Continuous Allergen Exposure Research Articles

Asymptomatic sensitization to a cow's milk protein induces sustained neuroinflammation and behavioral changes with chronic allergen exposure.

Mouse models of food allergy have contributed to our understanding of various aspects of the disease, including susceptibilities, symptom spectra, cellular mechanisms, and therapeutic approaches. Previously, we used a mouse model of non-anaphylactic cow’s milk allergy (CMA) and investigated sex- and strain-dependent differences in immunological, neurological, and behavioral sequelae. We showed that male C57BL/6J mice sensitized to a bovine whey protein, β-lactoglobulin (BLG; Bos d 5), exhibited anxiety- and depression-like behavior upon acute allergen challenge. Systemic levels of BLG-specific immunoglobulins, cytokines and chemokines were also elevated in the sensitized mice. Furthermore, neuroinflammation and intestinal dysbiosis were evident as the possible causes of the altered behavior. To assess whether frequent allergen exposure influences CMA-associated pathologies over an extended period in this subclinical model, we placed BLG-sensitized mice on a whey protein (WP)-containing or whey-free control (CTL) diet for 3 months. As expected, allergen-specific IgE was significantly elevated in the plasma after completing the 5-week sensitization phase. However, the IgE levels declined in both diet groups after 3 months. In contrast, allergen-specific IgG1 stayed elevated in sensitized mice with the CTL diet, and the WP diet to a lesser extent. Interestingly, BLG-sensitized mice on the WP diet exhibited anxiety-like behavior and a trend toward spatial memory decline compared to the sham or the sensitized mice on the CTL diet. Moreover, increased immunoreactivities for GFAP and Iba1 and elevated levels of CXCL13 and CCL12, the chemokines involved in central leukocyte recruitment and other neurological diseases, were also observed in the brain. We demonstrated that sensitization to the whey protein, particularly with continuous allergen exposure, resulted in persistent neuroinflammation and associated behavioral changes despite lowered allergen-specific immunoglobulin levels. These results suggested that continuous consumption of the offending allergen may lead to adverse consequences in the brain even after desensitization.

IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation

Severe inflammatory airway diseases are associated with inflammation that does not resolve, leading to structural changes and an overall environment primed for exacerbations. We sought to identify and inhibit pathways that perpetuate this heightened inflammatory state because this could lead to therapies that allow for a more quiescent lung that is less predisposed to symptoms and exacerbations. Using prolonged exposure to house dust mite in mice, we developed a mouse model of persistent and exacerbating airway disease characterized by a mixed inflammatory phenotype. We show that lung IL-33 drives inflammation and remodeling beyond the type 2 response classically associated with IL-33 signaling. IL-33 blockade with an IL-33 neutralizing antibody normalized established inflammation and improved remodeling of both the lung epithelium and lung parenchyma. Specifically, IL-33 blockade normalized persisting and exacerbating inflammatory end points, including eosinophilic, neutrophilic, and ST2+CD4+ T-cell infiltration. Importantly, we identified a key role for IL-33 in driving lung remodeling because anti-IL-33 also re-established the presence of ciliated cells over mucus-producing cells and decreased myofibroblast numbers, even in the context of continuous allergen exposure, resulting in improved lung function. Overall, this study shows that increased IL-33 levels drive a self-perpetuating amplification loop that maintains the lung in a state of lasting inflammation and remodeled tissue primed for exacerbations. Thus IL-33 blockade might ameliorate symptoms and prevent exacerbations by quelling persistent inflammation and airway remodeling.

