Drivers of Type 2 Inflammation in Allergic Airway Disease: Wnt You Like to Know?

ABSTRACTAscaris lumbricoides(roundworm) is the most common helminth infection globally and a cause of lifelong morbidity that may include allergic airway disease, an asthma phenotype. We hypothesize thatAscarislarval migration through the lungs leads to persistent airway hyperresponsiveness (AHR) and type 2 inflammatory lung pathology despite resolution of infection that resembles allergic airway disease. Mice were infected withAscarisby oral gavage. Lung AHR was measured by plethysmography and histopathology with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) stains, and cytokine concentrations were measured by using Luminex Magpix.Ascaris-infected mice were compared to controls or mice with allergic airway disease induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA).Ascaris-infected mice developed profound AHR starting at day 8 postinfection (p.i.), peaking at day 12 p.i. and persisting through day 21 p.i., despite resolution of infection, which was significantly increased compared to controls and OVA/OVA mice.Ascaris-infected mice had a robust type 2 cytokine response in both the bronchoalveolar lavage (BAL) fluid and lung tissue, similar to that of the OVA/OVA mice, including interleukin-4 (IL-4) (P < 0.01 andP< 0.01, respectively), IL-5 (P < 0.001 andP < 0.001), and IL-13 (P < 0.001 andP < 0.01), compared to controls. By histopathology,Ascaris-infected mice demonstrated early airway remodeling similar to, but more profound than, that in OVA/OVA mice. We found thatAscarislarval migration causes significant pulmonary damage, including AHR and type 2 inflammatory lung pathology that resembles an extreme form of allergic airway disease. Our findings indicate that ascariasis may be an important cause of allergic airway disease in regions of endemicity.

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Does unified allergic airway disease impact on lung function and type 2 biomarkers?

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-019-0388-4 ◽

2019 ◽

Vol 15 (1) ◽

Author(s):

Chris RuiWen Kuo ◽

Rory Chan ◽

Brian Lipworth

Keyword(s):

Allergic Rhinitis ◽

Lung Function ◽

Allergic Asthma ◽

Asthma Control ◽

Persistent Asthma ◽

Airway Disease ◽

Allergic Airway Disease ◽

Positive Skin Prick Test ◽

Positive Skin

AbstractThe concept of the unified allergic airway disease (UAD) recognises the association between allergic inflammation in the upper and lower airways. Patients with asthma and concomitant allergic rhinitis experience more asthma-related primary and secondary care visits. We therefore aimed to determine differences in asthma control (asthma control questionnaire ACQ-6), lung function (spirometry) and T2 biomarkers (FeNO and Eos) in relation to the presence of allergic rhinitis in patients with allergic asthma. Retrospectively, we evaluated a cohort of 60 consecutive patients with persistent asthma attending our research unit for screening into clinical trials. All included subjects were receiving inhaled corticosteroids (ICS) and had a positive skin prick test (SPT) to at least one common aeroallergen to fulfil the criterion of allergic asthma. Patients with UAD had a diagnosis of allergic asthma in addition to established concomitant allergic rhinitis. T2 biomarkers were significantly higher in patients with allergic rhinitis in contrast to those without. FEV1 % predicted and FEF25-75 % predicted were also significantly lower in patients with concomitant allergic rhinitis. However, there was no difference in ACQ-6 observed between groups. In summary, patients with allergic asthma, the presence of concomitant allergic rhinitis is associated with worse lung function and higher type 2 biomarkers.

