs show potent stimulatory activity with distinct cytokine secretion profiles. Since type 2 T cells predominate in asthma and increase in type 1 cells can prevent the differentiation of naïve T lymphocytes to a type 2 phenotype, we hypothesized that IMOs can prevent the development of allergic airway inflammation and AHR in the ovalbumin (OVA)-sensitized and challenged mouse model.