Persistent nasal symptoms and mediator release after continuous pollen exposure in an environmental challenge chamber

BackgroundImmediate- and late-phase reactions are associated with nasal symptoms of patients with allergic rhinitis. ObjectiveTo examine the symptoms and mediators released after continuous allergen exposure in an environmental challenge chamber (ECC). MethodsFifteen patients with Japanese cedar pollinosis were enrolled in this study and continuously exposed to cedar pollen at a concentration of 8,000 grains/m3 for 3 hours in an ECC. Nasal function tests were performed, and nasal secretions were collected before pollen exposure (0 hour), immediately after exiting the ECC (3 hours), and 6 hours after exiting the ECC (9 hours). Symptom scores were recorded every 30 minutes in the ECC and every 3 hours after exiting the ECC. The frequency of sneezing and nose blowing also was monitored. ResultsThe severity of symptoms in the ECC peaked approximately 2 hours after the beginning of pollen exposure and continued more than 6 hours after leaving the ECC. Concentrations of histamine, tryptase, interleukins 5, 3, 33, and 31, and substance P increased over time, whereas that of nasal fractional exhaled nitric oxide decreased. ConclusionVarious mediators are released during continuous allergen exposure, which subsequently induce persistent nasal symptoms. Effective treatment is required to control the intense inflammation observed after allergen exposure.

Rebamipide suppresses mite-induced asthmatic responses in NC/Nga mice.

Allergic asthma caused by continuous allergen exposure evokes allergen-specific Th2 responses and is characterized by chronic airway inflammation and hyperresponsiveness. A previous report showed that rebamipide improved asthmatic symptoms in an ovalbumin/trypsin mice model. However, it is still unclear how rebamipide exerts its effects in asthma. In this study, rebamipide improved the asthmatic responses induced by mite exposure in NC/Nga mice, revealing the mechanism of this therapeutic effect. Rebamipide suppressed the infiltration of eosinophils into the airways and lung as well as attenuating the production of reactive oxygen species in tissues. In addition to these anti-inflammatory effects, rebamipide inhibited the production of IL-33, a member of the IL-1 family that drives the subsequent production of Th2-associated cytokines. These observations identify the point where rebamipide exerts its suppressive action on asthma and suggest that rebamipide has therapeutic potential in preventing mite-induced asthma.

Morphological and functional changes of epithelial cells in allergic rhinitis

Summary The functions of epithelial cells in the nose can be summarized as follows: (1) building a physical barrier to prevent allergens and foreign bodies from penetrating into the subepithelial layers; (2) secreting airway fluid by transepithelial ion transport and mucin production; and (3) responding to various stimuli by producing mediators that recruit lymphocytes, eosinophils, and mast cells to the nasal mucosa. However, in the setting of allergic rhinitis (AR) various morphological and functional changes occur in these cells, and the physical barrier of epithelial cells becomes vulnerable, which enables allergens to penetrate into the subepithelial layers. Histamine and thrombin are factors that influence the physical barrier. Although it is believed that epithelial damage in AR is less extensive than that in bronchial asthma, continued allergen exposure does damage epithelial cells in allergic animal models. Changes in ion transport during acute allergic reactions in vivo can be studied by nasal transepithelial potential difference. Comparison of nasal potential differences during pollen season has revealed lower values in allergic patients than in normal control subjects; the lowest value was reached 15 min after nasal allergen challenge. In vitro studies revealed that various factors including leukotrienes increase mucin gene transcription. These changes may lead to abnormalities of nasal secretion during allergic reactions.

Links between allergic rhinitis and asthma

航线的过敏疾病，包括季节的鼻炎，长期的长期的鼻炎和气喘，作为航线 mucosa 的煽动性的混乱被认出，但是在煽动性的反应的地点和疾病的临床的表明不同。气喘和过敏鼻炎经常在一样的病人共存并且被认为分享普通预先安排与环境影响交往的基因因素。两疾病特别地在西洋化的国家在最近的十年在流行增加了。这增加过时的人或物大部分归因于象暴露那样的环境因素到天线污染物质，和早年生活事件，包括到可能影响 IgEproduction 的传染代理人的暴露的度，自从在基因水池的一个重要变化有不够的时间。

