Ezratty, Véronique; Bonay, Marcel; Neukirch, Catherine; Orset-Guillossou, Gaëlle; Dehoux, Monique; Koscielny, Serge; Cabanes, Pierre-André; Lambrozo, Jacques; Aubier, Michel
Background Exposure to formaldehyde may lead to exacerbation of asthma. Objectives Our aim in this study was to investigate whether exposure to a low level (500 μg/m3) of formaldehyde enhances inhaled allergen responses. Methods Twelve subjects with intermittent asthma and allergy to pollen were exposed, at rest, in a double-blind crossover study to either formaldehyde or purified air for 60 min. The order of exposure to formaldehyde and air-only was randomized, and exposures were separated by 2 weeks. We also performed an allergen inhalation challenge after each exposure. Airway responsiveness to methacholine and lower airway inflammation (induced sputum) were assessed 8 hr after allergen challenge. Results The median dose of allergen producing a 15% decrease in forced expiratory volume in 1 sec (PD15FEV1) was 0.80 IR (index of reactivity) after formaldehyde exposure compared with 0.25 IR after air-only exposure (p = 0.06). Formaldehyde exposure did not affect allergen-induced increase in responsiveness to methacholine (p = 0.42). We found no formaldehyde-associated effect on the airway inflammatory response, in particular the eosinophilic inflammatory response, induced by the allergen challenge 8 hr before. Conclusion In this study, exposure to 500 μg/m3 formaldehyde had no significant deleterious effect on airway allergen responsiveness of patients with intermittent asthma; we found a trend toward a protective effect. PMID:17384766
Davis, B E; Amakye, D O; Cockcroft, D W
Airway responsiveness to indirect stimuli correlates positively with airway inflammation. In atopic asthmatics, allergen inhalation is associated with an influx of inflammatory cells and increased responsiveness to the direct-acting stimuli methacholine at 3 and 24 h after exposure. We have shown mannitol responsiveness decreases 3 h after allergen inhalation. The current investigation assessed mannitol responsiveness 24 h after allergen challenge. Eleven mild atopic asthmatics completed allergen challenges on two separate occasions. In random order, methacholine or mannitol challenges were performed 24 h pre- and post-allergen challenge. Levels of fractional exhaled nitric oxide were also measured. Allergen challenge increased airway responsiveness to methacholine 24 h postchallenge; the geometric mean (95% CI) methacholine PC20 decreased from 5.9 mg/ml (1.8-19.4) to 2.2 mg/ml (0.81-5.89); P = 0.01. This coincided with a significant increase (P = 0.02) in FeNO levels. Conversely, allergen challenge decreased airway responsiveness to mannitol; geometric mean (95% CI) dose-response ratio was significantly higher after allergen exposure (57 mg/% FEV1 fall [27-121] to 147 mg/% FEV1 fall [57-379]; P = 0.03), and FeNO levels were not significantly increased (P = 0.054). Allergen-induced changes in airway responsiveness to direct and indirect stimuli are markedly different. The loss in responsiveness to mannitol is likely not explainable by a refractory state. The effect(s) of allergen exposure on airway responsiveness to indirect-acting stimuli require further investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Schelegle, Edward S.; Walby, William F.
Brown-Norway rats (n = 113) sensitized and challenged with nDer f 1 allergen were used to examine the contribution of lung sensory nerves to ozone (O3) exacerbation of asthma. Prior to their third challenge rats inhaled 1.0 ppm O3 for 8 hours. There were three groups: 1) control; 2) vagus perineural capsaicin treatment (PCT) with or without hexamethonium; and 3) vagotomy. O3 inhalation resulted in a significant increase in lung resistance (RL) and an exaggerated response to subsequent allergen challenge. PCT abolished the O3-induced increase in RL and significantly reduced the increase in RL induced by a subsequent allergen challenge, while hexamethonium treatment reestablished bronchoconstriction induced by allergen challenge. Vagotomy resulted in a significant increase in the bronchoconstriction induced by O3 inhalation and subsequent challenge with allergen. In this model of O3 exacerbation of asthma, vagal C-fibers initiate reflex bronchoconstriction, vagal myelinated fibers initiate reflex bronchodilation, and mediators released within the airway initiate bronchoconstriction. PMID:22525484
Kelly, Vanessa J.; Winkler, Tilo; Venegas, Jose G.; Kone, Mamary; Hamilos, Daniel L.; Afshar, Roshi; Cho, Josalyn L.; Luster, Andrew D.; Medoff, Benjamin D.; Harris, R. Scott
Background Allergic non-asthmatic (ANA) adults experience upper airway symptoms of allergic disease such as rhinorrhea, congestion and sneezing without symptoms of asthma. The aim of this study was to utilize PET-CT functional imaging to determine whether allergen challenge elicits a pulmonary response in ANA subjects or whether their allergic disease is truly isolated to the upper airways. Methods In 6 ANA subjects, bronchoalveolar lavages (BAL) were performed at baseline and 24h after instillation of an allergen and a diluent in separate lung lobes. After instillation (10h), functional imaging was performed to quantify and compare regional perfusion, ventilation, fractional gas content (Fgas), and glucose uptake rate (Ki) between the baseline, diluent and allergen lobes. BAL cell counts were also compared. Results In ANA subjects, compared to the baseline and diluent lobes, perfusion and ventilation were significantly lower in the allergen lobe (median [inter-quartile range], baseline vs. diluent vs. allergen: Mean-normalized perfusion; 0.87 [0.85–0.97] vs. 0.90 [0.86–0.98] vs. 0.59 [0.55–0.67]; p<0.05. Mean-normalized ventilation 0.89 [0.88–0.98] vs. 0.95 [0.89–1.02] vs. 0.63 [0.52–0.67], p<0.05). In contrast, no significant differences were found in Fgas between baseline, diluent and allergen lobes or in Ki. Total cell counts, eosinophil and neutrophil cell counts (cells/ml BAL) were significantly greater in the allergen lobe compared to the baseline lobe (all P<0.05). Conclusions Despite having no clinical symptoms of a lower airway allergic response (cough and wheeze) allergic non-asthmatic subjects have a pulmonary response to allergen exposure which manifests as reduced ventilation and perfusion. PMID:26640951
Leaker, Brian R; Scadding, Glenis; Jones, C Richard; Barnes, Peter J
Current rhinometric and flow assessments measure nasal patency and are often poorly correlated with rhinitis symptoms. To evaluate magnetic resonance imaging (MRI) as a new method to measure inflammatory changes in nasal and sinus mucosa following nasal allergen challenge. A pilot study (n = 6) determined the optimal technical settings for MRI to measure inflammatory change which were then adopted for the main study. This study was a single blind, placebo-controlled, three-way crossover trial in 14 subjects with seasonal allergic rhinitis. Effects of cetirizine, cetirizine and pseudoephedrine (Cet+PE), or placebo on total nasal symptom scores (TNSS), peak nasal inspiratory flow (PNIF), nasal nitric oxide (nNO), acoustic rhinometry, and MRI end points following nasal intranasal allergen challenge were measured. There were significant changes in all parameters after allergen challenge (P < 0.01), except for nNO. MRI end points were less variable and more consistent than PNIF and acoustic rhinometry in detecting changes after allergen challenge. Total nasal airspace volume was the most sensitive and reproducible MRI measurement, with a mean reduction from -5.37 cm(3) (95%CI -7.35, -3.38; P < 0.001), which was maximal 60 min after allergen challenge. A change of one in TNSS corresponded to a change in MRI volume of -0.57 cm(3). There was an improvement in all parameters (except nNO) in subjects taking Cet+PE compared with placebo, however this did not achieve significance probably because of the small study size (overall analysis P > 0.07; comparison of active versus placebo P > 0.09). MRI provides novel insights into the anatomical inflammatory changes post allergen challenge and provides a new method for assessment of nasal patency and objective measurement of inflammatory responses.
