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Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 43420

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Prof. Dr. Hiroaki Kume

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Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kindai University, Osakasayama 589-8511, Japan
Interests: respiratory medicine; allergy and pharmacology; β2-aderenergic agonists; muscarinic receptor antagonists; airway smooth muscle
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Yoshihiko Chiba

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Laboratory of Molecular Biology and Physiology, Hoshi University, Tokyo, Japan
Interests: allergic bronchial asthma; airway hyperresponsiveness; smooth muscle; allergic rhinitis
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Asthma and related respiratory tract allergic diseases (allergic rhinitis, sinusitis) are one of the most common chronic diseases among adults and children. However, the disease course is still difficult to be predicted, and the treatment remains non-specific and potentially hazardous. Allergic airway diseases are characterized by T-helper type 2 (Th2)-skewed eosinophilic inflammation, mucus hypersecretion as well as airway hyperresponsiveness. In addition, in the initiation and development of allergic airway disease, excessive activation of Th2 cells due to insufficient suppression of regulatory T cells (Tregs) is thought to play a key role. An improved understanding of the fundamental factors that initiate allergic inflammation, especially Th2 cell induction, may lead an improved clinical management of these diseases. Human monoclonal antibodies against IgE and IL-5 have been used clinically; however, there are still many problems to advance the therapy towards a cure for these diseases. Not only scientific but also clinical approaches are needed to achieve this objective.

This Special Issue will focus on, but not limited to, recent advances across the developmental spectrum on the mechanisms underlying allergic airways diseases, including molecular immunology, pathogenesis, inflammation, the role of genetic and environmental factors.

Prof. Dr. Hiroaki Kume
Prof. Dr. Yoshihiko Chiba
Guest Editors

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Keywords

Asthma
Allergic airway disease (allergic rhinitis, sinusitis)
Airway smooth muscle
Airway hyperresponsiveness
Eosinophil inflammation
Mast cells
Cytokines
Ca²⁺ signaling
Mucus hypersecretion
Ion channel
Airway eosinophilia
Immune
IgE
Genetic
Environmental factors

Related Special Issue

Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (10 papers)

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Research

Jump to: Review

15 pages, 2682 KiB

Open AccessArticle

Downregulation of miR-140-3p Contributes to Upregulation of CD38 Protein in Bronchial Smooth Muscle Cells

by Yoshihiko Chiba, Mayumi Matsumoto, Motohiko Hanazaki and Hiroyasu Sakai

Int. J. Mol. Sci. 2020, 21(21), 7982; https://doi.org/10.3390/ijms21217982 - 27 Oct 2020

Cited by 5 | Viewed by 2086

Abstract

In allergic bronchial asthma, an increased smooth muscle contractility of the airways is one of the causes of the airway hyperresponsiveness (AHR). Increasing evidence also suggests a possible involvement of microRNAs (miRNAs) in airway diseases, including asthma, although their roles in function and pathology largely unknown. The current study aimed to determine the role of a miRNA, miR-140-3p, in the control of protein expression of CD38, which is believed to regulate the contraction of smooth muscles, including the airways. In bronchial smooth muscles (BSMs) of the mice that were actively sensitized and repeatedly challenged with ovalbumin antigen, an upregulation of CD38 protein concurrently with a significant reduction of miR-140-3p was observed. In cultured human BSM cells (hBSMCs), transfection with a synthetic miR-140-3p inhibitor caused an increase in CD38 protein, indicating that its basal protein expression is regulated by endogenous miR-140-3p. Treatment of the hBSMCs with interleukin-13 (IL-13), an asthma-related cytokine, caused both an upregulation of CD38 protein and a downregulation of miR-140-3p. Transfection of the hBSMCs with miR-140-3p mimic inhibited the CD38 protein upregulation induced by IL-13. On the other hand, neither a CD38 product cyclic ADP-ribose (cADPR) nor its antagonist 8-bromo-cADPR had an effect on the BSM contraction even in the antigen-challenged mice. Taken together, the current findings suggest that the downregulation of miR-140-3p induced by IL-13 might cause an upregulation of CD38 protein in BSM cells of the disease, although functional and pathological roles of the upregulated CD38 are still unclear. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation 2.0)

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15 pages, 2440 KiB

Open AccessArticle

Acid Stripping of Surface IgE Antibodies Bound to FcεRI Is Unsuitable for the Functional Assays That Require Long-Term Culture of Basophils and Entire Removal of Surface IgE

by Caroline Galeotti, Anupama Karnam, Mrinmoy Das, Srini V. Kaveri and Jagadeesh Bayry

Int. J. Mol. Sci. 2020, 21(2), 510; https://doi.org/10.3390/ijms21020510 - 13 Jan 2020

