Asthma is a chronic inflammatory disorder of the airways. While the local infiltration of eosinophils and mast cells, and their role in the disease have long been recognized, neutrophil infiltration ...has also been assessed in many clinical studies. In these studies, airway neutrophilia was associated with asthma severity. Importantly, neutrophilia also correlates with asthma that is refractory to corticosteroids, the mainstay of asthma treatment. However, it is now increasingly recognized that neutrophils are a heterogeneous population, and a more precise phenotyping of these cells may help delineate different subtypes of asthma. Here, we review current knowledge of the role of neutrophils in asthma and highlight future avenues of research in this field.
Airway neutrophilia has been associated with asthma severity and asthma exacerbations; however, neutrophils can also be detected in the airways of both healthy subjects and mild asthmatics.
Multiple mediators, including chemokines, cytokines, and lipids, can promote neutrophil recruitment to the airways, and smoking and co-morbidities, such as gastroesophageal reflux and obesity, have shown positive relationships with sputum neutrophil counts.
Neutrophils can not only combat infections and kill pathogens, but also have adverse effects on the airways, through the effects of proteases and reactive oxygen species.
An improved understanding of neutrophil populations would allow better precision in using neutrophils to define asthma phenotypes.
Interluekin-17A (IL17A) Chen, Kong; Kolls, Jay K.
Gene,
05/2017, Volume:
614
Journal Article
Peer reviewed
Open access
The discovery of the key roles of interleukin-17A (IL-17A) and IL-17A producing cells in inflammation, autoimmune diseases and host defense has led to the experimental targeting of the IL-17A pathway ...in animal models of diseases as well as in clinical trials in humans. These therapeutic agents include biological products that target IL-17A and IL-23, an upstream regulator of IL-17A production. IL-17A producing T helper cells (Th17 cells) are a distinct lineage from the Th1 and Th2 CD4+ lineages and have been suggested to represent a good drug target in certain inflammatory conditions. Targeting IL-17A has been proven to be a good approach as anti-IL-17A is FDA approved for the treatment of psoriasis in 2015. In host defense, IL-17A has been shown to be mostly beneficial against infection caused by extracellular bacteria and fungi. This review will overview the discovery of IL-17A, the receptors used by this cytokine and its role in mucosal immunity and inflammation.
•Overview of the discovery, cloning and identification of the cellular sources of IL-17A•Summary of the roles of IL-17A in mucosal immunity and autoimmune diseases•Summary of IL-17A targeted drug development
The intestine is a critical site of immune cell development that not only controls intestinal immunity but extra‐intestinal immunity as well. Recent findings have highlighted important roles for gut ...microbiota in shaping lung inflammation. Here, we discuss interactions between the microbiota and immune system including T cells, protective effects of microbiota on lung infections, the role of diet in shaping the composition of gut microbiota and susceptibility to asthma, epidemiologic evidence implicating antibiotic use and microbiota in asthma and clinical trials investigating probiotics as potential treatments for atopy and asthma. The systemic effects of gut microbiota are partially attributed to their generating metabolites including short chain fatty acids, which can suppress lung inflammation through the activation of G protein‐coupled receptors. Thus, studying the interactions between microbiota and immune cells can lead to the identification of therapeutic targets for chronic lower respiratory diseases.
Interactions between the intestinal microbiota, environment and immune system contribute to the development of asthma and atopy. We discuss epidemiologic, clinical and mechanistic data on the role of microbes in regulating lung immunity. Dietary manipulation of microbiota is further discussed as potential adjunctive therapies for chronic inflammatory diseases.
Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a ...description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)₂D₃, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)₂D₃-Vitamin D₃ complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health.