Adams, David C.; Miller, Alyssa J.; Holz, Jasmin A.; Szabari, Margit V.; Hariri, Lida P.; Harris, R. Scott; Cho, Jocelyn L.; Hamilos, Daniel L.; Luster, Andrew D.; Medoff, Benjamin D.; Suter, Melissa J.
Asthma affects hundreds of millions of people worldwide, and the prevalence of the disease appears to be increasing. One of the most important aspects of asthma is the excessive bronchoconstriction that results in many of the symptoms experienced by asthma sufferers, but the relationship between bronchoconstriction and airway morphology is not clearly established. We present the imaging results of a study involving a segmental allergen challenge given to both allergic asthmatic (n = 12) and allergic non-asthmatic (n = 19) human volunteers. Using OCT, we have imaged and assessed baseline morphology in a right upper lobe (RUL) airway, serving as the control, and a right middle lobe (RML) airway, in which the allergen was to be administered. After a period of 24 hours had elapsed following the administration of the allergen, both airways were again imaged and the response morphology assessed. A number of airway parameters were measured and compared, including epithelial thickness, mucosal thickness and buckling, lumen area, and mucus content. We found that at baseline epithelial thickness, mucosal thickness, and mucosal buckling were greater in AAs than ANAs. We also observed statistically significant increases in these values 24 hours after the allergen had been administered for both the ANA and AA sets. In comparison, the control airway which received a diluent showed no statistically significant change.
Patients with bronchial asthma develop various types of asthmatic response to bronchial challenge with allergen, such as immediate/early asthmatic response (IAR), late asthmatic response (LAR) or delayed asthmatic response (DYAR), because of different immunologic mechanisms. The DYAR, occurring between 24 and 56 hours after the bronchial allergen challenge (p < 0.01), differs from IAR and LAR in clinical as well as immunologic features. This study investigates the expression of CD molecules (markers) on the surface of particular cell populations in the peripheral blood and their changes during the DYAR. In 17 patients developing the DYAR (p < 0.01), the bronchial challenge with allergen was repeated 2–6 weeks later. The repeated DYAR (p < 0.001) was combined with recording of CD molecule expression on various types of blood cells by means of flow cytometry up to 72 hours after the challenge. The results were expressed in percent of the mean relative fluorescence intensity. The DYAR was accompanied by (a) increased expression of CD11b, CD11b/18, CD16,CD32, CD35, CD62E, CD62L, CD64, and CD66b on neutrophils; CD203C on basophils; CD25 and CD62L on eosinophils; CD14, CD16, CD64, and CD86 on monocytes; CD3, CD4, CD8, CD11a, CD18, and CD69 on lymphocytes; CD16, CD56, CD57, and CD94 on natural killer (NK) cells; and CD31, CD41, CD61, CD62P, and CD63 on thrombocytes and (b) decreased expression of CD18 and CD62L on eosinophils, CD15 on neutrophils, and CD40 on lymphocytes. These results suggest involvement of cell-mediated hypersensitivity mechanism, on participation of Th1- lymphocytes, neutrophils, monocytes, NK cells, and thrombocytes in the DYAR. PMID:24988283
Background. Bronchial asthma patients can develop various asthmatic response types following bronchial allergen challenge, such as immediate (IAR), late (LAR), dual late (DLAR), or delayed (DYAR), due to different immunologic mechanisms. The DYAR, recorded in 24 patients, beginning between 26 and 32 hrs and lasting up to 56 hrs after the bronchial allergen challenge, differs from the IAR, LAR, and DLAR in clinical, diagnostic, and immunologic aspects. Objective. To investigate amounts of particular cytokines released by the blood cells after an additional nonspecific stimulation with Phorbol 12-myristate 13-acetate (PMA) during the DYAR. Methods. In 24 patients, the repeated DYAR was supplemented with determination of cytokines both in the nonstimulated plasma and in the supernatants of the blood cells stimulated with PMA before and up to 72 hours after the bronchial challenge, by means of enzyme-linked immunoassay. Results. No significant changes of the prechallenge cytokine concentrations in the non-stimulated serum were recorded in the DYAR patients as compared with the healthy subjects. The DYAR was accompanied by significantly increased postchallenge concentrations (P < 0.05) of IL-2, IL-8, IL-12p70, IL-13, IL-18, IFN-γ, G-CSF, TNF-α, and TGF-β, while decreased concentration of IL-7 (P < 0.05) in the nonstimulated plasma. The significantly increased postchallenge concentrations of IL-2, IL-8, IL-12p70, IL-13, IL-18, IFN-γ, TNF-α, and TGF-β were released by peripheral blood cells after stimulation with PMA, as compared with both their prechallenge concentrations and with the PBS control values. Conclusions. These results would support evidence for an important role of the Th1 cells, neutrophils, monocytes, and probably also NK cells in the immunologic mechanism(s) leading to the development of the clinical DYAR. Nevertheless, an additional role of macrophages, endothelial and epithelial cells in these mechanisms cannot be even excluded. PMID:24049660
Carlos, A G; Carlos, M L; Ferreira, M B; Santos, A S; Santos, M C; Pedro, E
Nasal allergen challenges, despite not reproducing exactly natural allergen exposure, are a very useful method to understand the complex cellular kinetics and cellular interactions that occur in allergic rhinitis. Cell-specific soluble mediator measurements can give useful diagnostic information. In this paper we present data concerning eosinophil cationic protein (ECP) and tryptase measurements after nasal allergen challenge.
