Th17 cells: new players in asthma pathogenesis.
TL;DR: Th17 cells are found to be a new players in asthma pathogenesis and may play a role in predicting wheezing and asthma-like symptoms.
Abstract: CD4+ T effector lymphocytes are distinguished in different subsets on the basis of their patterns of cytokine secretion. Th1 cells, thank to IFN-γ production, are responsible for cell-mediated immunity against intracellular pathogens, Th2 cells, through the production of IL-4, provide some degree of protection against helminthes, and Th17 cells, via IL-17, promote neutrophils recruitment for the clearance of bacteria and fungi. However, beyond their protective role, these T-helper subsets can also be involved in the pathogenesis of several inflammatory diseases. Asthma is an inflammatory disease characterized by different clinical phenotypes. Allergic asthma is the result of an inflammatory process driven by allergen-specific Th2 lymphocytes, whereas Th17 cells are mainly involved in those forms of asthma, where neutrophils more than eosinophils, contribute to the inflammation. The identification in allergic asthma of Th17/Th2 cells, able to produce both IL-4 and IL-17, is in keeping with the observation that different clinical phenotypes can coexist in the same patient. In conclusion, a picture in which different T-cell subpopulations are active in different phase of bronchial asthma is emerging, and the wide spectrum of clinical phenotypes is probably the expression of different cellular characters playing a role in lung inflammation.
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TL;DR: The regulation of the intestinal TJ barrier is discussed together with its implications for the pathogenesis of diseases.
Abstract: The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.
914 citations
Journal Article•
TL;DR: Inhaled, nebulized SCG seem to offer better protection against EIA than inhalation of SCG as a powder and is most effective in children.
Abstract: All asthmatics have exercise-induced asthma (EIA). In periods where the asthma spontaneously deteriorate, there will be more exercise-induced asthma. About 3/4 of the asthmatics will have a positive exercise test on the first challenge. Exercise is not the best test to obtain the diagnosis of asthma, as other tests, e.g. inhalation of histamine, is more sensitive and specific. The best pretreatment of EIA is inhaled beta 2-agonists. Inhaled, nebulized SCG seem to offer better protection against EIA than inhalation of SCG as a powder and is most effective in children. EIA should today primarily be used in studies concerning the pathogenesis of asthma and in the evaluation of medication against asthma.
370 citations
TL;DR: In this article, the authors evaluated relationships between the bronchial microbiome and features of severe asthma using 16S ribosomal RNA-based methods and found that specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes.
Abstract: Background Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma Whether similar relationships exist among patients with severe asthma is unknown Objective We sought to evaluate relationships between the bronchial microbiome and features of severe asthma Methods Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA–based methods Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41) Results In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index ( P P P = 06), and bronchial biopsy eosinophil values (per square millimeter, P = 07) Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes) In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5) , an indicator of steroid responsiveness, correlated with Actinobacteria Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria No taxa were associated with a T H 2-related epithelial gene expression signature, but expression of T H 17-related genes was associated with Proteobacteria Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (78-fold increase in patients with severe asthma, adjusted P Conclusions Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use
346 citations
TL;DR: Whether newly defined asthma endotypes predict the individual course of asthma has to be validated in longitudinal studies and the identification of corresponding molecular biomarkers for individual pathogenic mechanism underlying phenotypes or subgroups within a phenotype is important.
Abstract: Asthma phenotypes have been developed to address the complexities of the disease. However, owing to a lack of longitudinal studies, little is known about the onset as well as the stability of phenotypes. Distinguishing phenotypes with regard to the severity or duration of the disease is essential. A phenotype covers the clinically relevant properties of the disease, but does not show the direct relationship to disease etiology and pathophysiology. Different pathogenetic mechanisms might cause similar asthma symptoms and might be operant in a certain phenotype. These putative mechanisms are addressed by the term ‘endotype’. Classification of asthma based on endotypes provides advantages for epidemiological, genetic, and drug-related studies. A successful definition of endotypes should link key pathogenic mechanisms with the asthma phenotype. Thus, the identification of corresponding molecular biomarkers for individual pathogenic mechanism underlying phenotypes or subgroups within a phenotype is important. Whether newly defined asthma endotypes predict the individual course of asthma has to be validated in longitudinal studies. The accurate endotyping reflects natural history of asthma and should help to predict treatment response. Thus, understanding asthma endotypes might be useful in clinical practice.
286 citations
Cites background from "Th17 cells: new players in asthma p..."
...Furthermore, the role of Th17 lymphocytes in asthmatic airway inflammation is being investigated (41)....
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TL;DR: Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients’ needs.
Abstract: Asthma is a complex respiratory disorder characterized by marked heterogeneity in individual patient disease triggers and response to therapy. Several asthma phenotypes have now been identified, each defined by a unique interaction between genetic and environmental factors, including inflammatory, clinical and trigger-related phenotypes. Endotypes further describe the functional or pathophysiologic mechanisms underlying the patient's disease. type 2-driven asthma is an emerging nomenclature for a common subtype of asthma and is characterized by the release of signature cytokines IL-4, IL-5 and IL-13 from cells of both the innate and adaptive immune systems. A number of well-recognized biomarkers have been linked to mechanisms involved in type 2 airway inflammation, including fractional exhaled nitric oxide, serum IgE, periostin, and blood and sputum eosinophils. These type 2 cytokines are targets for pharmaceutical intervention, and a number of therapeutic options are under clinical investigation for the management of patients with uncontrolled severe asthma. Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients' needs.
273 citations
References
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Journal Article•
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
7,567 citations
"Th17 cells: new players in asthma p..." refers background in this paper
...About 20 years ago, two subsets of effector CD4+ Th cells with different functions and patterns of cytokine secretion were identified, in both mice and humans, and were named as type 1 Th (Th1) and type 2 Th (Th2), respectively (1, 2)....
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TL;DR: It is shown that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage of proinflammatory T helper cells and its potential as a therapeutic target in inflammatory diseases is highlighted.
4,616 citations
TL;DR: It is shown that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL- 12, is the critical factor in this response.
Abstract: Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
2,915 citations
TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...
2,898 citations
"Th17 cells: new players in asthma p..." refers background in this paper
...To further underline the role of Th2 lymphocytes in asthma pathogenesis, there is the observation that allergen-specific Th2 cells are present in the lungs of patients with allergic asthma, whereas in chronic obstructive pulmonary disease Th1 lymphocytes have been predominantly found (60, 61)....
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TL;DR: Human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells and induces strong proliferation of mouse memory T cells.
2,823 citations
"Th17 cells: new players in asthma p..." refers background in this paper
...Moreover, a new IL-12 family member, IL-23, was identified in the last years, that shares with IL-12 the p40 subunit, the heterodimer of IL-12 being composed of p40 and p35, and the IL-23 heterodimer being composed of p40 and p19 (5)....
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...Although the existence of IL-17 as a product of activated CD4+ T cells has been known for more than 10 years, Th17 lymphocytes have only recently been recognized as a distinct subset of Th cells (5, 6)....
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...These effector cells have been named Th17, because the main cytokine they produce are IL-17A and F (5, 6) (Fig....
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