Cited by 5 | Viewed by 3400

Abstract

Basophils are rare granulocytes and dysregulated functions of these cells are associated with several atopic and non-atopic allergic diseases of skin, respiratory system and gastrointestinal tract. Both cytokines and immunoglobulin E (IgE) are implicated in mediating the basophil activation and pathogenesis of these disorders. Several reports have shown that healthy individuals, and patients with allergic disorders display IgG autoantibodies to IgE and hence functional characterization of these anti-IgE IgG autoantibodies is critical. In general, anti-IgE IgG autoantibodies modulate basophil activation irrespective of allergen specificity by interacting with constant domains of IgE. Therefore, an ideal solution to prove the functions of such anti-IgE IgG autoantibodies would be to completely eliminate type I high affinity immunoglobulin E receptor (FcɛRI)-bound IgE from the surface of basophils and to demonstrate in an unequivocal manner the role of anti-IgE IgG autoantibodies. In line with previous reports, our data show that FcɛRI on peripheral blood basophils are almost saturated with IgE. Further, acetic acid buffer (pH 4) efficiently removes these FcɛRI-bound IgE. Although immediately following acetic acid-elution of IgE had no repercussion on the viability of basophils, following 24 h culture with interleukin-3 (IL-3), the viability and yield of basophils were drastically reduced in acid-treated cells and had repercussion on the induction of activation markers. Lactic acid treatment on the other hand though had no adverse effects on the viability of basophils and IL-3-induced activation, it removed only a small fraction of the cell surface bound IgE. Thus, our results show that acid buffers could be used for the elution of FcɛRI-bound IgE on the basophil surface for the biochemical characterization of IgE antibodies or for the immediate use of basophils to determine their sensitivity to undergo degranulation by specific allergens. However, these methods are not utile for the functional assays of basophils that require longer duration of culture and entire removal of surface IgE to validate the role of anti-IgE IgG autoantibodies that interact with FcɛRI-bound IgE irrespective of allergen specificity. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation 2.0)

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20 pages, 14388 KiB

Open AccessArticle

IgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling

by Lei Fang, Xinggang Wang, Qingzhu Sun, Eleni Papakonstantinou, Chongteck S’ng, Michael Tamm, Daiana Stolz and Michael Roth

Int. J. Mol. Sci. 2019, 20(4), 875; https://doi.org/10.3390/ijms20040875 - 18 Feb 2019

Cited by 45 | Viewed by 5048

Abstract

The patho-mechanism leading to airway wall remodeling in allergic asthma is not well understood and remodeling is resistant to therapies. This study assessed the effect of immunoglobulin E (IgE) in the absence of allergens on human primary airway smooth muscle cell (ASMC) remodeling in vitro. ASMCs were obtained from five allergic asthma patients and five controls. Proliferation was determined by direct cell counts, mitochondrial activity by expression of cytochrome c, protein expression by immunoblotting and immuno-fluorescence, cell migration by microscopy imaging, and collagen deposition by cell based ELISA and RNA expression by real time PCR. Non-immune IgE activated two signaling pathways: (i) signal transducer and activator of transcription 3 (STAT3)→miR-21-5p→downregulating phosphatase and tensin homolog (PTEN) expression, and (ii) phosphatidylinositol 3-kinases (PI3K)→protein kinase B (Akt)→mammalian target of rapamycin (mTOR)→ribosomal protein S6 kinase beta-1 (p70s6k)→peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α)→peroxisome proliferator-activated receptor-γ (PPAR-γ)→cyclooxygenase-2 (COX-2)→mitochondrial activity, proliferation, migration, and extracellular matrix deposition. Reduced PTEN expression correlated with enhanced PI3K signaling, which upregulated ASMC remodeling. The inhibition of microRNA-21-5p increased PTEN and reduced mTOR signaling and remodeling. Mimics of microRNA-21-5p had opposing effects. IgE induced ASMC remodeling was significantly reduced by inhibition of mTOR or STAT3. In conclusion, non-immune IgE alone is sufficient for stimulated ASMC remodeling by upregulating microRNA-21-5p. Our findings suggest that the suppression of micoRNA-21-5p may present a therapeutic target to reduce airway wall remodeling. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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11 pages, 2516 KiB

Open AccessArticle

Prostaglandin D₂ Induces Ca²⁺ Sensitization of Contraction without Affecting Cytosolic Ca²⁺ Level in Bronchial Smooth Muscle

by Wataru Suto, Yusuke Ando, Takahiro Hirabayashi, Fumiko Takenoya, Seiji Shioda, Junzo Kamei, Hiroyasu Sakai and Yoshihiko Chiba

Int. J. Mol. Sci. 2018, 19(10), 3036; https://doi.org/10.3390/ijms19103036 - 05 Oct 2018