The protective effects of disodium cromoglycate (DSCG) and beclomethasone dipropionate (BDA) on the "delayed nasal response" to allergen challenge (DNR) were investigated in 37 patients with allergic rhinitis. These thirty-seven patients, from a group of 268, developed 43 "delayed nasal responses" (DNR), 16 cases of "isolated delayed responses" (IDNR) and 27 cases of "dual delayed responses" (DDNR), where the delayed response (DLDNR) was preceded by an immediate response (INR). BDA demonstrated significant protective effects on the DNR in both its modifications; however, to a higher degree in the case of the IDNR. DSCG significantly decreased only the INR, being a part of the DDNR, while in the case of the DNR in both its modifications, DSCG was completely ineffective. It is suggested that BDA should be the drug of first choice in allergic rhinitis patients demonstrating the DNR. When immediate responses to the same or other allergens are also present, DSCG should be added at the beginning of the treatment for a temporary period of a few months.
Jahnsen, F; Moloney, E; Hogan, T; Upham, J; Burke, C; Holt, P
BACKGROUND—Airway dendritic cells (DC) play an important role in chronic allergic airway inflammation in experimental animals, but a similar role for DC in human allergic asthma has been difficult to define. This pilot study was undertaken to elucidate the role of DC in allergic asthma by examining their potential to migrate to the lower airways in response to bronchial challenge with specific allergen. METHODS—Bronchial biopsy specimens were obtained from seven patients with allergic asthma before and 4-5 hours after allergen challenge. Multicolour immunofluorescence staining was performed on mucosal cryosections to identify changes in the number and phenotypes of DC. RESULTS—A dramatic increase in the number of CD1c+HLA-DR+ DC were observed in the lamina propria after challenge compared with baseline (22.4 v 7.8 cells/mm2). The rapid accumulation (within 4-5 hours) of these cells strongly suggests that they were directly recruited from peripheral blood. CONCLUSION—We have shown for the first time that a specific DC subset rapidly emigrates into the human bronchial mucosa during allergic inflammation. While this study is based on relatively few patients, the consistency of the overall results strongly suggests that the rapid population dynamics of human airway DC closely parallel those in animal models of acute inflammation. These findings support suggestions that DC have an important role in human airway allergy. PMID:11641504
Ferreira, M B; Carlos, A G
Even simple and relatively safe provocation procedures like nasal allergen challenges, should aim to allow detection of positivity with the less possible discomfort to the patient. The objective of this work was to evaluate if the use of rhinomanometric measurements during nasal provocation procedures could allow a decrease in the total administered allergen dose, causing less symptoms to the patients but without increasing the number of false-negatives, comparatively to clinical scores or nasal peak-flow measurements. Our results showed that performing rhinomanometric measurements during nasal HDM challenge procedures can lead in many patients to a reduction in the total dose of allergen administered during the challenge, without loss of sensitivity or specificity. This allergen dose reduction translates in less time consumed during the provocation and less patients' discomfort.
Dharajiya, Nilesh; Vaidya, Swapnil; Sinha, Mala; Luxon, Bruce; Boldogh, Istvan; Sur, Sanjiv
According to the current paradigm, allergic airway inflammation is mediated by Th2 cytokines and pro-inflammatory chemokines. Since allergic inflammation is self-limited, we hypothesized that allergen challenge simultaneously induces anti-inflammatory genes to counter-balance the effects of Th2 cytokines and chemokines. To identify these putative anti-inflammatory genes, we compared the gene expression profile in the lungs of ragweed-sensitized mice four hours after challenge with either PBS or ragweed extract (RWE) using a micro-array platform. Consistent with our hypothesis, RWE challenge concurrently upregulated Th1-associated early target genes of the Il12/Stat4 pathway, such as p47 and p65 GTPases (Iigp, Tgtp and Gbp1), Socs1, Cxcl9, Cxcl10 and Gadd45g with the Th2 genes Il4, Il5, Ccl2 and Ccl7. These Th1-associated genes remain upregulated longer than the Th2 genes. Augmentation of the local Th1 milieu by administration of Il12 or CpG prior to RWE challenge further upregulated these Th1 genes. Abolition of the Th1 response by disrupting the Ifng gene increased allergic airway inflammation and abrogated RWE challenge-induced upregulation of GTPases, Cxcl9, Cxcl10 and Socs1, but not Gadd45g. Our data demonstrate that allergen challenge induces two sets of Th1-associated genes in the lungs: 1) Ifng-dependent genes such as p47 and p65 GTPases, Socs1, Cxcl9 and Cxcl10 and 2) Ifng-independent Th1-inducing genes like Gadd45g. We propose that allergen-induced airway inflammation is regulated by simultaneous upregulation of Th1 and Th2 genes, and that persistent unopposed upregulation of Th1 genes resolves allergic inflammation.
Holmberg, K.; Bake, B.; Pipkorn, U.
The nasal mucosal blood flow in patients with allergic rhinitis was determined at nasal allergen challenges with the /sup 133/Xenon washout method. Determinations were made in 12 subjects before and 15 minutes after challenge with diluent and increasing doses of allergen. The time course was followed in eight subjects by means of repeated measurements during 1 hour after a single allergen dose. Finally, the blood flow was measured after unilateral allergen challenge in the contralateral nasal cavity. A dose-dependent decrease in blood flow was found after nasal challenge with increasing doses of allergens, whereas challenge with diluent alone did not induce any changes. The highest allergen dose, which also induced pronounced nasal symptoms, resulted in a decrease in blood flow of 25% (p less than 0.001). The time-course study demonstrated a maximum decrease in blood flow 10 to 20 minutes after challenge and then a gradual return to baseline. Unilateral allergen challenge resulted in a decrease in blood flow in the contralateral, unchallenged nasal cavity, suggesting that part of the allergen-induced changes in blood flow were reflex mediated.
