Chronic House Dust Mite Exposure Research Articles

Chronic HDM exposure shows time-of-day and sex-based differences in inflammatory response associated with lung circadian clock disruption

Circadian rhythms and sex differences are involved in the pathophysiology of asthma. Yet, there are no reports that simultaneously address the role of the circadian clock and sex-based differences in chronic house dust mite (HDM)-induced asthma. Here, we sought to determine if chronic HDM exposure during the resting phase (zeitgeber time: ZT0/6:00 a.m.) versus the active phase (ZT12/6:00 p.m.) differentially affects the circadian clock and alters asthma pathobiology in female and male mice. HDM exposure at ZT12 exaggerated infiltration of eosinophil subtypes and associated chemokines in females compared to males. Furthermore, HDM exposure augmented eosinophil chemokines, Th2 gene expression and cytokine release, and humoral immune response in females compared to males at ZT12. Concurrently, histopathological evaluation confirmed increased airway inflammation at ZT12 in both females and males. Overall, we showed a time-of-day response and sex-based differences in HDM-induced exaggerated asthmatic phenotypes (inflammation/remodeling) and circadian clock disruption in females compared to males.

CD200Fc limits dendritic cell and B-cell activation during chronic allergen exposures.

Allergic asthma is a chronic inflammatory disease characterized by Th2, conventional dendritic cell, and B-cell activation. In addition to excessive inflammation, asthma pathogenesis includes dysregulation of anti-inflammatory pathways, such as the CD200/CD200R pathway. Thus, we investigated whether a CD200R agonist, CD200Fc, could disrupt the inflammatory cascade in chronic allergic asthma pathogenesis using a mice model of experimental asthma. Mice were exposed to house dust mites for 5 wk, and CD200Fc treatment was initiated after chronic inflammation was established (starting on week 4). We demonstrate that chronic house dust mite exposure altered CD200 and CD200R expression on lung immune cell populations, including upregulation of CD200 on alveolar macrophages and reduced expression of CD200 on conventional dendritic cells. CD200Fc treatment does not change bronchoalveolar cellular infiltration, but it attenuates B-cell activation and skews the circulating immunoglobulin profile toward IgG2a. This is accompanied by reduced activation of conventional dendritic cells, including lower expression of CD40, especially on conventional dendritic cell subset 2 CD200R+. Furthermore, we confirm that CD200Fc can directly modulate conventional dendritic cell activation in vitro using bone marrow-derived dendritic cells. Thus, the CD200/CD200R pathway is dysregulated during chronic asthma pathogenesis, and the CD200R agonist modulates B-cell and dendritic cell activation but, in our chronic model, is not sufficient to alter inflammation measured in bronchoalveolar lavage.

Targeting TL1A/DR3 Signaling Offers a Therapeutic Advantage to Neutralizing IL13/IL4Rα in Muco-Secretory Fibrotic Disorders.

Mucus secretion is an important feature of asthma that highly correlates with morbidity. Current therapies, including administration of mucolytics and anti-inflammatory drugs, show limited effectiveness and durability, underscoring the need for novel effective and longer lasting therapeutic approaches. Here we show that mucus production in the lungs is regulated by the TNF superfamily member 15 (TL1A) acting through the mucus–inducing cytokine IL-13. TL1A induces IL13 expression by innate lymphoid cells leading to mucus production, in addition to promoting airway inflammation and fibrosis. Reciprocally, neutralization of IL13 signaling through its receptor (IL4Rα), completely reverses TL1A-induced mucus secretion, while maintaining airway inflammation and fibrosis. Importance of TL1A is further demonstrated using a preclinical asthma model induced by chronic house dust mite exposure where TL1A neutralization by genetic deletion or antagonistic blockade of its receptor DR3 protected against mucus production and fibrosis. Thus, TL1A presents a promising therapeutic target that out benefits IL13 in reversing mucus production, airway inflammation and fibrosis, cardinal features of severe asthma in humans.

Physiologic response to chronic house dust mite exposure in mice is dependent on lot characteristics

Physiologic response to chronic house dust mite exposure in mice is dependent on lot characteristics

Downregulation of semaphorin 3E promotes hallmarks of experimental chronic allergic asthma.

Guidance cues such as semaphorins are attractive novel therapeutic targets for allergic disorders. We have previously described an inhibitory effect of semaphorin 3E (Sema3E) on human airway smooth muscle cell function. We have further addressed a canonical role for Sema3E in acute model of allergic asthma in vivo. Considering the chronic nature of the disease, the potential implication of Sema3E to alleviate long-lasting deficits should be investigated. Expression of Sema3E in a chronic model of allergic asthma was assessed after exposure to house dust mite (HDM) as a clinically relevant allergen. Chronic features of allergic asthma including airway hyper-responsiveness (AHR), inflammation, and remodeling were studied in Sema3E-deficient mice. Additionally, the effect of exogenous Sema3E treatment was evaluated in prophylactic and therapeutic experimental models. We have demonstrated that expression of Sema3E is robustly suppressed in the airways upon chronic HDM exposure. Chronic allergic airway disease was significantly augmented in Sema3E-deficient mouse model which was associated with an increased AHR, remodeling, and Th2/Th17 inflammation. Intranasal Sema3E administration restored chronic deficits of allergic asthma in mice. Data from this study unveil a key regulatory role of Sema3E in chronic course of asthma via orchestration of impaired inflammatory and remodeling responses.

