Th2 cells promote eosinophil‐independent pathology in a murine model of allergic bronchopulmonary aspergillosis

Dietschmann, Axel; Schruefer, Sebastian; Krappmann, Sven; Voehringer, David

doi:10.1002/eji.201948411

Cited by 17 publications

(23 citation statements)

References 61 publications

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“…Dietschmann et al showed that in a mouse model of ABPA, T-cells released huge amounts of IL4, IL5 and IL13 upon stimulation with Aspergillus fumigatus conidia. They further demonstrated that T cell-specific IL4/IL13-deficient-knockout mice exhibited reduced peripheral and lung eosinophilia, suggesting that IL4 and IL13 signaling leads to recruitment of eosinophils to the lung and blood from the bone marrow [3].…”

Section: Discussionmentioning

confidence: 97%

“…Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to aspergillus species that predominantly affects cystic fibrosis and asthma patients [1]. Aspergillus colonization of the bronchial mucus leads to an activation of the innate immune system with a Th2predominant T cell response [2][3][4][5]. Clinical features of ABPA comprise frequent asthma exacerbations, productive cough, airway obstruction, fever, and finally leads to end-stage lung disease.…”

Section: Introductionmentioning

confidence: 99%

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Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?

Mümmler

Kemmerich²,

Behr

et al. 2020

Allergy Asthma Clin Immunol

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Background Allergic bronchopulmonary aspergillosis (ABPA) is a severe hypersensitivity reaction to aspergillus species colonizing the airways of patients with asthma or cystic fibrosis. Biologics including anti-IgE and anti-IL5 antibodies have strongly changed the treatment of severe asthmatics and have partly been reported to be effective in the treatment of ABPA. Recently, dupilumab, an anti-IL4-Rα antibody which inhibits signaling by the Th2-cytokines IL4 and IL13, has been approved for the treatment of severe asthma. Case presentation Here, we report the case of a 49-year-old woman with severe asthma and ABPA, who was uncontrolled despite maximum inhalative therapy, anti-IL5-Rα antibody and continuous oral steroid therapy. Moreover, trials of itraconazole as well as omalizumab showed insufficient efficacy. Lung function revealed peripheral obstruction. FeNO and IgE were increased, eosinophils were suppressed under treatment while marked increases had been documented previously. Switching to dupilumab led to a complete resolution of pulmonary symptoms, resolution of exacerbations and complete withdrawal of oral steroids. A drastic improvement in lung function was noted, with an increase in FEV1 of almost 1 l. FeNO was normalized and IgE strongly reduced. Conclusion Our case highlights that a patient may exhibit differential treatment responses to the currently available asthma biologics and suggests switching treatment if outcome is insufficient. A potential role for dupilumab in the treatment of ABPA warrants future studies.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?

Mümmler

Kemmerich²,

Behr

et al. 2020

Allergy Asthma Clin Immunol

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“…Other models of allergic aspergillosis have been described including one featuring repetitive intranasal instillation of live A . fumigatus conidia [ 55 ]. In that model, eosinophil-deficient mice had decreased expression of IL-17A.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, consistent with previously published data with ova and house dust mite induced allergies [31,54], the Siglec F + eosinophils could be divided into subpopulations based on relative expression levels of CD11c. Other models of allergic aspergillosis have been described including one featuring repetitive intranasal instillation of live A. fumigatus conidia [55]. In that model, eosinophil-deficient mice had decreased expression of IL-17A.…”

Section: Plos Pathogensmentioning

confidence: 99%

Lung eosinophils elicited during allergic and acute aspergillosis express RORγt and IL-23R but do not require IL-23 for IL-17 production

et al. 2021

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Exposure to the mold, Aspergillus, is ubiquitous and generally has no adverse consequences in immunocompetent persons. However, invasive and allergic aspergillosis can develop in immunocompromised and atopic individuals, respectively. Previously, we demonstrated that mouse lung eosinophils produce IL-17 in response to stimulation by live conidia and antigens of A. fumigatus. Here, we utilized murine models of allergic and acute pulmonary aspergillosis to determine the association of IL-23, IL-23R and RORɣt with eosinophil IL-17 expression. Following A. fumigatus stimulation, a population of lung eosinophils expressed RORɣt, the master transcription factor for IL-17 regulation. Eosinophil RORɣt expression was demonstrated by flow cytometry, confocal microscopy, western blotting and an mCherry reporter mouse. Both nuclear and cytoplasmic localization of RORɣt in eosinophils were observed, although the former predominated. A population of lung eosinophils also expressed IL-23R. While expression of IL-23R was positively correlated with expression of RORɣt, expression of RORɣt and IL-17 was similar when comparing lung eosinophils from A. fumigatus-challenged wild-type and IL23p19-/- mice. Thus, in allergic and acute models of pulmonary aspergillosis, lung eosinophils express IL-17, RORɣt and IL-23R. However, IL-23 is dispensable for production of IL-17 and RORɣt.

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“…Dietschmann et al concluded that T-cell-derived IL-4/IL-13 is essential for A . fumigatus -induced lung eosinophilia and inflammation, while eosinophils seem to have immunomodulatory and not only inflammatory function [ 33 ]. Taken together, these results suggest that the increased susceptibility of CF patients to ABPA might be due to an exaggerate Th2 response and a deficient Th1 response.…”

Section: Pathogenesis Of Aspergillus Fumigatus mentioning

confidence: 99%

Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis: An Update on the Newest Diagnostic Tools and Therapeutic Approaches

et al. 2020

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Cystic fibrosis (CF), the most common autosomal-recessive genetic disease in the Caucasian population, is characterized by frequent respiratory infections and progressive lung disease. Fungal species are commonly found in patients with CF, and among them, Aspergillus fumigatus is the most frequently isolated. While bacteria, particularly Pseudomonas aeruginosa, have a well-established negative effect on CF lung disease, the impact of fungal infections remains unclear. In patients with CF, inhalation of Aspergillus conidia can cause allergic bronchopulmonary aspergillosis (ABPA), a Th2-mediated lung disease that can contribute to disease progression. Clinical features, diagnostic criteria and treatment of ABPA are still a matter of debate. Given the consequences of a late ABPA diagnosis or the risk of ABPA overdiagnosis, it is imperative that the diagnostic criteria guidelines are reviewed and standardized. Along with traditional criteria, radiological features are emerging as tools for further classification as well as novel immunological tests. Corticosteroids, itraconazole and voriconazole continue to be the bedrock of ABPA therapy, but other molecules, such as posaconazole, vitamin D, recombinant INF-γ and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, have been showing positive results. However, few studies have been conducted recruiting CF patients, and more research is needed to improve the prevention and the classification of clinical manifestations as well as to personalize treatment. Early recognition and early treatment of fungal infections may be fundamental to prevent progression of CF disease. The aim of this narrative review is to give an update on ABPA in children with CF.

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Th2 cells promote eosinophil‐independent pathology in a murine model of allergic bronchopulmonary aspergillosis

Cited by 17 publications

References 61 publications

Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?

Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?

Lung eosinophils elicited during allergic and acute aspergillosis express RORγt and IL-23R but do not require IL-23 for IL-17 production

Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis: An Update on the Newest Diagnostic Tools and Therapeutic Approaches

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