Cited by 5 | Viewed by 3389

Abstract

Prostaglandin D₂ (PGD₂) is one of the key lipid mediators of allergic airway inflammation, including bronchial asthma. However, the role of PGD₂ in the pathogenesis of asthma is not fully understood. In the present study, the effect of PGD₂ on smooth muscle contractility of the airways was determined to elucidate its role in the development of airway hyperresponsiveness (AHR). In isolated bronchial smooth muscles (BSMs) of naive mice, application of PGD₂ (10⁻⁹–10⁻⁵ M) had no effect on the baseline tension. However, when the tissues were precontracted partially with 30 mM K⁺ (in the presence of 10⁻⁶ M atropine), PGD₂ markedly augmented the contraction induced by the high K⁺ depolarization. The PGD₂-induced augmentation of contraction was significantly inhibited both by 10⁻⁶ M laropiprant (a selective DP₁ antagonist) and 10⁻⁷ M Y-27632 (a Rho-kinase inhibitor), indicating that a DP₁ receptor-mediated activation of Rho-kinase is involved in the PGD₂-induced BSM hyperresponsiveness. Indeed, the GTP-RhoA pull-down assay revealed an increase in active form of RhoA in the PGD₂-treated mouse BSMs. On the other hand, in the high K⁺-depolarized cultured human BSM cells, PGD₂ caused no further increase in cytosolic Ca²⁺ concentration. These findings suggest that PGD₂ causes RhoA/Rho-kinase-mediated Ca²⁺ sensitization of BSM contraction to augment its contractility. Increased PGD₂ level in the airways might be a cause of the AHR in asthma. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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Review

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15 pages, 848 KiB

Open AccessReview

Role of CD4⁺ T Cells in Allergic Airway Diseases: Learning from Murine Models

by Kento Miura, Kimiko Inoue, Atsuo Ogura and Osamu Kaminuma

Int. J. Mol. Sci. 2020, 21(20), 7480; https://doi.org/10.3390/ijms21207480 - 11 Oct 2020

Cited by 12 | Viewed by 3199

Abstract

The essential contribution of CD4⁺ T cells in allergic airway diseases has been demonstrated, especially by using various murine models of antigen-induced airway inflammation. In addition to antigen-immunized mouse models employing mast cell-deficient mice and CD4⁺ T cell-depleting procedure, antigen-specific CD4⁺ T cell transfer models have revealed the possible development of allergic inflammation solely dependent on CD4⁺ T cells. Regardless of the classical Th1/Th2 theory, various helper T cell subsets have the potential to induce different types of allergic inflammation. T cell receptor (TCR)-transgenic (Tg) mice have been used for investigating T cell-mediated immune responses. Besides, we have recently generated cloned mice from antigen-specific CD4⁺ T cells through somatic cell nuclear transfer. In contrast to TCR-Tg mice that express artificially introduced TCR, the cloned mice express endogenously regulated antigen-specific TCR. Upon antigen exposure, the mite antigen-reactive T cell-cloned mice displayed strong airway inflammation accompanied by bronchial hyperresponsiveness in a short time period. Antigen-specific CD4⁺ T cell-cloned mice are expected to be useful for investigating the detailed role of CD4⁺ T cells in various allergic diseases and for evaluating novel anti-allergic drugs. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation 2.0)

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18 pages, 1131 KiB

Open AccessReview

Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management

by Jae Seok Jeong, Jong Seung Kim, So Ri Kim and Yong Chul Lee

Int. J. Mol. Sci. 2019, 20(14), 3525; https://doi.org/10.3390/ijms20143525 - 18 Jul 2019

Cited by 17 | Viewed by 5490

Abstract

Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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17 pages, 844 KiB

Open AccessReview

Multi-Faceted Notch in Allergic Airway Inflammation

by Miao-Tzu Huang, Chiao-Juno Chiu and Bor-Luen Chiang

Int. J. Mol. Sci. 2019, 20(14), 3508; https://doi.org/10.3390/ijms20143508 - 17 Jul 2019

Cited by 15 | Viewed by 3438

Abstract

Notch is an evolutionarily conserved signaling family which iteratively exerts pleiotropic functions in cell fate decisions and various physiological processes, not only during embryonic development but also throughout adult life. In the context of the respiratory system, Notch has been shown to regulate ciliated versus secretory lineage differentiation of epithelial progenitor cells and coordinate morphogenesis of the developing lung. Reminiscent of its role in development, the Notch signaling pathway also plays a role in repair of lung injuries by regulation of stem cell activity, cell differentiation, cell proliferation and apoptosis. In addition to functions in embryonic development, cell and tissue renewal and various physiological processes, including glucose and lipid metabolism, Notch signaling has been demonstrated to regulate differentiation of literally almost all T-cell subsets, and impact on elicitation of inflammatory response and its outcome. We have investigated the role of Notch in allergic airway inflammation in both acute and chronic settings. In this mini-review, we will summarize our own work and recent advances on the role of Notch signaling in allergic airway inflammation, and discuss potential applications of the Notch signaling family in therapy for allergic airway diseases. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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16 pages, 1294 KiB