Lung CD103+ dendritic cells restrain allergic airway inflammation through IL-12 production.

DCs are necessary and sufficient for induction of allergic airway inflammation. CD11b+ DCs direct the underlying Th2 immunity, but debate surrounds the function of CD103+ DCs in lung immunity and asthma after an allergic challenge. We challenged Batf3-/- mice, which lacked lung CD103+ DCs, with the relevant allergen house dust mite (HDM) as a model to ascertain their role in asthma. We show that acute and chronic HDM exposure leads to defective Th1 immunity in Batf3-deficient mice. In addition, chronic HDM challenge in Batf3-/- mice results in increased Th2 and Th17 immune responses and exacerbated airway inflammation. Mechanistically, Batf3 absence does not affect induction of Treg or IL-10 production by lung CD4+ T cells following acute HDM challenge. Batf3-dependent CD103+ migratory DCs are the main source of IL-12p40 in the mediastinal lymph node DC compartment in the steady state. Moreover, CD103+ DCs selectively increase their IL-12p40 production upon HDM administration. In vivo IL-12 treatment reverts exacerbated allergic airway inflammation upon chronic HDM challenge in Batf3-/- mice, restraining Th2 and Th17 responses without triggering Th1 immunity. These results suggest a protective role for lung CD103+ DCs to HDM allergic airway inflammation through the production of IL-12.

Development of eosinophilic inflammation is independent of B-T cell interaction in a chronic house dust mite-driven asthma model.

Chronic exposure to environmental triggers, such as house dust mite (HDM), drives T helper 2 (Th2) cell-mediated asthma. Recent evidence has shown that B-T cell interaction, and in particular germinal centre reactions and follicular T helper (Tfh) cells are required for the development of eosinophilic airway inflammation in HDM-driven models containing a sensitization and challenge phase. Whether B-T cell interactions are essential for pulmonary eosinophilic inflammation following chronic allergen provocation remains unknown. In this study, we investigated the importance of B-T cell interaction in the development of eosinophilic airway inflammation and pulmonary remodelling in a chronic HDM-driven asthma model. We exposed C57BL/6, Cd40l-/- , and Mb1-/- mice to HDM three times a week for five consecutive weeks. Chronic HDM exposure induced a pronounced eosinophilic allergic airway inflammation in broncho-alveolar lavage fluid (BALf) and lung tissue, associated with the formation of immunologically active inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. The absence of B cells or lack of CD40L signalling did not hamper eosinophilic inflammation in the airways, although the number of Tfh and Th2 cells was substantially reduced in the lungs. Importantly, type 2 innate lymphoid cell (ILC2) numbers in BALf and lung were not affected by the absence of B cells or B-T cell interaction. Furthermore, eosinophilic airway inflammation is not sufficient to induce pulmonary remodelling and airway hyperresponsiveness. From these findings, we conclude that B-T cell interaction is required for robust Tfh and Th2 cell induction, but not essential for eosinophilic airway inflammation during a chronic HDM-driven asthma model.

Induction of immunological tolerance by pulmonary macrophages during chronic exposure to house dust mite antigen (P6212)

Abstract Allergic asthma is a leading cause of morbidity in industrialized nations. While the emphasis of most studies pertaining to the attenuation of asthma after chronic antigen exposure has focused on the local generation of Tregs, little attention has been paid to the potentially crucial role of pulmonary macrophages (MΦ) in disease resolution. To determine whether these MΦ are involved in tolerance generation, C57BL/6 mice were challenged intranasally with house dust mite (HDM) extract both acutely (2 and 5 weeks) and chronically (11 weeks) to induce an asthma-like phenotype (n=3-6 per group). Compared to acutely-challenged mice, MΦ frequency increased over two-fold in the airways of chronic HDM-exposed mice (P<0.001). This finding correlated with increases in local Foxp3+ Tregs as well as resolution of pulmonary eosinophilia (P<0.01) and airway hyper-reactivity (P<0.01). Flow cytometric analysis of naïve IL-10 GFP mice confirmed that pulmonary MΦ produce high amounts of IL-10. Following chronic HDM exposure, these MΦ may expand in the lungs and influence tolerance development directly through IL-10 or indirectly through effects on Tregs. We also observed 3- to 7-fold increases in serum MCP-1, MIP-1α, and MIP-1β following chronic but not acute HDM exposure, which suggests that these MΦ are derived from monocytes recruited to the site of inflammation. Collectively, these data suggest a novel role for pulmonary MΦ in the generation of tolerance in an experimental model of asthma.

