Allergic Immune Responses Research Articles

Interleukin-33 in the developing lung-Roles in asthma and infection.

It has become increasingly clear that interleukin-33 (IL-33) plays a crucial role in initiation of type 2 immunity. The last decade of intense research has uncovered multiple mechanisms through which IL-33 targets key effector cells of the allergic immune response. Recently, IL-33 has been implicated in shaping the immune system of the lungs early in life, at a time which is crucial in the subsequent development of allergic asthma. In this review, we will address the current literature describing the role of IL-33 in the healthy and diseased lung. In particular, we will focus on the evidence for IL-33 in the development of immune responses in the lung, including the role of IL-33-responsive immune cells that may explain susceptibility to allergic sensitization at a young age and the association between genetic variants of IL-33 and asthma in humans. Finally, we will indicate areas for potential therapeutic modulation of the IL-33 pathway.

Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response.

The Keap1-Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of the wild-type but not of the Nrf2-deficient ILC2s. This effect on viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3-dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33 administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the number of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response by determining the survival and death of ILC2s, and these findings suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.

Therapeutic effects of isomaltodextrin in a BALB/c mouse model of egg allergy

Earlier studies reported that administration of prebiotics may prevent allergic inflammation, however, results remain controversial. The aim of this study was to evaluate the effects of isomaltodextrin (IMD) against hen egg ovalbumin (OVA)-induced allergic response in mice. BALB/c mice were sensitized to OVA and subsequently administered different doses of IMD in drinking water. Our results showed that IMD supplementation led to significantly milder clinical signs and lower histamine levels in serum. Interestingly, administration of IMD did not affect serum OVA-specific IgE concentration, but led to lower total IgE titers, suggesting that the therapeutic effect of IMD may be due to immune tolerance to OVA allergen. Differences in the immune response was observed in the IMD intervention groups by lower production of IL-4. Our study suggests that the oral administration of IMD effectively attenuated OVA-induced allergic immune response in mice.

Oral administration of a mixture of probiotics protects against food allergy via induction of CD103+ dendritic cells and modulates the intestinal microbiota

Abstract Although the prevalence of food allergies is rising, the standard of care for these allergies is suboptimal. Probiotics have been reported to regulate the allergic immune response, but the underlying mechanisms are not fully understood. In this study, we aimed to evaluate the effect of a mixture of probiotics on food allergy in an ovalbumin (OVA)-induced murine model. Treatment with the probiotics attenuated OVA-induced allergic symptoms in mice. Flow cytometry analysis showed that oral administration of probiotics induced mucosal CD103+ dendritic cells (DCs), which promoted differentiation of regulatory T cells (Tregs). 16S rRNA analysis revealed that the probiotics modulated the composition of microbiota, especially by increasing the proportion of the Deferribacteres and Verrucomicrobia phyla and the Mucispirillum and Clostridium XlVa genera, which in turn regulated the immune system. Our findings provide molecular insight into the application of a mixture of probiotics to alleviate food allergies and even gut immune homeostasis.

Macrophage Response to Particulates Plays a Pivotal Role in Development of Allergic Immune Response to Airborne Pollens

Innate immune responses in respiratory mucosa, such as those mediated by airway epithelial cells, likely play pivotal roles in development of type 2 immunity to inhaled allergens. The goal of this project was to investigate the roles for another innate immune cell type, namely airway macrophages, to induce allergic sensitization to pollens by using mouse models. Naïve BALB/c mice were exposed intranasally (i.n.) to ragweed pollen particles or ragweed extract twice a week for up to 3 weeks. Development of allergic immune responses was examined by analyzing sera and by challenging the animals i.n. with ragweed extract. The roles for macrophages were examined by in vitro culture and by depleting them in CD169-DTR transgenic mice. Clodronate liposome particles were used to characterize macrophage responses. Mice developed allergic immune responses to ragweed, including increased serum levels of IgE antibodies and airway eosinophilia, when exposed to ragweed pollen particles but not to ragweed extract. Pollen particles showed adjuvant activities to promote development of follicular helper T cells and allergen-specific IgE antibodies. Isolated airway macrophages produced IL-1α in response to pollen particles or clodronate liposome particles, but not to ragweed extract, in vitro. IL-1α and clodronate liposomes showed similar adjuvant activities as ragweed pollen particles to promote allergic immune responses in vivo. Finally, depletion of airway macrophages in CD169-DTR mice abolished IL-1α production and development of allergic immune response to ragweed pollens. Airway macrophages play a pivotal role to promote development of allergic immune responses to inhaled allergen particles.