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Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease

Journal of Experimental Medicine ◽

10.1084/jem.20190865 ◽

2020 ◽

Vol 217 (9) ◽

Cited By ~ 3

Author(s):

Rod A. Rahimi ◽

Keshav Nepal ◽

Murat Cetinbas ◽

Ruslan I. Sadreyev ◽

Andrew D. Luster

Keyword(s):

Allergic Asthma ◽

Lung Parenchyma ◽

Airway Disease ◽

Gene Signature ◽

Allergic Airway Disease ◽

Transcriptional Analysis ◽

Th2 Cells ◽

Perivascular Inflammation

Memory CD4+ T helper type 2 (Th2) cells drive allergic asthma, yet the mechanisms whereby tissue-resident memory Th2 (Th2 Trm) cells and circulating memory Th2 cells collaborate in vivo remain unclear. Using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm cells and circulating memory Th2 cells perform nonredundant functions. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+ T cell recruitment. In contrast, Th2 Trm cells proliferated near airways and induced mucus metaplasia, airway hyperresponsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm cells and circulating memory Th2 cells share a core Th2 gene signature but also exhibit distinct transcriptional profiles. Th2 Trm cells express a tissue-adaptation signature, including genes involved in regulating and interacting with extracellular matrix. Our findings demonstrate that Th2 Trm cells and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.

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Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease

10.1101/250217 ◽

2018 ◽

Author(s):

F. I. Uwadiae ◽

C.J. Pyle ◽

S.A. Walker ◽

C.M. Lloyd ◽

J.A. Harker

Keyword(s):

T Cell ◽

Airway Disease ◽

Specific Ige ◽

Germinal Centre ◽

Allergic Airway Disease ◽

T Cell Subsets ◽

T Follicular Helper Cells ◽

Helper Cells ◽

Follicular Helper

ABSTRACTAllergic asthma is a disease of chronic airway inflammation and remodelling, characterised by a dysregulated type 2 response and allergen-specific IgE. T follicular helper cells (TFH) are critical to antibody production and have recently been implicated in allergic airway disease (AAD) pathogenesis. The role of TFH in established disease and the therapeutic potential of targeting them are however not fully understood. Using two aeroallergen driven murine models of chronic AAD, TFH were first identified in the lung draining lymph nodes but with prolonged exposure were present in the lung itself. Sustained allergen exposure led to the accumulation of TFH, and concomitant development of germinal centre B cells. Blockade of Inducible T cell co-stimulator (ICOS) signalling during established AAD depleted TFH without adversely affecting the differentiation of other CD4+ T cell subsets. This resulted in impaired germinal centre responses, reduced allergen specific IgE and ameliorated inflammation and airway hyper-responsiveness, including reduced pulmonary IL-13. TFH did not however appear to produce IL-13 directly, suggesting they indirectly promote type-2 inflammation in the lungs. These data show that TFH play a pivotal role in the regulation of AAD and that targeting the ICOS-L pathway could represent a novel therapeutic approach in this disease.

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Neonatal epithelial hypoxia inducible factor-1α expression regulates the response of the lung to experimental asthma

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00193.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. L455-L462 ◽

Cited By ~ 8

Author(s):

Krista K. Greenwood ◽

Steven P. Proper ◽

Yogesh Saini ◽

Lori A. Bramble ◽

Daven N. Jackson-Humbles ◽

...

Keyword(s):

Airway Resistance ◽

Hypoxia Inducible Factor ◽

Airway Disease ◽

Supplemental Oxygen ◽

Allergic Airway Disease ◽

T Helper ◽

Early Postnatal Development ◽

Hypoxia Inducible Factor 1Α ◽

Deficient Mice

Allergic airway disease is characterized by a T helper type 2 cell-mediated airway inflammation and airway hyperresponsiveness. Little is known about the role of hypoxia-mediated signaling in the progression of the disease. To address this knowledge gap, a mouse model was created in which doxycycline exposure induces the functional deletion of hypoxia inducible factor-1α from alveolar type II and Clara cells of the lung. When hypoxia inducible factor-1α deletion was induced during the early postnatal development period of the lung, the mice displayed an enhanced response to the ovalbumin model of allergic airway disease. These hypoxia inducible factor-1α-deficient mice exhibit increased cellular infiltrates, eosinophilia in the lavage fluid and parenchyma, and T helper type 2 cytokines, as compared with ovalbumin-treated control mice. Moreover, these hypoxia inducible factor-1α-deficient mice display increased airway resistance when compared with their control counterparts. Interestingly, if the loss of hypoxia inducible factor-1α was induced in early adulthood, the exacerbated phenotype was not observed. Taken together, these results suggest that epithelial hypoxia inducible factor-1α plays an important role in establishing the innate immunity of the lung and epithelial-specific deficiency in the transcription factor, during early postnatal development, increases the severity of inflammation and functional airway resistance, following ovalbumin challenge. Finally, these results might explain some of the chronic respiratory pathology observed in premature infants, especially those that receive supplemental oxygen. This early hyperoxic exposure, from normal ambient and supplemental oxygen, would presumably inhibit normal hypoxia inducible factor-1α signaling, mimicking the functional deletion described.

