Transcriptional Dynamics of NRF2 Overexpression and KEAP1-NRF2 Inhibitors in Human Cell Line and Primary Lung Cells.

Oxidative stress in the human lung is caused by both internal (e.g., inflammation) and external stressors (smoking, pollution, and infection) to drive pathology in a number of lung diseases.

Early diagnostic BioMARKers in exacerbations of chronic obstructive pulmonary disease: protocol of the exploratory, prospective, longitudinal, single-centre, observational MARKED study.

Introduction: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) play a pivotal role in the burden and progressive course of chronic obstructive pulmonary disease (COPD). As such, disease management is predominantly based on the prevention of these episodes of acute worsening of respiratory symptoms. However, to date, personalised prediction and early and accurate diagnosis of AECOPD remain unsuccessful.

Non-heme iron overload impairs monocyte to macrophage differentiation mitochondrial oxidative stress.

Iron is a key element for systemic oxygen delivery and cellular energy metabolism. Thus regulation of systemic and local iron metabolism is key for maintaining energy homeostasis. Significant changes in iron levels due to malnutrition or hemorrhage, have been associated with several diseases such as hemochromatosis, liver cirrhosis and COPD.

Allergic sensitization impairs lung resident memory CD8 T-cell response and virus clearance.

Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections.

Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance.

Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells.

Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses.

Unmet needs in the management of exacerbations of chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive pulmonary disease (COPD) are episodes of acute worsening of respiratory symptoms that require additional therapy. These events play a pivotal role in the natural course of the disease and are associated with a progressive decline in lung function, reduced health status, a low physical activity level, tremendous health care costs, and increased mortality. Although most exacerbations have an infectious origin, the underlying mechanisms are heterogeneous and specific predictors of their occurrence in individual patients are currently unknown.

Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity.

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g.

Cytokine-regulated Th17 plasticity in human health and diseases.

Upon activation, naïve CD4 T helper (Th) cells differentiate into distinct Th effector cell lineages depending on the local cytokine environment. However, these polarized Th cells can also adapt their function and phenotype depending on the changing cytokine environment, demonstrating functional plasticity. Here, Th17 cells, which play a critical role in host protection from extracellular pathogens and in autoimmune disorders, are of particular interest.

A MALT1 inhibitor suppresses human myeloid DC, effector T-cell and B-cell responses and retains Th1/regulatory T-cell homeostasis.

The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or T-cell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-ɣ) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells.

Human Lung Conventional Dendritic Cells Orchestrate Lymphoid Neogenesis during Chronic Obstructive Pulmonary Disease.

Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined. To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD.

Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation.

Naive CD4 T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4 T cell plasticity.

Author Correction: Extracellular nanovesicles released from the commensal yeast Malassezia sympodialis are enriched in allergens and interact with cells in human skin.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

A Phenotypic Screening Approach Using Human Treg Cells Identified Regulators of Forkhead Box p3 Expression.

Regulatory T (Treg) cells, expressing the transcription factor forkhead box p3 (FOXP3), are the key cells regulating peripheral autoreactive T lymphocytes by suppressing effector T cells. FOXP3 Treg cells play essential roles controlling immune responses in autoimmune diseases and cancer. Several clinical approaches (e.

Extracellular nanovesicles released from the commensal yeast Malassezia sympodialis are enriched in allergens and interact with cells in human skin.

Malassezia sympodialis is a dominant commensal fungi in the human skin mycobiome but is also associated with common skin disorders including atopic eczema (AE). M. sympodialis releases extracellular vesicles, designated MalaEx, which are carriers of small RNAs and allergens, and they can induce inflammatory cytokine responses.

Toll-like Receptor 4 Engagement on Dendritic Cells Restrains Phago-Lysosome Fusion and Promotes Cross-Presentation of Antigens.

The initiation of cytotoxic immune responses by dendritic cells (DCs) requires the presentation of antigenic peptides derived from phagocytosed microbes and infected or dead cells to CD8(+) T cells, a process called cross-presentation. Antigen cross-presentation by non-activated DCs, however, is not sufficient for the effective induction of immune responses. Additionally, DCs need to be activated through innate receptors, like Toll-like receptors (TLRs).

Harnessing the exosome-induced immune response for cancer immunotherapy.