House dust microbiome and human health risks

People spend a lot of time indoors and the indoor microbiome is a major part of the environment that we are exposed to. However, awareness of the exposure to the indoor microbiome and its health effects remains poor. Outdoor environment (soil and air), indoor sources (ventilation, dampness and building materials), human occupants, and pets compose the indoor microbial community. It has been estimated that up to 500-1000 different species can be present in house dust. House dust is a major source and reservoir of indoor microbiome, which influences human microbiome and determines health and disease. Herein, we review the origins and the components of the fungal and bacterial communities in house dust and their possible effect on human health, in particular on allergic disorders, intestinal microbiome, and immune responses. We expect to lay a solid foundation for the further study on the mechanisms of how the house dust microbes interact with the host microbiome and the human immune system.

Disease-specific primed human adult stem cells effectively ameliorate experimental atopic dermatitis in mice

Although human mesenchymal stem cells (hMSCs) hold considerable promise as an alternative therapeutic reagent for allergic disorders including atopic dermatitis (AD), the strategy for enhancing hMSC-based therapy remains challenging. We sought to investigate whether preconditioning with mast cell (MC) granules could enhance the therapeutic efficiency of human umbilical cord blood-derived MSCs (hUCB-MSCs) against AD.Methods: AD was experimentally induced in NC/Nga mice by repeated applications of 4% sodium dodecyl sulfate (SDS) and dermatophagoides farinae (Df) extract, and preconditioned hUCB-MSCs were subcutaneously injected. The therapeutic effect was determined by gross examination and additional ex vivo experiments performed using blood and skin samples to determine the resolution of allergic inflammation. To explore the underlying mechanisms, several co-culture assays with primary isolated immune cells and wound closure assays were conducted.Results: Pretreatment of MC granules enhanced the therapeutic effects of hUCB-MSCs by attenuating the symptoms of AD in an experimental animal model. MC granule-primed cells suppressed the activation of major disease-inducing cells, MCs and B lymphocytes more efficiently than naïve cells both in vitro and in vivo. Histamine-mediated upregulation of the COX-2 signaling pathway was shown to play a crucial role in suppression of the allergic immune response by MC-pretreated hUCB-MSCs. Moreover, MC pretreatment improved the wound healing ability of hUCB-MSCs.Conclusions: Our findings indicate that pre-exposure to MC granules improved the therapeutic effect of hUCB-MSCs on experimental AD by resolving the allergic immune reaction and accelerating the tissue regeneration process more efficiently than naïve cells, suggesting a potential enhancement strategy for stem cell-based therapy.

Mixed fermentation of soybean meal by protease and probiotics and its effects on the growth performance and immune response in broilers

ABSTRACT Soybean meal (SBM) contains several anti-nutritional factors, which limit the use of soy protein. Exogenous enzyme supplementation and microbial fermentation can reduce anti-nutritional factors and increase the bioavailability of nutrients in SBM. In this study, we investigated the optimal parameters for the solid-state fermentation (SSF) of SBM by protease in combination with probiotics and evaluated its effect on the growth performance and immune response in broilers. Protease in combination with Bacillus subtilis significantly increased the degradation of soybean protein and soybean allergens in a dose-dependent manner during the SSF of soybean meal. Broilers fed 10% fermented SBM (FSBM), which was produced with protease and B. subtilis, consumed more daily feed on average during the entire feeding period than the SBM group did (P < 0.05). Dietary supplementation with 10% FSBM attenuated IL-4 mRNA expression in the spleen and bursa of Fabricius of broilers (P < 0.05). Furthermore, 10%-FSBM-fed broilers had significantly lower serum anti-soybean IgG levels than SBM-fed broilers (P < 0.05). These results suggest that the supplementation of B. subtilis and protease during the SSF of SBM reduces anti-nutritional factors. Moreover, dietary supplementation of 10% FSBM could inhibit the allergic immune response in broilers.