Eosinophils Are Dispensable for Allergic Remodeling and Immunity in a Model of House Dust Mite–induced Airway Disease

Current thinking accredits eosinophils with preeminent contributions to allergic airway responses, including a major role in the development of airway remodeling, a process thought to significantly contribute to airway dysfunction. However, direct evidence in support of this notion is limited and often controversial. We elucidated the requirement for eosinophils in the generation of allergic sensitization, airway inflammation, and remodeling in a model involving chronic respiratory exposure to house dust mite (HDM). We used three methods to selectively eliminate eosinophils, a depleting antibody (anti-CCR3), and two strains of eosinophil-deficient mice (ΔdblGATA and the transgenic line PHIL). Anti-CCR3 treatment markedly reduced pulmonary eosinophilia (> 80%) over the course of HDM exposure but had no effect on the remaining inflammatory response, the extent of lung Th2 cells, or the development of remodeling-associated changes, including subepithelial collagen deposition and smooth muscle thickening. In addition, we observed that, despite the absence of eosinophils, HDM-exposed GATA mice mounted robust airway and lung inflammation and hyperresponsiveness and showed a remodeling response equivalent to that observed in wild-type mice. Moreover, these mice had similar serum HDM-specific IgE levels and Th2-associated splenocyte cytokine production as HDM-exposed wild-type control mice. Similar observations were made in PHIL eosinophil-deficient mice subjected to chronic HDM exposure, although slight decreases in airway mononuclear cells, but not lung Th2 cells, and remodeling were noted. Collectively, these data demonstrate that, at variance with the prevailing paradigm, eosinophils play negligible roles in the generation of HDM-induced allergic immunity and airway remodeling.

Induction of Vascular Remodeling in the Lung by Chronic House Dust Mite Exposure

Structural changes to the lung are associated with chronic asthma. In addition to alterations to the airway wall, asthma is associated with vascular modifications, although this aspect of remodeling is poorly understood. We sought to evaluate the character and kinetics of vascular remodeling in response to chronic aeroallergen exposure. Because many ovalbumin-driven models used to investigate allergic airway disease do so in the absence of persistent airway inflammation, we used a protocol of chronic respiratory exposure to house dust mite extract (HDME), which has been shown to induce persistent airway inflammation consistent with that seen in humans with asthma. Mice were exposed to HDME intranasally for 7 or 20 consecutive weeks, and resolution of the inflammatory and remodeling response to allergen was investigated 4 weeks after the end of a 7-week exposure protocol. Measures of vascular remodeling, including total collagen deposition, procollagen I production, endothelial and smooth muscle cell proliferation, smooth muscle area, and presence of myofibroblasts, were investigated histologically in lung vessels of different sizes and locations. We observed an increase in total collagen content, which did not resolve upon cessation of allergen exposure. Other parameters were significantly increased after 7 and/or 20 weeks of allergen exposure but returned to baseline after allergen withdrawal. We conclude that respiratory HDME exposure induces airway remodeling and pulmonary vascular remodeling, and, in accordance with airway remodeling, some components of these structural changes may be irreversible.

Evidence for a Th2-to-Th1 shift in IL-4 deficient mice in response to chronic house dust mite exposure

Rationale IL-4 is an important mediator in the development of Th2-type inflammation in the airway. We therefore examined the response of IL-4 deficient (4KO) mice to chronic house dust mite (HDM) exposure, a protocol that results in a Th2-skewed response in wild type (WT) mice. Methods HDM was administered intranasally for five consecutive weeks. After full resolution of this inflammatory response, mice were rechallenged on five consecutive days with HDM. Lung inflammation, in vitro cytokine production, serum immunoglobulins and lung cell phenotype were assessed. Results Both WT and 4KO mice mounted an airway inflammatory response after 5 weeks of HDM exposure. However, the degree of inflammation was significantly greater in WT mice. Upon in vivo recall, both WT and 4KO mice mounted a robust inflammatory response of similar magnitude. At these two time points, inflammation in 4KO mice was comprised of macrophages and lymphocytes and, in contrast to WT mice, a near complete absence of eosinophils. Splenocytes from both strains produced similar levels of IFN-γ; however, splenocytes from 4KO mice produced minimal amounts of IL-5 and IL-13 upon HDM recall. In addition, 4KO mice had markedly reduced numbers of CD3 +/CD4 + lung cells expressing IL-5 and T1/ST2. In serum, we observed increased levels of IgG1 and modest levels of IgG2 in WT mice, and the reverse profile in 4KO mice. Conclusions The genetic deletion of IL-4 does not impede the generation of airway inflammation in response to chronic HDM exposure. However, the absence of IL-4 facilitates the generation of a Th1-polarized immune-inflammatory response.

Increase in skin mast cells following chronic house dust mite exposure.

Application of inhalant allergens in high concentration to the mildly abraded skin of sensitive patients with atopic dermatitis gave rise to eczematous skin responses at 48 h. These lesions, infiltrated by basophils, eosinophils and mononuclear cells, are examples of cutaneous basophil hypersensitivity. Repeated application of allergen induced an increase in skin mast cells by 6 days, the mast cell hyperplasia replacing the earlier basophil infiltration. No electron microscopic evidence of mast cell heterogeneity among the recruited cells was found.