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      Th17/Treg homeostasis, but not Th1/Th2 homeostasis, is implicated in exacerbation of human bronchial asthma

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          Th17 and regulatory T cell (Treg) play crucial roles in the pathogenesis of asthma. However, the association between Th17/Treg homeostasis and asthma exacerbation remains unclear.

          Patients and methods

          To investigate the role of Th17/Treg bias in asthma exacerbation, 49 asthma patients were enrolled in the current study, of whom 31 had acute asthma exacerbation (exacerbation group) and 18 did not (non-exacerbation group). Meanwhile, 17 healthy subjects were recruited as normal controls (control group). By measuring interleukin (IL)-4, IL-13, interferon (IFN)-γ, IL-10, and IL-17A levels in plasma using enzyme-linked immunosorbent assay (ELISA) and determining the mRNA expression of T-bet, GATA-3, forkhead/winged helix transcription factor (Foxp3), and receptor-related orphan receptor γt (RORγt) in peripheral blood mononuclear cells (PBMCs) by quantitative real-time PCR.


          We found that IL-17A/IL-10 and RORγt/Foxp3 ratios were significantly increased in the exacerbation group compared with that in the non-exacerbation group, while IL-4/IFN-γ and GATA-3/T-bet ratios remained unchanged. Moreover, IL-17A/IL-10 and RORγt/Foxp3 ratios, but not IL-4/IFN-γ or GATA-3/T-bet ratios, negatively correlated with forced expiratory volume in the first second (FEV 1)/FEV 1pred and Asthma Control Test Questionnaire (ACT) scores in both exacerbation group and non-exacerbation group. In contrast, the IL-4/IFN-γ ratio was negatively correlated with FEV 1/FEV 1pred and ACT scores only in the non-exacerbation group but not in the exacerbation group, while the ratio of GATA-3/T-bet was correlated with neither FEV 1/FEV 1pred nor ACT scores in both groups with asthma.


          Our results suggest that the homeostasis of the Treg and Th17 cells is broken in asthma exacerbation and correlates with asthma severity and disease control status. The outcome has significant implication in understanding the progression of asthma and providing helpful information for physicians in the diagnosis and treatment of asthma patients.

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          Most cited references 25

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          Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness.

          In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route and instead use intraperitoneal injections of allergen using aluminum hydroxide as an adjuvant. We investigated whether allergic sensitization through the airway elicits immune responses qualitatively different than those arising in the peritoneum. Mice were sensitized to allergen through the airway using low-dose LPS as an adjuvant, or through the peritoneum using aluminum hydroxide as an adjuvant. After a single allergen challenge, ELISA and flow cytometry were used to measure cytokines and leukocyte subsets. Invasive measurements of airway resistance were used to measure allergen-induced airway hyperreactivity (AHR). Sensitization through the peritoneum primed strong Th2 responses and eosinophilia, but not AHR, after a single allergen challenge. By contrast, allergic sensitization through the airway primed only modest Th2 responses, but strong Th17 responses. Th17 cells homed to the lung and released IL-17 into the airway on subsequent encounter with inhaled allergen. As a result, these mice developed IL-17-dependent airway neutrophilia and AHR. This AHR was neutrophil-dependent because it was abrogated in CXCR2-deficient mice and also in wild-type mice receiving a neutrophil-depleting antibody. Individually, neither IL-17 nor ongoing Th2 responses were sufficient to confer AHR, but together they acted synergistically to promote neutrophil recruitment, eosinophil recruitment and AHR. Allergic sensitization through the airway primes modest Th2 responses but strong Th17 responses that promote airway neutrophilia and acute AHR. These findings support a causal role for neutrophils in severe asthma.
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            An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation.

            CD4 T(h) are critical for orchestrating adaptive immune responses. The expression of the transcription factor GATA3 (GATA-binding protein 3) is up-regulated or down-regulated during T(h)2 or T(h)1 cell differentiation, respectively. Furthermore, GATA3 is responsible for induction of T(h)2 differentiation and represses T(h)1 differentiation. In this review, we present an updated view on the molecular mechanisms through which GATA3 regulates T(h)1/T(h)2 differentiation. During T(h)2 cell differentiation, GATA3 directly binds to the T(h)2 cytokine gene locus at several regions and regulates expression. On the other hand, GATA3 inhibits T(h)1 cell differentiation by preventing up-regulation of IL-12 receptor β2 and STAT4 (signal transducer and activator of transcription 4) and neutralization of Runx3 (runt-related transcription factor 3) function through protein-protein interaction. GATA3 may also directly act on the Ifng gene. In summary, GATA3 serves as a transcriptional activator or repressor through direct action on transcriptional machinery and/or affecting chromatin remodeling at many critical loci encoding cytokines, cytokine receptors, signaling molecules as well as transcription factors that are involved in the regulation of T(h)1 and T(h)2 differentiation.
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              Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling.

              The role of T-helper type 17 (Th17) responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization, followed by allergen inhalation, leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce tumor necrosis factor-α or interleukin (IL)-22. Eosinophilia predominated in acute inflammation, while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3-, Helios-, and glycoprotein-A repetitions predominant-expressing regulatory T cells (Treg) and IL-10/interferon-γ priming. This Treg phenotype was altered in inflamed lungs and abrogated by inhalation of IL-17. Using Th17-deficient mice with genetic disruption of gp130 in T cells, we showed that Th17 cells induce airway remodeling independent of the Th2 response. All-trans retinoic acid administration ameliorated Th17-mediated disease and increased Treg activity, while dexamethasone inhibited eosinophilia but not neutrophilia, and enhanced Th17 development in vitro. Targeting the Th17/Treg axis might therefore be therapeutic in neutrophilic and glucocorticoid-refractory asthma.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                06 September 2018
                : 14
                : 1627-1636
                [1 ]Department of Pulmonary Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China, zhtituli@ 123456163.com
                [2 ]Institute of Respiratory Disease of Sun Yat-Sen University, zhtituli@ 123456163.com
                [3 ]Department of Pediatrics Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China
                Author notes
                Correspondence: Tian-tuo Zhang, Department of Pulmonary Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, Guangdong Province 510630, People’s Republic of China, Email zhtituli@ 123456163.com

                These authors contributed equally to this work

                © 2018 Zou et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research


                th17/treg, bronchial asthma, t cell, exacerbation


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