Coupled dynamics of intestinal microbiome and immune system—A mathematical study

An immune system sometimes causes an exaggerated response to harmless materials, such as pollens, eggs, and metals, which is known as an allergy. The regulatory T (Treg) cells suppress such allergic responses. Recently, it has been observed that intestinal microbiota have a close association with immune systems. For example, some strains of bacteria induce Treg cells by producing short-chain fatty acids, such as butyrate. Moreover, a sufficiently diverse T cell receptor repertoire of Treg cells is required to prevent inflammation of intestine driven by the commensal intestinal microbiome. In this study, we develop a simple mathematical model describing the dynamic interaction of T helper cells, Treg cells, and Treg-inducing intestinal microbes. The proposed model may have multiple stable equilibria, and the allergic response is intense at the dysbiotic equilibrium, in which the Treg-inducing microbes are scarce. First, we search for the condition by getting rid of the stable dysbiotic steady state. Further, we examine different methods to reduce the allergic response at the equilibrium (which may be dysbiotic or non-dysbiotic). Furthermore, we discuss the possible therapeutic interventions focusing on the intestinal microbiome to suppress the allergic immune responses.

Methods for Assessing Mast Cell Responses to Engineered Nanomaterial Exposure.

Mast cells are key effector cells in inflammatory and allergic immune responses such as asthma, rhinitis, and atopic dermatitis. Activation of mast cells leads to immediate release of preformed mediators such as histamine and proteases, which can regulate vascular permeability and the function of a number of immune and nonimmune cells. Engineered nanomaterials (ENM) have been utilized for a wide range of applications and introduced into a number of consumer products; yet the consequent increase in human exposure and any potential adverse effects have not been fully evaluated. Modulation of the immune system function has been shown to be a major toxicological consequence of ENM exposure. The implication of mast cells in ENM-mediated toxicity, including the most widely utilized carbon and metal-based ENMs, has been previously demonstrated; and therefore, understanding direct ENM interaction with mast cells at the cellular and molecular level is of critical importance for the safe implementation of ENMs into consumer products.

Regulatory Immune Mechanisms in Tolerance to Food Allergy.

Oral tolerance can develop after frequent exposure to food allergens. Upon ingestion, food is digested into small protein fragments in the gastrointestinal tract. Small food particles are later absorbed into the human body. Interestingly, some of these ingested food proteins can cause allergic immune responses, which can lead to food allergy. So far it has not been completely elucidated how these proteins become immunogenic and cause food allergies. In contrast, oral tolerance helps to prevent the pathologic reactions against different types of food antigens from animal or plant origin. Tolerance to food is mainly acquired by dendritic cells, epithelial cells in the gut, and the gut microbiome. A subset of CD103+ DCs is capable of inducing T regulatory cells (Treg cells) that express anti-inflammatory cytokines. Anergic T cells also contribute to oral tolerance, by reducing the number of effector cells. Similar to Treg cells, B regulatory cells (Breg cells) suppress effector T cells and contribute to the immune tolerance to food allergens. Furthermore, the human microbiome is an essential mediator in the induction of oral tolerance or food allergy. In this review, we outline the current understanding of regulatory immune mechanisms in oral tolerance. The biological changes reflecting early consequences of immune stimulation with food allergens should provide useful information for the development of novel therapeutic treatments.

Inherent allergic potential of α-dioxygenase fragment: A pathogenesis related protein

In the course of analyzing amino acid sequence of an allergen (≈20 kDa), we found this protein has a homology with the amino acid sequence of putative α-Dioxygenase fragment (ADF). Allergy caused by many allergens having an enzymatic activity have been reported previously, but allergenicity to neither α-Dioxygenase enzyme nor to it’s any constituents has been reported. We sought to purify an ADF (≈19.5 kDa) from chickpea to investigate it’s inherent allergic potential in BALB/c mice. The ADF showed IgE-affinity in sera of sensitized BALB/c mice and allergic patients. Enhanced levels of histamine, specific IgE as well as IgG1, IL-4, IL-17, IL-6, IL-2 and IL-10 were observed in the sera of mice treated with ADF allergen. A positive skin Type 1 test and elevated number of mast cells were found in the treated mice. Apart from this, enhanced number of immune cells i.e. CD19+ and CD4+ were also noticed in the ADF treated group. Higher expressions of IL-4 as well as GATA-3 and prominent histological changes were observed in tissues of treated animals. Furthermore, expressions of Th2 cytokines, associated transcription factors and mast cell signaling proteins were also increased at mRNA and protein levels in the intestines of ADF treated mice. Conclusively, present study demonstrated that ADF with molecular weight of 19.5 kDa is a clinical relevant allergen which causes allergic immune responses in BALB/c mice and may play a pivotal role in allergy caused by food containing α-Dioxygenase enzyme in sensitive individuals.

