Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients

Wawrzyniak, Paulina; Wawrzyniak, Marcin; Wanke, Kerstin; Sokołowska, Milena; Bendelja, Krešo; Rückert, Beate; Głobińska, Anna; Jakieła, Bogdan; Kast, Jeannette I.; Idzko, Marco; Akdiş, Mübeccel; Sanak, Marek

doi:10.1016/j.jaci.2016.03.050

Cited by 191 publications

(234 citation statements)

References 53 publications

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“…38,39 In air-liquid interface cultures containing bronchial epithelial cells obtained from asthmatic patients, IL-4 and IL-13 decreased TJ integrity by enhancing the production of enzymes that suppress gene transcription through histone modification (histone deacetylases, Fig 2). 40 Moreover, inhibition of histone deacetylase restored barrier integrity, thereby confirming the ability for a T H 2-rich milieu to modify the epithelial barrier through epigenetic effects. In other work, the IL-6 family member oncostatin M, levels of which are increased in bronchoalveolar lavage (BAL) fluid of allergic asthmatic patients, reduced airway epithelial integrity by disrupting TJ assembly but did not influence the production of TJ components.…”

Section: Innate Cytokines That Promote Th2-driven Asthma At the Epithmentioning

confidence: 79%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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Section: Innate Cytokines That Promote Th2-driven Asthma At the Epithmentioning

confidence: 79%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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“…Intestinal mucins and cytokines coming from epithelial cells and innate lymphoid cells contribute to tolerance by modifying the phenotype of gastrointestinal DC. In addition, mucosal epithelial barrier regulation may play an important role 75. Oral tolerance by early dietary introduction can prevent peanut allergy in infants at high risk of peanut allergy.…”

Section: Resultsmentioning

confidence: 99%

Role of Regulatory Cells in Oral Tolerance

Wawrzyniak

O’Mahony

Akdiş

2017

Allergy Asthma Immunol Res

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The immune system is continuously exposed to great amounts of different antigens from both food and intestinal microbes. Immune tolerance to these antigens is very important for intestinal and systemic immune homeostasis. Oral tolerance is a specific type of peripheral tolerance induced by exposure to antigen via the oral route. Investigations on the role of intestinal immune system in preventing hypersensitivity reactions to innocuous dietary and microbial antigens have been intensively performed during the last 2 decades. In this review article, we discuss how food allergens are recognized by the intestinal immune system and draw attention to the role of regulatory T (Treg) and B (Breg) cells in the establishment of oral tolerance and tolerogenic features of intestinal dendritic cells. We also emphasize the potential role of tonsils in oral tolerance induction because of their anatomical location, cellular composition, and possible usage to develop novel ways of specific immunotherapy for the treatment of allergic diseases.

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“…and monoclonal antibodies that block cytokine signaling or eliminate key allergic effector cells such as eosinophils and mast cells (IL-5, IL-13, IL-5Rα, IL-4/IL-13Rα, Siglec-8 etc.). The pursuit of barrier restorative therapies is another emerging field 152 . Based on the hypothesis advanced here that endocrine defects are important in disease pathogenesis, it will be worthwhile to test manipulation of signaling of other hormones (insulin, growth hormone, thyroid hormone etc.…”

Section: Targets For Therapeutic Interventionmentioning

confidence: 99%

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Schleimer

Berdnikovs

2017

Journal of Allergy and Clinical Immunology

141

122

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Epithelial barriers of the skin, gastrointestinal tract and airway serve common critical functions such as maintaining a physical barrier against environmental insults and allergens, as well as providing a tissue interface balancing the communication between the internal and external environments. We now understand that in allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed towards loss of differentiation, reduced junctional integrity and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in the initiation of allergic disease, many important questions remain to be answered regarding the mechanisms disrupting the normal barrier function. Although our external environment (proteases, allergens, injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction, using both systems biology tools and causality-driven laboratory experimentation, will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergy.

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Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients

Abstract: Our data demonstrate that barrier leakiness in asthmatic patients is induced by T2 cells, IL-4, and IL-13 and HDAC activity. The inhibition of endogenous HDAC activity reconstitutes defective barrier by increasing TJ expression.

Cited by 191 publications

References 53 publications

Pathogenic CD4 + T cells in patients with asthma

Pathogenic CD4 + T cells in patients with asthma

Role of Regulatory Cells in Oral Tolerance

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

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