Open AccessReview

Potential Mechanisms of T Cell-Mediated and Eosinophil-Independent Bronchial Hyperresponsiveness

by Mayumi Saeki, Tomoe Nishimura, Noriko Kitamura, Takachika Hiroi, Akio Mori and Osamu Kaminuma

Int. J. Mol. Sci. 2019, 20(12), 2980; https://doi.org/10.3390/ijms20122980 - 18 Jun 2019

Cited by 13 | Viewed by 4569

Abstract

Bronchial asthma is a chronic disease characterized by reversible airway obstruction, mucus production, and bronchial hyperresponsiveness (BHR). Although Th2 cell-mediated eosinophilic inflammation is an important disease mechanism in the majority of patients with bronchial asthma, recent studies suggest the possible development of Th2-independent airway inflammation and BHR. These non-Th2 endotype patients seem to consist of multiple subgroups, and often do not respond to inhaled corticosteroids. Therefore, to understand the pathogenesis of asthma, it is important to characterize these non-Th2 subgroups. Recently, we demonstrated that Th9 cells induce eosinophil infiltration and eosinophil-independent BHR, and Th9 cells-mediated BHR may be resistant to glucocorticoid. In this review, we summarize the contribution of several T cell subsets in the development of bronchial asthma and introduce our recent study demonstrating Th9 cell-mediated and eosinophil-independent BHR. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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13 pages, 531 KiB

Open AccessReview

Recent Advances in Inflammation and Treatment of Small Airways in Asthma

by Elisabetta Zinellu, Barbara Piras, Giulia G. M. Ruzittu, Sara S. Fois, Alessandro G. Fois and Pietro Pirina

Int. J. Mol. Sci. 2019, 20(11), 2617; https://doi.org/10.3390/ijms20112617 - 28 May 2019

Cited by 23 | Viewed by 4530

Abstract

Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few years we have learned that they are not so “silent”. Asthma is still a worldwide health issue due to the great share of patients being far from optimal management. Several studies have shown that the deeper lung inflammation plays a critical role in asthma pathogenesis, mostly in these not well-controlled subjects. Therefore, assessing the degree of small airways inflammation and impairment appears to be a pivotal step in the asthmatic patient’s management. It is now possible to evaluate them through direct and indirect measurements, even if some obstacles still affect their clinical application. The success of any treatment obviously depends on several factors but reaching the deeper lung has become a priority and, for inhaled drugs, this is strictly connected to the molecule’s size. The aim of the present review is to summarize the recent evidence concerning the small airway involvement in asthma, its physiopathological characteristics and how it can be evaluated in order to undertake a personalized pharmacological treatment and achieve a better disease control. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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12 pages, 750 KiB

Open AccessReview

The Role of the Microbiome in Asthma: The Gut–Lung Axis

by Franco Frati, Cristina Salvatori, Cristoforo Incorvaia, Alessandro Bellucci, Giuseppe Di Cara, Francesco Marcucci and Susanna Esposito

Int. J. Mol. Sci. 2019, 20(1), 123; https://doi.org/10.3390/ijms20010123 - 30 Dec 2018

Cited by 163 | Viewed by 16112

Abstract

Asthma is one of the most common chronic respiratory diseases worldwide. It affects all ages but frequently begins in childhood. Initiation and exacerbations may depend on individual susceptibility, viral infections, allergen exposure, tobacco smoke exposure, and outdoor air pollution. The aim of this review was to analyze the role of the gut–lung axis in asthma development, considering all asthma phenotypes, and to evaluate whether microbe-based therapies may be used for asthma prevention. Several studies have confirmed the role of microbiota in the regulation of immune function and the development of atopy and asthma. These clinical conditions have apparent roots in an insufficiency of early life exposure to the diverse environmental microbiota necessary to ensure colonization of the gastrointestinal and/or respiratory tracts. Commensal microbes are necessary for the induction of a balanced, tolerogenic immune system. The identification of commensal bacteria in both the gastroenteric and respiratory tracts could be an innovative and important issue. In conclusion, the function of microbiota in healthy immune response is generally acknowledged, and gut dysbacteriosis might result in chronic inflammatory respiratory disorders, particularly asthma. Further investigations are needed to improve our understanding of the role of the microbiome in inflammation and its influence on important risk factors for asthma, including tobacco smoke and host genetic features. Full article

(This article belongs to the Special Issue Allergic Airway Disease: Molecular Immunology, Pathogenesis and Inflammation)

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