Abstract
Pneumocystis jirovecii can cause life-threatening pneumonia in immunocompromised patients. Traditional diagnostic testing has relied on staining and direct visualization of the life-forms in ...bronchoalveolar lavage fluid. This method has proven insensitive, and invasive procedures may be needed to obtain adequate samples. Molecular methods of detection such as polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and antibody-antigen assays have been developed in an effort to solve these problems. These techniques are very sensitive and have the potential to detect Pneumocystis life-forms in noninvasive samples such as sputum, oral washes, nasopharyngeal aspirates, and serum. This review evaluates 100 studies that compare use of various diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) in patient samples. Novel diagnostic methods have been widely used in the research setting but have faced barriers to clinical implementation including: interpretation of low fungal burdens, standardization of techniques, integration into resource-poor settings, poor understanding of the impact of host factors, geographic variations in the organism, heterogeneity of studies, and limited clinician recognition of PCP. Addressing these barriers will require identification of phenotypes that progress to PCP and diagnostic cut-offs for colonization, generation of life-form specific markers, comparison of commercial PCR assays, investigation of cost-effective point of care options, evaluation of host factors such as HIV status that may impact diagnosis, and identification of markers of genetic diversity that may be useful in diagnostic panels. Performing high-quality studies and educating physicians will be crucial to improve the rates of diagnosis of PCP and ultimately to improve patient outcomes.
T helper 17 (Th17) cells belong to a recently identified T helper subset, in addition to the traditional Th1 and Th2 subsets. These cells are characterized as preferential producers of ...interleukin-17A (IL-17A), IL-17F, IL-21, and IL-22. Th17 cells and their effector cytokines mediate host defensive mechanisms to various infections, especially extracellular bacteria infections, and are involved in the pathogenesis of many autoimmune diseases. The receptors for IL-17 and IL-22 are broadly expressed on various epithelial tissues. The effector cytokines of Th17 cells, therefore, mediate the crucial crosstalk between immune system and tissues, and play indispensable roles in tissue immunity.
Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal ...airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens.
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•Human alveospheres are composed of renewing AT2 cells and AT1-like cells•Alveolar epithelial cells are efficiently infected by SARS-CoV-2 in vitro•Interferon signaling is activated in SARS-CoV-2-infected alveolar epithelial cells•Lung organoid models provide a platform for drug discovery and disease modeling
In vitro models of human lung epithelium, including diverse cell types of the proximo-distal axis, are critical for modeling infection. Mulay et al. show that alveospheres, with epithelial type 2- and type 1-like cells, are infected by SARS-CoV-2, initiating an interferon response, and serve as a platform for screening antiviral drugs.
Summary
Respiratory infections and diseases are among the leading causes of death worldwide, and effective treatments probably require manipulating the inflammatory response to pathogenic microbes or ...allergens. Here, we review mechanisms controlling the production and functions of interleukin‐17 (IL‐17) and IL‐22, cytokines that direct several aspects of lung immunity. Innate lymphocytes (γδ T cells, natural killer cells, innate lymphoid cells) are the major source of IL‐17 and IL‐22 during acute infections, while CD4+ T‐helper 17 (Th17) cells contribute to vaccine‐induced immunity. The characterization of dendritic cell (DC) subsets has revealed their central roles in T‐cell activation. CD11b+ DCs stimulated with bacteria or fungi secrete IL‐1β and IL‐23, potent inducers of IL‐17 and IL‐22. On the other hand, recognition of viruses by plasmacytoid DCs inhibits IL‐1β and IL‐23 release, increasing susceptibility to bacterial superinfections. IL‐17 and IL‐22 primarily act on the lung epithelium, inducing antimicrobial proteins and neutrophil chemoattractants. Recent studies found that stimulation of macrophages and DCs with IL‐17 also contributes to antibacterial immunity, while IL‐22 promotes epithelial proliferation and repair following injury. Chronic diseases such as asthma and chronic obstructive pulmonary disease have been associated with IL‐17 and IL‐22 responses directed against innocuous antigens. Future studies will evaluate the therapeutic efficacy of targeting the IL‐17/IL‐22 pathway in pulmonary inflammation.
Summary
Interleukin‐17 (IL‐17)‐producing cells play a critical role in mucosal immunity including the respiratory tract. This review will highlight recent advances in our understanding of these cells ...in mucosal immunity in the lung as well as their potential pathogenic roles in respiratory diseases. The IL‐17‐producing cells include γδ T cells, natural killer cells, group 3 innate lymphoid cells, and T helper type 17 (Th17) cells. There have been recent advances in our understanding of these cell populations in the lung as well as emerging data on how these cells are regulated in the lung. Moreover, Th17 cells may be a key component of tissue‐resident memory cells that may be acquired over time or elicited by mucosal immunization that provides the host with enhanced immunity against certain pathogens.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to ...be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.
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