In recent years exosomes have emerged as potent stimulators of immune responses and as agents for cancer therapy. Exosomes can carry a broad variety of immunostimulatory molecules depending on the cell of origin and in vitro culture conditions. Dendritic cell-derived exosomes (dexosomes) have been shown to carry NK cell activating ligands and can be loaded with antigen to activate invariant NKT cells and to induce antigen-specific T and B cell responses.

Potentiating antitumor immunity with αGC-loaded exosomes.

Anticancer immunotherapy is a promising treatment modality since it bears the potential of being highly specific, but effective clinical applications are still under development. We have recently described an exosome-based strategy for co-delivery of α-galactosylceramide and a tumor-associated antigen that synergistically potentiates tumor-specific adaptive immune responses while preventing the anergy of invariant natural killer T (iNKT) cells. We propose that the next generation of exosome-based immunotherapies should involve iNKT-cell ligands to induce a broad, amplified and sustainable antitumor immune response.

Cancer immunotherapy with exosomes requires B-cell activation.

Exosomes derived from dendritic cells (dexosomes) induce potent antitumor immune responses in mice. We have shown that the efficacy of dexosome-elicited antitumor immunity relies on the presence of both T- and B-cell dexosome-associated epitopes. Hence, the inclusion of B-cell epitopes in anticancer vaccines is crucial for the success of this immunotherapeutic intervention.

Synergistic induction of adaptive antitumor immunity by codelivery of antigen with α-galactosylceramide on exosomes.

Exosomes and the invariant NKT (iNKT) immune cell ligand α-galactosylceramide (αGC) may offer novel tools for cancer immunotherapy. In this study, we investigated whether exosomes loaded with αGC can activate iNKT cells and potentiate a cancer-specific adaptive immune response. αGC loaded exosomes readily activated iNKT cells both in vitro and in vivo.

Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity.

Exosomes are secreted membrane nanovesicles of endosomal origin and are considered potential cancer vaccine vectors. Phase I clinical trials have been successfully conducted with tumor peptide-loaded exosomes derived from dendritic cells (dexosomes), and a phase II clinical trial is ongoing. However, much is still unknown regarding the in vivo role of dexosomes and whether their immunogenicity can be enhanced.

Effects of subtoxic concentrations of TiO2 and ZnO nanoparticles on human lymphocytes, dendritic cells and exosome production.

Metal oxide nanoparticles are widely used in the paint and coating industry as well as in cosmetics, but the knowledge of their possible interactions with the immune system is very limited. Our aims were to investigate if commercially available TiO(2) and ZnO nanoparticles may affect different human immune cells and their production of exosomes, nano-sized vesicles that have a role in cell to cell communication. We found that the TiO(2) or ZnO nanoparticles at concentrations from 1 to 100μg/mL did not affect the viability of primary human peripheral blood mononuclear cells (PBMC).

Nanovesicles from Malassezia sympodialis and host exosomes induce cytokine responses--novel mechanisms for host-microbe interactions in atopic eczema.

Background: Intercellular communication can occur via the release of membrane vesicles. Exosomes are nanovesicles released from the endosomal compartment of cells. Depending on their cell of origin and their cargo they can exert different immunoregulatory functions.

Zymosan suppresses leukotriene C₄ synthase activity in differentiating monocytes: antagonism by aspirin and protein kinase inhibitors.

Cysteinyl leukotrienes (cysLTs) are potent proinflammatory mediators with particular relevance for asthma. However, control of cysLT biosynthesis in the time period after onset of acute inflammation has not been extensively studied. As a model for later phases of inflammation, we investigated regulation of leukotriene (LT) C(4) synthase (LTC(4)S) in differentiating monocytes, exposed for several days to fungal zymosan.

Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration.

Background: Leukotrienes (LTs) are potent proinflammatory lipid mediators with key roles in the pathogenesis of asthma and inflammation. Recently, nanovesicles (exosomes), released from macrophages and dendritic cells (DCs), have become increasingly appreciated as messengers in immunity.

Objective: We investigated whether exosomes from human macrophages, DCs, and plasma contain enzymes for LT biosynthesis and studied potential roles for exosomes in transcellular LT metabolism and granulocyte chemotaxis.