Bonefeld, Charlotte Menné; Nielsen, Morten Milek; Rubin, Ingrid Maria Cecilia; Vennegaard, Marie Torp; Dabelsteen, Sally; Gimenéz-Arnau, Elena; Lepoittevin, Jean-Pierre; Geisler, Carsten; Johansen, Jeanne Duus
Perfumes are complex mixtures composed of many fragrance ingredients, many of which are known to be only weak allergens when tested individually. It is therefore surprising that fragrance contact allergy is one of the most common forms of contact allergy. To investigate whether mixing different fragrance allergens leads to increased sensitization potency, and to examine the difference in the challenge response to one chemical in mice sensitized either with the mixture of allergens or with only the relevant allergen. CBA mice were sensitized with three different concentrations of three fragrance allergens alone or as a mixture. The sensitization and elicitation responses were measured by ear thickness plus infiltration of B and T cells and T cell proliferation in the draining lymph nodes. We found a dose-dependent sensitization response for each of the allergens. An increased response was seen when the allergens were mixed. A stronger challenge response to cinnamal was seen in mice sensitized with the allergen mixture than in mice sensitized with cinnamal alone. Our findings suggest that mixtures of allergens increase the primary response that potentiates the generation of memory T cells in response to the specific allergen. Thus, allergen mixtures enhance both induction and elicitation of contact allergy. © 2011 John Wiley & Sons A/S.
Lie, W J; Van Der Veen, M J; Knol, E F; Mul, F P; Jansen, H M; Roos, D; Van Der Zee, J S
Basophils can be primed by cytokines such as interleukin (IL) -3, IL-5 or granulocyte macrophage-colony stimulating factor (GM-CSF). It has been described that the concentrations of these cytokines are enhanced at sites of allergic inflammation as well as systemic in allergic asthma. To investigate the priming status of basophils as detected by thapsigargin-induced histamine release during bronchial allergen challenge. Ten subjects allergic to house dust mite were challenged via an aerosol delivery system. Spontaneous leucocyte histamine release as well as histamine release induced by various stimuli was measured in vitro at several time points. In addition, lung function parameters, serum IL-5 and blood eosinophil counts were evaluated. We found no effect of bronchial allergen challenge upon spontaneous leucocyte histamine release, nor upon histamine release induced by anti-immunoglobulin (Ig) E, house dust mite extract, C5a, fMLP, IL-3, PMA+ thapsigargin or IL-3+ thapsigargin. However, the priming status of basophils as measured by thapsigargin-induced histamine release was enhanced at 24 h after bronchial allergen challenge. Analysis of the individual data showed a heterogeneous initial response (30 min, 6 h) followed by a predominant increase at 24 h after allergen challenge. This increase in the thapsigargin-induced histamine release correlated with the increase in serum IL-5 levels at 24 h after allergen challenge. The priming status of human basophils as measured by thapsigargin-induced histamine release is enhanced 24 h after allergen challenge.
Paggiaro, P L; Giannini, D; Di Franco, A; Bacci, E; Dente, F L; Vagaggini, B; Tonelli, M; Zingoni, M
In order to assess whether the administration of salmeterol/fluticasone propionate combination (50/250 mcg by Diskus) for 1 week induces tolerance to the bronchoprotective effect of salmeterol on allergen challenge, a single-blind, cross-over study was carried out. We studied nine subjects (eight men and one woman; mean age+/-SD: 31.3+/-11.0 yr) with mild intermittent allergic asthma, never treated with regular beta2-agonists or inhaled corticosteroids. In a previous allergen challenge all subjects had shown a positive early airway response (EAR) to allergen. They underwent allergen challenge after 1-week treatment with placebo and a single dose of placebo immediately before allergen challenge (T1), or 1-week treatment with placebo and a single dose of salmeterol/fluticasone immediately before allergen challenge (T2), or 1-week treatment with salmeterol/fluticasone combination bid and a single dose of salmeterol/fluticasone immediately before allergen challenge (T3). EAR was evaluated both as maximum decrease in FEV1 (MaxDeltaFEV1 %) after allergen challenge and as area under FEV1 -time curve. MaxDeltaFEV1 % during allergen challenge protected by placebo (T1) was significantly greater than MaxDeltaFEV1 % during allergen challenges protected by single dose of salmeterol/fluticasone (T2) and by salmeterol/fluticasone 1-week treatment (T3). No difference was found in MaxDeltaFEV1 % between T2 and T3. The same results were observed also after computing the area under the curve for each challenge. When individually considered, all subjects were protected against EAR (protection index > or = 80%) at T2, while at 3 seven out of nine subjects were still protected against EAR. In conclusion, the simultaneous administration of salmeterol and fluticasone in the same device prevents in almost 80% of examined subjects the development of tolerance to the protective effect of salmeterol on allergen challenge. This observation may contribute to explain the positive interaction
Dearman, R J; Kimber, I
Food allergy is an important health issue. With an increasing interest in novel foods derived from transgenic crop plants, there is a growing need for the development of approaches suitable for the characterization of the allergenic potential of proteins. There are methods available currently (such as homology searches and serological testing) that are very effective at identifying proteins that are likely to cross-react with known allergens. However, animal models may play a role in the identification of truly novel proteins, such as bacterial or fungal proteins, that have not been experienced previously in the diet. We consider here the potential benefits, pitfalls and challenges of the selection of various animal models, including the mouse, the rat, the dog and the neonatal swine. The advantages and disadvantages of various experimental end-points are discussed, including the measurement of specific IgE by ELISA, Western blotting or functional tests such as the passive cutaneous anaphylaxis assay, and the assessment of challenge-induced clinical symptoms in previously sensitized animals. The experimental variables of route of exposure to test proteins and the incorporation of adjuvant to increase the sensitivity of the responses are considered also. It is important to emphasize that currently none of these approaches has been validated for the purposes of hazard identification in the context of a safety assessment. However, the available evidence suggests that the judicious use of an accurate and robust animal model could provide important additional data that would contribute significantly to the assessment of the potential allergenicity of novel proteins.
Scadding, Guy W; Calderon, Moises A; Bellido, Virginia; Koed, Gitte Konsgaard; Nielsen, Niels-Christian; Lund, Kaare; Togias, Alkis; Phippard, Deborah; Turka, Laurence A; Hansel, Trevor T; Durham, Stephen R; Wurtzen, Peter Adler
Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions. 20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose-response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-γ, Tryptase and Eosinophil Cationic Protein (ECP). Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5 min after challenge and returned to baseline levels at 1h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2-3 h and showed progressive increases to 5-6 h. Sponges proved the superior nasal fluid sampling technique. We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and -4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge.