Human exposure to airborne pollen and relationships with symptoms and immune responses: Indoors versus outdoors, circadian patterns and meteorological effects in alpine and urban environments

Pollen exposure is a major cause of respiratory allergies worldwide. However, it is unclear how everyday exposure is related to symptoms and how allergic patients may be affected spatially and temporally. Hence, we investigated the relationship of pollen, symptoms and immune responses under a controlled regime of ‘high-low-moderate’ pollen exposure in urban versus alpine environment.The research was conducted in 2016 in two locations in Germany: urban Augsburg (494 m) and Schneefernerhaus (UFS) on Zugspitze mountain (2656 m). Monitoring of airborne pollen took place using Hirst-type volumetric traps. On UFS, both indoor and outdoor samples were taken. Grass pollen allergic human volunteers were monitored daily during the peak of the grass pollen season, in Augsburg, on UFS, then again in Augsburg. Nasal biosamples were obtained throughout the study to investigate immune responses.All symptoms decreased significantly during the stay on UFS and remained low even after the return to Augsburg. The same was observed for nasal total IgE and IgM levels and for nasal type 2 cytokines and chemokines. Augsburg showed higher pollen concentrations than those on UFS. At all sites, pollen were present throughout each day, but were more abundant in Augsburg during morning. On UFS, outdoor pollen levels were up to 6-fold higher than those indoors. Nasal, ocular and pulmonary symptoms correlated with current and previous days' pollen concentrations and relative humidity.Stays in low-exposure environments during the peak pollen season can be an efficient means of reducing allergic symptoms and immune responses. However, in alpine environments, even occasional pollen exposure during short intervals may still trigger symptoms because of the additional environmental stress posed onto allergics. This highlights the need for the consideration of additional environmental factors, apart from symptom diaries and immune responses, so as to efficiently predict high-risk allergy periods.

Virus-Like Particles as Carrier Systems to Enhance Immunomodulation in Allergen Immunotherapy.

Utilization of virus-like particles (VLPs) is considered to improve allergen-specific immunotherapy (AIT). AIT aims at the efficient uptake of the target allergen by antigen-presenting cells (APCs) subsequently inducing adaptive allergen-specific immune responses to induce tolerance. The purpose of this review is to describe the immune-modulating properties of VLPs per se and to summarize the application of VLPs as antigen carriers, preferably for Th2 cytokines or allergens, with and without simultaneous administration of adjuvants in order to modulate allergic immune responses. Currently, a broad variety of approaches considering the origin of the VLPs, the choice of the adjuvant and antigen, and the coupling of the antigen are under preclinical investigation. The data provide evidence that VLPs used as carrier for antigens/allergens strongly increase antigen immunogenicity, and might be suitable to prevent allergies. However, systematic studies in mice showing the immunological mechanism and data from clinical studies are scarce.

Ambient particulate matter enhances the pulmonary allergic immune response to house dust mite in a BALB/c mouse model by augmenting Th2- and Th17-immune responses.

Ambient particulate matter (PM) exacerbates airway inflammation and hyper‐reactivity in asthmatic patients. Studies show that PM has adjuvant‐like properties that enhance the allergic inflammatory response; however, the mechanisms through which PM enhances these processes remain elusive. The objective of the study was to examine how ambient PM enhances the allergic immune response. Eight‐week‐old BALB/c mice were sensitized with house dust mite (HDM) or HDM and ambient particulate matter (PM, 2.5 μm; Sacramento, CA) to assess how PM modulates the development of adaptive immune responses against allergens. Both groups were challenged with HDM only. Bronchoalveolar lavage (BAL) was analyzed for extent of airway inflammation. Lung tissue was used for histological analysis, mucosubstance quantification, and heme oxygenase‐1 (HO‐1) localization/quantification. Gene expression was analyzed in whole lung to characterize immune markers of inflammation: cytokines, chemokines, antioxidant enzymes, and transcription factors. Cytokine and chemokine protein levels were quantified in whole lung to confirm gene expression patterns. Compared to HDM‐only sensitization, exposure to PM during HDM sensitization led to significant immune cell recruitment into the airway subepithelium, IgE gene expression, mucosubstance production, and Th2‐associated cytokine expression. HO‐1 levels were not significantly different between the treatment groups. Gene expression profiles suggest that polycyclic aromatic hydrocarbon (PAH) content in PM activated the aryl hydrocarbon receptor (AhR) and enhanced Th17‐responses in the mice that received HDM and PM compared to mice that received HDM‐only. The findings suggest that PM enhances allergic sensitization via enhancement of Th2‐mediated inflammation and that AhR activation by PAHs in PM promotes Th17‐immune responses.

