Immunological self tolerance is maintained at least in part by regulatory T (Treg) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery. Antigens that stimulate self-reactive T cells may also activate natural Treg cells, thereby maintaining dominant self tolerance. Conversely, genetic anomalies or environmental agents that specifically or predominantly affect Treg cells cause or predispose to autoimmunity. With recent advances in our understanding of Treg cell development in the thymus and periphery and the molecular mechanism of Treg cell–mediated suppression, new ways of treating immunological diseases by targeting Treg cells at the cellular and molecular levels are envisaged.

Regulatory T cells exert checks and balances on self tolerance and autoimmunity

Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation--into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes)--has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.

/pdf/type-2-inflammation-in-asthma-present-in-most-absent-in-many-4md8y85wjs.pdf

Type 2 inflammation in asthma — present in most, absent in many

The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides gene expression profiles associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, characterization, and treatment of solid tumor stem cells.

Compositions and methods for treating and diagnosing cancer

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.

Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of IL-1β and IL-18. While wild type Salmonella typhimurium infection is lethal to mice, a strain that persistently expresses flagellin was cleared by the cytosolic flagellin detection pathway via NLRC4 activation of caspase-1; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1 induced pyroptotic cell death released bacteria from macrophages, exposing them to uptake and killing by reactive oxygen species in neutrophils. Similarly, caspase-1 cleared Legionella and Burkholderia by cytokine independent mechanisms. Our results show, for the first time, that caspase-1 can clear intracellular bacteria in vivo independent of IL-1β and IL-18, and establish pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.

Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria (111.33)

The invention provides molecules, e.g., antibodies or antibody fragments, that specifically bind thymic stromal lymphopoietin (TSLP), compositions comprising these molecules, and methods of using and producing these molecules.

Thymic stromal lymphopoietin (tslp)-binding molecules and methods of using the molecules

Phosphoinositide 3-kinase (PI3K) family of signalling enzymes and their role in asthma

bcbio/bcbio-nextgen: v1.1.9

bcbio/bcbio-nextgen: v1.2.7

Rhinovirus (RV) infection is the most common cause of asthma exacerbations (AE), however mechanisms are poorly understood. Conventional sampling techniques such as bronchoalveolar lavage dilute many cytokines below limits of detection and consequently it has not been possible to measure key mediators of Th1, Th2 and Th17 pathways during virus-induced AE’s . In addition, IL-33, an epithelial-derived alarmin, has recently been shown to be essential for mouse virus-induced airway hyperresponsiveness, however the relationship between IL-33 and exacerbations in human asthma remains unknown. Using the human model of experimental RV induced AE along with novel techniques to sample upper and lower airway mucosal lining fluid (MLF) we investigated the roles of IL-33 and several other prominent cytokines in virus-induced AE’s. Methods 32 mild-to-moderate asthmatics and 14 healthy subjects were inoculated nasally with RV-16. Symptom scores were recorded daily. Bronchoscopies were performed 2 weeks prior to inoculation and on d4 post-inoculation. Novel techniques to sample MLF called ‘bronchosorption’ and ‘nasosorption’ were performed. Cytokines were measured in both bronchial and nasal samples at baseline and on d4 with further nasal sampling on days 2, 3, 5, 7, 10 and 42. Results In asthma, nasal IL-4, –5, –13, –17, –33, and IFN-γ levels were significantly increased during infection compared to baseline (all P Conclusion Sampling MLF permits the direct measurement of previously undetectable mediators across multiple inflammatory pathways. Increased IL-33 and Th2 induction are associated with increased AE severity. IL-33 correlated strongly with Th2 cytokine levels and may represent a novel target for the treatment of virus-induced AE’s. In addition, nasal Th2 inflammation correlated with bronchial levels whilst baseline levels predicted the magnitude of Th2 induction during the AE. Therefore it may be possible to use nasosorption to guide therapy with anti-IL-5 and anti-IL-13 mAb treatments.

https://thorax.bmj.com/content/thoraxjnl/67/Suppl_2/A3.1.full.pdf

Matthew J. Edwards

Papers

Thymic stromal lymphopoietin (tslp)-binding molecules and methods of using the molecules

Phosphoinositide 3-kinase (PI3K) family of signalling enzymes and their role in asthma

bcbio/bcbio-nextgen: v1.1.9

bcbio/bcbio-nextgen: v1.2.7

T5 Sampling Airway Mucosal Lining Fluid Identifies Roles For IL-33 and Multiple Inflammatory Pathways in Virus-Induced Asthma Exacerbations