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Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life

eLife ◽

10.7554/elife.67740 ◽

2021 ◽

Vol 10 ◽

Author(s):

Rozlyn CT Boutin ◽

Charisse Petersen ◽

Sarah E Woodward ◽

Antonio Serapio-Palacios ◽

Tahereh Bozorgmehr ◽

...

Keyword(s):

Gut Microbiota ◽

Airway Disease ◽

Short Chain Fatty Acids ◽

Allergic Airway Disease ◽

Causal Association ◽

Pichia Kudriavzevii ◽

Asthma Risk ◽

Fungal Microbiota ◽

Fungal Interactions

Bacterial members of the infant gut microbiota and bacterial-derived short-chain fatty acids (SCFAs) have been shown to be protective against childhood asthma, but a role for the fungal microbiota in asthma etiology remains poorly defined. We recently reported an association between overgrowth of the yeast Pichia kudriavzevii in the gut microbiota of Ecuadorian infants and increased asthma risk. In the present study, we replicated these findings in Canadian infants and investigated a causal association between early life gut fungal dysbiosis and later allergic airway disease (AAD). In a mouse model, we demonstrate that overgrowth of P. kudriavzevii within the neonatal gut exacerbates features of type-2 and -17 inflammation during AAD later in life. We further show that P. kudriavzevii growth and adherence to gut epithelial cells are altered by SCFAs. Collectively, our results underscore the potential for leveraging inter-kingdom interactions when designing putative microbiota-based asthma therapeutics.

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The role of eosinophilopoietins and integrins on eosinophils biology in asthma

Pulmonology and allergology ◽

10.37499/pia.116 ◽

2020 ◽

Vol 4 (2) ◽

Author(s):

Jolita Palacionyte ◽

Andrius Januškevičius ◽

Kęstutis Malakauskas

Keyword(s):

Biological Significance ◽

Airway Disease ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Inflammatory Airway Disease ◽

Macrophage Colony ◽

Stimulating Factor ◽

Type 2 Inflammation

Asthma is a chronic inflammatory airway disease that affects about 300 million peopleworldwide, and the incidence is continuously increasing. Patientswith asthma aremost commonly diagnosedwith type 2 inflammation,which is characterized by eosinophilia, which is an increased amount of eosinophils in the blood and airways. Asthma with predominant eosinophilic inflammation is characterized by amore severe course of the disease,more frequent exacerbations, andmore intense symptoms. To reduce symptoms, facilitate the course of the disease, and treat asthma more effectively is important to understand asthma pathogenesis better. Eosinophils survivalmaturation, activation, and quantity in the lungs are promoted by cytokines, of which eosinophilopoietins – interleukin (IL) 3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are themost important. Eosinophilia is also associated with the activation of integrins present on the surface of eosinophils. Integrins areresponsible for eosinophils adhesion to airway structural cells, thus prolonging their survival leading to more intense airway eosinophilia. Eosinophilopoietins, their receptors, and integrins might be suitable targets reducing eosinophilia in blood and airway, as well as airway inflammation.Humanizedmonoclonal antibodies are used for this purpose. Biological therapy allows for the specific inhibition of relevant asthma pathways and offers patients individualized treatment. This review will discuss the biological significance of eosinophilopoietins and their receptors, integrins on eosinophils functions, anti-cytokine and anti-integrin therapy efficiency in asthma.

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