Dotson, G S; Maier, A; Siegel, P D; Anderson, S E; Green, B J; Stefaniak, A B; Codispoti, C D; Kimber, I
Chemical allergens represent a significant health burden in the workplace. Exposures to such chemicals can cause the onset of a diverse group of adverse health effects triggered by immune-mediated responses. Common responses associated with workplace exposures to low molecular weight (LMW) chemical allergens range from allergic contact dermatitis to life-threatening cases of asthma. Establishing occupational exposure limits (OELs) for chemical allergens presents numerous difficulties for occupational hygiene professionals. Few OELs have been developed for LMW allergens because of the unique biological mechanisms that govern the immune-mediated responses. The purpose of this article is to explore the primary challenges confronting the establishment of OELs for LMW allergens. Specific topics include: (1) understanding the biology of LMW chemical allergies as it applies to setting OELs; (2) selecting the appropriate immune-mediated response (i.e., sensitization versus elicitation); (3) characterizing the dose (concentration)-response relationship of immune-mediated responses; (4) determining the impact of temporal exposure patterns (i.e., cumulative versus acute exposures); and (5) understanding the role of individual susceptibility and exposure route. Additional information is presented on the importance of using alternative exposure recommendations and risk management practices, including medical surveillance, to aid in protecting workers from exposures to LMW allergens when OELs cannot be established.
Davis, B E; Illamperuma, C; Gauvreau, G M; Watson, R M; O'Byrne, P M; Deschesnes, F; Boulet, L P; Cockcroft, D W
Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.
Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial.
Scadding, Guy W; Calderon, Moises A; Shamji, Mohamed H; Eifan, Aarif O; Penagos, Martin; Dumitru, Florentina; Sever, Michelle L; Bahnson, Henry T; Lawson, Kaitie; Harris, Kristina M; Plough, Audrey G; Panza, Joy Laurienzo; Qin, Tielin; Lim, Noha; Tchao, Nadia K; Togias, Alkis; Durham, Stephen R
Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5
Masid-de-Brito, Daniela; Queto, Túlio; Gaspar-Elsas, Maria Ignez C.
Diethylcarbamazine (DEC), which blocks leukotriene production, abolishes the challenge-induced increase in eosinopoiesis in bone-marrow from ovalbumin- (OVA-) sensitized mice, suggesting that 5-lipoxygenase (5-LO) products contribute to the hematological responses in experimental asthma models. We explored the relationship between 5-LO, central and peripheral eosinophilia, and effectiveness of DEC, using PAS or BALB/c mice and 5-LO-deficient mutants. We quantified eosinophil numbers in freshly harvested or cultured bone-marrow, peritoneal lavage fluid, and spleen, with or without administration of leukotriene generation inhibitors (DEC and MK886) and cisteinyl-leukotriene type I receptor antagonist (montelukast). The increase in eosinophil numbers in bone-marrow, observed in sensitized/challenged wild-type mice, was abolished by MK886 and DEC pretreatment. In ALOX mutants, by contrast, there was no increase in bone-marrow eosinophil counts, nor in eosinophil production in culture, in response to sensitization/challenge. In sensitized/challenged ALOX mice, challenge-induced migration of eosinophils to the peritoneal cavity was significantly reduced relative to the wild-type PAS controls. DEC was ineffective in ALOX mice, as expected from a mechanism of action dependent on 5-LO. In BALB/c mice, challenge significantly increased spleen eosinophil numbers and DEC treatment prevented this increase. Overall, 5-LO appears as indispensable to the systemic hematological response to allergen challenge, as well as to the effectiveness of DEC. PMID:25477712
Masid-de-Brito, Daniela; Queto, Túlio; Gaspar-Elsas, Maria Ignez C; Xavier-Elsas, Pedro
Diethylcarbamazine (DEC), which blocks leukotriene production, abolishes the challenge-induced increase in eosinopoiesis in bone-marrow from ovalbumin- (OVA-) sensitized mice, suggesting that 5-lipoxygenase (5-LO) products contribute to the hematological responses in experimental asthma models. We explored the relationship between 5-LO, central and peripheral eosinophilia, and effectiveness of DEC, using PAS or BALB/c mice and 5-LO-deficient mutants. We quantified eosinophil numbers in freshly harvested or cultured bone-marrow, peritoneal lavage fluid, and spleen, with or without administration of leukotriene generation inhibitors (DEC and MK886) and cisteinyl-leukotriene type I receptor antagonist (montelukast). The increase in eosinophil numbers in bone-marrow, observed in sensitized/challenged wild-type mice, was abolished by MK886 and DEC pretreatment. In ALOX mutants, by contrast, there was no increase in bone-marrow eosinophil counts, nor in eosinophil production in culture, in response to sensitization/challenge. In sensitized/challenged ALOX mice, challenge-induced migration of eosinophils to the peritoneal cavity was significantly reduced relative to the wild-type PAS controls. DEC was ineffective in ALOX mice, as expected from a mechanism of action dependent on 5-LO. In BALB/c mice, challenge significantly increased spleen eosinophil numbers and DEC treatment prevented this increase. Overall, 5-LO appears as indispensable to the systemic hematological response to allergen challenge, as well as to the effectiveness of DEC.
Naji, Nizar; Smith, Steven G; Gauvreau, Gail M; O'Byrne, Paul M
T helper (Th)17 cells may play a role in allergic asthma. This study assessed the effect of allergen inhalation challenge on circulating Th17 cells and related cytokines in allergic asthmatics. Peripheral blood mononuclear cells were collected from 16 atopic asthmatics before and 24 h after allergen challenge, as well as from 10 atopic nonasthmatics and 10 normal controls. Cells were stained for Th17 cytokines and their receptors (IL-17A, IL-17F, IL-21, IL-22, IL-17R, and IL-23R) using flow cytometry. Cytokine concentrations from cell culture supernatants were quantified using a multiplex assay for IL-17A, IL-17F, IL-21, IL-22, and IL-23. At baseline, asthmatics had a higher percentage of circulating Th17 cells (1.2 ± 0.5%) compared to normal controls (0.9 ± 0.66%, p < 0.001) but not compared to atopic nonasthmatics (1.13 ± 0.5%). There was a significant increase in Th17 cells in asthmatics after allergen challenge to 1.55 ± 0.4% (p < 0.05) and a trend toward significance in IL-17R expression from 3.4 ± 4.3 to 6.86 ± 6.84% after allergen challenge (p = 0.06). There was also a significant reduction in IL-21-positive cells following allergen challenge from 3.46 ± 1.85 to 2.33 ± 1.37% (p < 0.001). There were no significant differences in IL-17F, IL-22 and IL-23R expression. The concentration of IL-17A in culture supernatant was significantly higher in asthmatics compared to normal controls and IL-17A significantly increased 24 h after allergen challenge. The increase of Th17 cells and IL-17A in atopic asthma after allergen inhalation challenge suggests a possible role for Th17 in allergen-induced airway responses. © 2014 S. Karger AG, Basel.