Regulatory T cells and asthma.

Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 (Th2) response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinophilic inflammation, but cannot change the immune tolerance of the body to external allergens. Regulatory T cells (Tregs) are the main negative regulatory cells of the immune response. Tregs play a great role in regulating allergic, autoimmune, graft-versus-host responses, and other immune responses. In this review, we will discuss the classification and biological characteristics, the established immunomodulatory mechanisms, and the characteristics of induced differentiation of Tregs. We will also discuss the progress of Tregs in the field of asthma. We believe that further studies on the regulatory mechanisms of Tregs will provide better treatments and control strategies for asthma.

The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response

The migration of mature dendritic cells (DCs) into thedraining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b+ DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b+ DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b+ DCs and its ligand CCL8, toexit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma. After allergen exposure, CD169+SIGN-R1+ macrophages in interfollicular regions produced CCL8, which synergized with CCL21 in a Src-kinase-dependent manner to promote CD301b+ DC migration. In CCR8-deficient mice, CD301b+ DCs remained in the SCS and wereunable to enter the LN parenchyma, resulting in defective Th2 differentiation. We have defined aCCR8-dependent stepwise mechanism of DC-subset-specific migration through which LN CD169+SIGN-R1+ macrophages control the polarization of the adaptive immune response.

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83

New perspectives on the initiation of allergic immune responses at barrier sites.

Although allergies exert a devastating global impact and often lack effective treatment strategies, our knowledge on the mechanisms that initiate and propagate type-2 immune responses remain enigmatic. Recent advances have highlighted additional roles for epithelial cells (e.g. tuft cells) and sensory neurons as initiators and amplifiers of type-2 immune responses. In response to protease activity of allergens, Toll-like receptor stimulation or cellular damage, these type-2 sentinels can release cytokines, alarmins or neuropeptides capable of (i) activating and expanding innate immune cells, (ii) polarizing T helper type-2 cells and (iii) promoting allergic inflammation. Overexpression of these type-2 immune mediators has been associated with allergic disorders and together with their disease promoting role in experimental model systems have paved the way for the generation of new biologics. The aim of this review is to provide a concise view on recent developments in the field and to discuss these findings in the context of allergic inflammation.

Enhancing the Safety and Efficacy of Food Allergy Immunotherapy: a Review of Adjunctive Therapies.

Food allergy is a potentially life-threatening condition with no approved curative therapy. A number of food allergen immunotherapies are being investigated in phase II/III trials; however, these are limited in their ability to restore immune tolerance to food allergens and often result in high rates of allergic side effects, sometimes involving anaphylaxis, that may curtail their impact. A variety of adjunctive therapies have been developed in order to enhance the efficacy and/or improve the safety of food allergen immunotherapy through either shifting the immune response from a Th2 polarized response to a Th1 and regulatory T cell dominated response or by blocking downstream effects of the allergic inflammatory response by targeting IgE or mast cell mediators. Upstream therapies that shift towards a Th1/Treg response include toll-like receptor (TLR) 4 agonists (e.g., MPL and GLA), TLR9 agonists (CpG oligonucleotides), nanoparticles encapsulating peanut allergen (with and without adjuvants, such as CpG or rapamycin), Chinese herbal medicine (food allergy herbal formula (FAHF-2)), probiotics, and interferon-gamma. In contrast, anti-IgE therapies such as omalizumab, anti-histamines like ketotifen, and leukotriene receptor antagonists all target the downstream allergic response. Anti-IgE-based therapies appear to be furthest along with probiotics, Chinese herbal medicines, and TLR-4 agonists currently in early phase clinical trials. Meanwhile, nanoparticles represent an innovative delivery vehicle for immunotherapy that could improve both efficacy and decrease allergic side effects. Furthermore, other biologic therapies directed towards the allergic immune response are on the horizon. A number of factors will need to be evaluated in comparing these treatments, including ability to decrease allergic adverse events, safety of the adjunctive therapies themselves, effect on long-term sustained unresponsiveness, and cost. Further phenotyping of food allergy patients may be necessary to determine which ones respond best to each therapy. However, with so many promising adjunctive therapies, it appears likely that clinicians will have a variety of options to optimize the administration of food allergen immunotherapy. We provided a review of these methods, their influence on allergic adverse events, and utility in improving the immunomodulatory effects of food allergen immunotherapy.