Revisiting the “hygiene hypothesis” in gastrointestinal allergy

The "hygiene hypothesis" in its original form hypothesized that infection in early childhood acquired through unhygienic contact with siblings or the mother may prevent the development of allergic disease. Several recent epidemiologic surveys showing an inverse relationship between the frequency of infectious disease and the incidence of allergic diseases lend support to this hypothesis. Allergen sensitization of the immune system can occur early in utero against a background of neonatal commitment to a Th2 immune response involving the production of Th2 cytokines (eg, interleukin (IL)-4, IL-5, IL-13) that are the principal mediators of allergic inflammation. Continued allergen exposure is associated with predominantly CD4+ Th2 cell proliferation but does not exclude a minor Th1 allergen-specific subpopulation that can be further expanded nonspecifically and polyclonally by microbial superantigens or as bystanders, by interferon-gamma (IFN-gamma) and IL-2 released from Th1 effectors responding to antigens associated with infectious pathogens. Th1 cytokines can also subvert allergen-specific Th2 lymphocytes to become allergen-specific Th1 cells-a process reminiscent of the increased tendency of the maturing immune system of growing adults to mount a Th1 response to some environmental and dietary antigens. Unlike Th2 cytokines, IFN-gamma and IL-2 inhibit B-cell production of IgE and, hence, delimit the capacity of mast cells to degranulate and release allergenic mediators. The ability of infectious agents through their danger signals to initiate a Th1 response that deviates the Th2 allergenic bias is the basis of the hygiene hypothesis.

Humoral Responses to Bovine Dust in Dairy Farmers with Allergic Rhinitis

During the indoor cattle feeding season, dairy farmers are continuously exposed to allergenic bovine-derived materials for a long time every year. Limited information is available about the dynamics of exposed people's antibody responses under the influence of this kind of exposure. In this study, the level of antibodies to bovine epithelial antigen (BEA) was found to reflect the level of clinical allergy. On the other hand, the level of immunoglobulin (Ig)E, IgA and IgG antibodies to bovine urinary antigen (BUA) was lower in the group of bovine-allergic farmers than among other farmers. It was concluded that antibodies to different allergen extracts reflect different phenomena. Antibodies to BEA seem to be associated more with allergic symptoms, where as anti-BUA antibodies might reflect the level of bovine exposure. The indoor cattle feeding season did not cause any major changes in dairy farmers' humoral responses. The continued allergen exposure did not increase the level of sensitization as determined by antibody responses.

Effects of prolonged repeated exposure to ovalbumin in sensitized brown Norway rats.

The effects of chronic exposure to ovalbumin (OA) aerosol were studied in Brown Norway rats following intraperitoneal injections with OA and AI(OH)3 and exposure to OA or saline aerosols, once or every third day for 3 to 8 wk. Measurements of airway responsiveness to acetylcholine (ACh) aerosol at 18 to 24 h after allergen exposure showed a significant increase in -logPC150, the concentration of ACh needed to cause a 150% increase in baseline lung resistance, in animals single-exposed or chronic OA-exposed for 3 wk, compared with saline-exposed control animals. The group receiving 8 wk of OA exposure demonstrated no difference from the control animals with -logPC150 lower than that of the two previous groups (p < 0.001). In all three groups, BAL fluid showed a significant increase in neutrophils, but a significant increase in eosinophils (p < 0.01) was only observed in the single-exposed group when compared with saline-exposed control animals. In the 8-wk exposed rats, there was a higher recovery of macrophages and lymphocytes (p < 0.01) compared with control animals and the other two groups. AHR, present after single or 3-wk repeated exposure, disappears by 8 wk of continuous allergen exposure. Both the enhancement and suppression of AHR may be linked to OA-induced immune and inflammatory mechanisms.

Allergens and Asthma

In many medical textbooks allergens are still listed as one of the "trigger factors" for asthma, with the implication that irritability of the lungs is an underlying physiologic property of the lungs. Over the last few years it has become clear that asthma is an inflammatory disease. In addition, it has been shown that changes in allergen exposure can lead to changes in bronchial reactivity. These results lead to the view that continued allergen exposure of the lungs of allergic individuals with resulting "inflammation" is an important primary cause of asthma. In parallel with this has come a progressive increase in awareness and understanding of the importance of house dust allergens. In many parts of the world, the dust mite dominates house dust allergy and appears to be responsible for up to 85% of asthma. In the United States three indoor allergens appear to play an equal role: dust mites, cats, and cockroaches. In the future, management of asthma will increasingly focus on allergen avoidance both as a method of treating symptomatic allergic patients and also as an approach to controlling the development of a disease which currently has increasing morbidity and mortality.