Pedroletti, Christophe; Lundahl, Joachim; Alving, Kjell; Hedlin, Gunilla
Epidemiological data suggest a comorbidity link between nasal and bronchial allergic disease. Exhaled nitric oxide (FENO) is a sensitive marker of bronchial inflammation and increases after bronchial allergen provocation. We studied FENO in 19 children and adolescents with allergic asthma and 10 controls before and 2, 6 and 24 h after a single nasal allergen challenge. The correlation between FENO and other markers of allergic inflammation, such as eosinophils in blood and eosinophil cationic protein (ECP) in serum and nasal lavage was also assessed. FENO remained unchanged 24 h post-challenge in both steroid and steroid-naive patients. At 6 h post-challenge, FENO decreased in both asthmatics and controls. The asthmatic subjects showed a positive correlation between FENO and blood eosinophils before (r=0.71, p=0.001) and after the challenge, and between FENO and ECP in nasal lavage (r=0.62, p=0.02) 2 h after the challenge. Mean ECP in nasal lavage increased post-challenge but not significantly. We conclude that a single nasal allergen challenge does not augment bronchial inflammation although FENO, is related to blood eosinophil count and to the nasal inflammatory response. Our data do not support the theory of a direct transmission of the nasal inflammation to the lower airways.
Broide, D H; Firestein, G S
Airway inflammation is thought to play an important role in the pathogenesis of asthma. We have used in situ hybridization and an immunoassay to determine whether granulocyte macrophage colony-stimulating factor (GM-CSF) (a cytokine capable of eosinophil activation) is present in the airway of asthmatics (n = 6) who have 37.0 +/- 15.1% airway eosinophilia after endobronchial allergen challenge. Levels of immunoreactive GM-CSF (less than 4 pg/ml pre-allergen versus 180.5 +/- 46.9 pg/ml post-allergen) increased significantly 24 h after endobronchial allergen stimulation. The cellular source of bronchoalveolar lavage (BAL) GM-CSF, as determined by in situ hybridization and immunoperoxidase staining, was derived predominantly from UCHL-1 positive BAL lymphocytes, as well as from a smaller population of alveolar macrophages. Before local endobronchial allergen challenge, less than 1% of lymphocytes and alveolar macrophages recovered by BAL expressed GM-CSF mRNA, whereas after allergen stimulation 92.6 +/- 3.4% of lymphocytes and 17.5 +/- 22.7% of alveolar macrophages expressed GM-CSF mRNA. This study provides evidence that in an experimental model of allergen-induced asthma, activation of the immune and inflammatory response (BAL lymphocyte and alveolar macrophage production of GM-CSF) is temporally associated with an inflammatory cell influx of eosinophils into the airway. Images PMID:1885766
Dente, Federico L; Bacci, Elena; Bartoli, Maria Laura; Cianchetti, Silvana; Di Franco, Antonella; Costa, Francesco; Vagaggini, Barbara; Paggiaro, Pier Luigi
Late asthmatic response (LAR) to allergen challenge is a validated method for studying the pathogenesis of and new treatments for asthma in the laboratory. To evaluate the relationship between the magnitude of allergen-induced LAR and clinical and biological determinants, including sputum and blood eosinophil percentages and eosinophil cationic protein concentrations. Thirty-eight untreated mild asthmatic patients (mean age, 21.2 years) were selected for the presence of allergen-induced early asthmatic response (EAR) and LAR. Each patient measured methacholine responsiveness (provocation dose that caused a decrease in forced expiratory volume in 1 second of 20% [PD20FEV1]) at baseline, differential blood cell counts and eosinophil cationic protein levels in blood and induced sputum, and serum neutrophil chemotactic activity at baseline and 24 hours after allergen challenge. A correlation was found between LAR (as area under the curve [AUC]) and sputum eosinophil percentages at baseline (r = 0.51; P = .001) and 24 hours after allergen challenge (r = 0.44; P < .007). Furthermore, we found significant correlations between AUC LAR and AUC EAR, baseline methacholine PD20FEV1, baseline blood eosinophil percentages, and baseline serum neutrophil chemotactic activity. A stepwise multiple regression analysis showed that the stronger determinants of AUC LAR were baseline sputum eosinophilia and AUC EAR. Baseline sputum eosinophilia and functional findings are determinants of the magnitude of allergen-induced LAR.
Dente, F.; Bancalari, L.; Bacci, E.; Bartoli, M.; Carnevali, S.; Cianchetti, S.; Di, F; Giannini, D.; Vagaggini, B.; Testi, R.; Paggiaro, P.
BACKGROUND—The long acting β2 agonist salmeterol is very effective in preventing asthmatic responses to specific stimuli, and this effect could theoretically be due to some anti-inflammatory property in addition to bronchodilator property. METHODS—The protective effect of a single dose of salmeterol (50 µg) on allergen induced early and late responses and on the associated airway inflammation was investigated in a double blind, placebo controlled, crossover study in 11 atopic asthmatic subjects. Eosinophil percentages and concentrations of eosinophil cationic protein (ECP) in peripheral blood and in hypertonic saline induced sputum were measured 24 hours after allergen inhalation. RESULTS—Salmeterol effectively inhibited both early and late asthmatic responses in comparison with placebo. Salmeterol also inhibited the increase in the percentage of eosinophils in the sputum 24hours after allergen inhalation (median (range) baseline 6% (1-36), after placebo 31% (5-75), after salmeterol 12% (1-63)). However, the increase in both sputum and serum ECP concentrations 24 hours after allergen challenge was not affected by pretreatment with salmeterol. CONCLUSIONS—A single dose of salmeterol inhibits the allergen induced airway responses and the increase in sputum eosinophils after allergen challenge. PMID:10377209
Diamant, Z; Sidharta, P N; Singh, D; O'Connor, B J; Zuiker, R; Leaker, B R; Silkey, M; Dingemanse, J
CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test. Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (AUC(3-10 h) ) by on average 25.6% (P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (P = 0.0029). There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments. Setipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders. © 2014 John Wiley & Sons Ltd.
Chen, Lisa L; Tager, Ira B; Peden, David B; Christian, Dorothy L; Ferrando, Ronald E; Welch, Barbara S; Balmes, John R
Controlled human exposure studies have produced conflicting results regarding the effect of ozone on the early bronchoconstrictor response to inhaled allergen in specifically sensitized asthmatic subjects. Spirometric parameters do not necessarily reflect the airway inflammatory effects of inhaled ozone or allergen. This study was designed to investigate whether exposure to ozone enhances the late airway inflammatory response, as well as the early bronchoconstrictor response, to inhaled house dust mite allergen in sensitized asthmatic subjects. Randomized, counter-balanced, cross-over study. Human exposure laboratory. Fourteen subjects were exposed to 0.2 ppm O(3) or filtered air, on separate days, for 1 h during exercise. After each exposure, the subjects were challenged with doubling doses of Dermatophagoides farinae (DF) allergen (provocative concentration of DF causing a 15% decrease in FEV(1) [PC(15)]). At 6 h after allergen challenge, bronchoscopy with BAL, proximal airway lavage (PAL), and endobronchial biopsy were performed. The second exposure/allergen challenge/bronchoscopy sequence was performed at least 4 weeks after the first sequence. No significant difference in cellular or biochemical markers of the late inflammatory response after allergen was found between the ozone and air exposures (although a trend toward increased neutrophils was noted after ozone exposure in the PAL fluid, p = 0.06). For the group as a whole, no significant difference in PC(15) was demonstrated after ozone exposure compared to air exposure. However, subjects with the greatest ozone-induced decrements in FEV(1) tended to have lower PC(15) values after ozone exposure. Exposure to a relatively low-level concentration of ozone does not enhance the late inflammatory or early bronchoconstrictor response to inhaled antigen in most allergic asthmatic subjects. Our results do suggest, however, that a subgroup of asthmatics may acquire increased sensitivity to aeroallergens after
Common allergens include: Animal proteins and animal dander Dust Drugs (such as antibiotics or medicines you put on your skin) Foods (such as egg, peanut, milk, nuts, soy, fish, animal meat, and wheat) Fungal spores ...
Berlin, Aaron A; Lukacs, Nicholas W
In the present study it was determined whether a pharmacologic approach to blocking receptor tyrosine kinase-mediated activation during allergic airway responses could be beneficial. To examine these responses, allergic mice were given a single oral dose of imatinib at clinically relevant concentrations, ranging from 0.05 to 50 mg/kg, by oral gavages just before allergen challenge. The reduction in the allergen-induced responses was significant and centered on reducing overall inflammation as well as pulmonary cytokine levels. In particular, the treatment of the mice with imatinib significantly attenuated airway hyperreactivity and peribronchial eosinophil accumulation, and significantly reduced Th2 cytokines, interleukin-4 and interleukin-13. In addition, chemokines previously associated with allergen-induced pulmonary disease, CCL2, CCL5, and CCL6, were significantly reduced in the lungs of the imatinib-treated animals. Together these data demonstrate that the pharmacologic inhibitor imatinib may provide a clinically attractive therapy for allergic, asthmatic responses.
Allergen-specific immunotherapy is recognized as a highly effective practice in the treatment of patients with severe allergic rhinitis and/or asthma and is recommended by World Health Organization as an integrated part of allergy management strategy. Several studies have shown that allergen-specific immunotherapy, based on the administration of increasing doses of allergen, achieves a hyposensitization and reduces both early and late responses occurring during the natural exposure to the allergen itself. This is the unique antigen-specific immunomodulatory treatment in current use for human diseases. Successful immunotherapy is associated with reductions in symptoms and medication scores and improved quality of life. After interruption it usually confers long-term remission of symptoms and prevents the onset of new sensitizations in children up to a number of years. Subcutaneous immunotherapy usually suppresses the allergen-induced late response in target organs, likely due to the reduction of the infiltration of T cells, eosinophils, basophils, mast cells and neutrophils. In addition to the reduction of cells of allergic inflammation, immunotherapy also decreases inflammatory mediators at the site of allergen exposure. This review provides an update on the immunological T cell responses induced by conventional subcutaneous and sublingual immunotherapy, and gives a unifying view to reconciling the old dualism between immunoredirecting and immunoregulating mechanisms. PMID:20408857
Stebbins, Karin J; Broadhead, Alexander R; Musiyenko, Alla; Barik, Sailen; Scott, Jill M; Truong, Yen P; Stearns, Brian A; Hutchinson, John H; Prasit, Peppi; Evans, Jilly F; Lorrain, Daniel S
Allergic conjunctivitis is characterized by itchy, watery and swollen eyes which occur in response to exposure to seasonal or environmental allergens. The early phase reaction of allergic conjunctivitis is primarily mediated by mast cell degranulation while the late phase reaction is driven by Th2 cells and eosinophils. Prostaglandin D(2) (PGD(2)), released from mast cells, is present in allergic conjunctival tears and may elicit classical allergic responses via interaction with the high-affinity DP2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells, CRTh2). Furthermore, antagonism of this receptor is well known to inhibit eosinophil chemotaxis, basophil activation and Th2 cytokine production. PGD(2), therefore, may be involved in both early and late phase reactions in response to allergen challenge. Thus, we explored whether our novel and selective DP2 antagonist AM156 would be efficacious in animal models of allergic conjunctivitis. Furthermore, as respiratory syncytial virus (RSV) has been implicated in the pathogenesis of allergic conjunctivitis, we examined the effects of DP2 antagonism in a murine model of RSV ocular infection. Utilizing a guinea pig ovalbumin model and a murine ragweed model we demonstrated that AM156 reduces redness, discharge and swelling in response to allergen challenge. These effects were equal to or greater than those of current clinical treatment options for allergic conjunctivitis including topical corticosteroids and a dual-mechanism antihistamine and decongestant. AM156 significantly reduced RSV-induced ocular inflammation and IL-4 production. These results suggest that a topical DP2 antagonist such as AM156 may represent a novel therapeutic for allergic conjunctivitis. Copyright © 2011 S. Karger AG, Basel.
Cockcroft, Donald W; Hargreave, Fredrick E; O’Byrne, Paul M; Boulet, Louis-Philippe
The allergen challenge has evolved, in less than 150 years, from a crude tool used to document the etiology of allergen-induced disease to a well-controlled tool used today to investigate the pathophysiology and pharmacotherapy of asthma. Highlights of the authors’ involvement with the allergen challenge include confirmation of the immunoglobulin E-dependence of the late asthmatic response, importance of (nonallergic) airway hyper-responsiveness as a determinant of the airway response to allergen, identification of allergen-induced increase in airway hyper-responsiveness, documentation of beta2-agonist-induced increase in airway response to allergen (including eosinophilic inflammation), advances in understanding the pathophysiology and kinetics of allergen-induced airway responses, and development of a muticentre clinical trial group devoted to using the allergen challenge for investigating promising new therapeutic strategies for asthma. PMID:17948142
Arm, J P; Horton, C E; Spur, B W; Mencia-Huerta, J M; Lee, T H
The effects of dietary supplementation with fish oil lipids on the airways responses to allergen and neutrophil biochemistry and function have been studied in 17 atopic asthmatic subjects. Nine subjects received 18 capsules of Max-EPA (3.2 g eicosapentaenoic acid and 2.2 g docosahexaenoic acid) a day and eight subjects received identical capsules containing olive oil, for 10 wk in a double-blind fashion. There were no differences between prediet values and those observed after dietary supplementation with Max-EPA or placebo in the dose of allergen causing an acute asthmatic response as assessed by a 35% fall in specific airways conductance (PD35), the extinction dose of allergen on skin prick testing, the histamine PD35, or the total serum IgE concentrations. Twelve of the 17 subjects developed late asthmatic responses after allergen challenge prediet. Six of these subjects received Max-EPA, and six received placebo capsules. As compared to prediet values, the magnitude of the allergen-induced late asthmatic response was significantly attenuated from 2 to 7 h after allergen challenge following dietary supplementation with Max-EPA (p less than 0.005) but not with placebo. The attenuation of the late response was not accompanied by any significant change in the clinical severity of disease as assessed by diurnal peak expiratory flow rates, symptom scores, or bronchodilator drug usage.(ABSTRACT TRUNCATED AT 250 WORDS)
Stagg, Nicola J; Ghantous, Hanan N; Ladics, Gregory S; House, Robert V; Gendel, Steven M; Hastings, Kenneth L
A workshop entitled "Challenges and Opportunities in Evaluating Protein Allergenicity across Biotechnology Industries" was held at the 51st Annual Meeting of the Society of Toxicology (SOT) in San Francisco, California. The workshop was sponsored by the Biotechnology Specialty Section of SOT and was designed to present the science-based approaches used in biotechnology industries to evaluate and regulate protein allergenicity. A panel of experts from industry and government highlighted the allergenicity testing requirements and research in the agricultural, pharmaceutical/biopharma, and vaccine biotechnology industries and addressed challenges and opportunities for advancing the science of protein allergenicity. The main learning from the workshop was that immunoglobulin E-mediated allergenicity of biotechnology-derived products is difficult to assess without human data. The approaches currently being used to evaluate potential for allergenicity across biotechnology industries are very different and range from bioinformatics, in vitro serology, in vivo animal testing, in vitro and in vivo functional assays, and "biosimilar" assessments (ie, biotherapeutic equivalents to innovator products). The challenge remains with regard to the different or lack of regulatory requirements for allergenicity testing across industries, but the novel approaches being used with bioinformatics and biosimilars may lead to opportunities in the future to collaborate across biotechnology industries.
Brussino, L; Badiu, I; Sciascia, S; Bugiani, M; Heffler, E; Guida, G; Malinovschi, A; Bucca, C; Rolla, G
Allergen exposure may increase airway oxidative stress, which causes lipid membrane peroxidation and an increased formation of 8-isoprostane. The aim of the study was to investigate oxidative stress induced by allergen challenge in mild asthmatics, by measuring 8-isoprostane in exhaled breath condensate (EBC), and to examine their relationship with mediators derived from arachidonic acid. Methods 8-isoprostane, cysteinyl leukotrienes (cys-LTs) and prostaglandin E2 (PGE(2) ) concentrations in EBC were measured at baseline and after allergen challenge in 12 patients with mild allergic asthma sensitized to cat allergen. At 24 h after allergen challenge, compared with baseline values, EBC 8-isoprostane increased [48.64 pg/mL (44.14-53.61) vs. 21.56 pg/mL (19.92, 23.35), P<0.001], cys-LTs increased [27.37 pg/mL (24.09-31.10) vs. 13.28 pg/mL (11.32, 15.57), P<0.001] and PGE(2) decreased [18.69 pg/mL (12.26, 28.50) vs. 39.95 pg/mL (34.37, 46.43), P<0.001]. The trend of increasing 8-isoprostane after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.85, P<0.001) whereas the trend of decreasing PGE(2) after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.52, P=0.001). The increase in EBC 8-isoprostane observed after allergen challenge indicates that allergen exposure increases airway oxidative stress in allergic asthma. The strict correlation between cys-LTs and 8-isoprostane underlines the relationship between allergic inflammation and oxidative stress. A shift of arachidonic acid metabolism towards lipoxygenase pathway is induced by the allergen challenge. Airway oxidative stress occurs after allergen challenge even in patients with mild intermittent allergic asthma. © 2010 Blackwell Publishing Ltd.
Boldogh, Istvan; Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Choudhury, Barun K; Saavedra-Molina, Alfredo; Kruzel, Marian
Colostrinin (CLN), isolated from mothers' pre-milk fluid (colostrum), is a uniform mixture of low-molecular-weight, proline-rich polypeptides. CLN induces neurite outgrowth of pheochromocytoma cells, extends the lifespan of diploid fibroblast cells, inhibits beta-amyloid-induced apoptosis and improves cognitive functions when administered to Alzheimer's disease patients. The aim of this study was to investigate potential allergic responses to CLN and its impact on allergic sensitization and inflammation caused by common allergens. We used a well-characterized mouse model of allergic airway inflammation. Changes in IgE/IgG1 and mucin levels, airway eosinophilia and hyperreactivity to methacholine were determined by ELISA, differential cell counting and whole-body plethysmography, respectively. CLN did not increase IgE/IgG1 levels or induce cutaneous hypersensitivity reaction, airway inflammation and mucin production. Importantly, CLN significantly (p < 0.001) decreased IgE/IgG1 production, airway eosinophilia, mucin production and hypersensitivity induced by allergenic extracts from ragweed pollen grains and house dust mites. CLN itself is non-allergenic; however, it is effective in preventing allergic responses to known indoor and outdoor allergens. These data support the safe application of CLN and its potential use in the prevention of allergic inflammation in humans. Copyright 2008 S. Karger AG, Basel.
Bose, Oishee; Baluk, Peter; Looney, Mark R; Cheng, Laurence E; McDonald, Donald M; Caughey, George H; Krummel, Matthew F
Mast cells (MC) and myeloid dendritic cells (DC) act proximally in detecting and processing antigens and immune insults. We sought to understand their comparative dynamic behavior with respect to the airway epithelium in the steady state and in response to an allergic stimulus in mouse trachea. We devised methods to label MC in living trachea and to demonstrate that MC and DC occupy distinct layers of the tracheal mucosa, with DC being closer to the lumen. DC numbers doubled after allergen challenge, but MC numbers remained stable. MC and DC migrated minimally in either steady state or allergen-challenge conditions, and their interactions with one another appeared to be stochastic and relatively infrequent. While DC, unlike MC, exhibited probing behaviors involving dendrites, these projections did not cross the epithelium into the airway lumen. MC typically were located too far from the epithelial surface to contact the tracheal lumen. However, MC had protrusions toward and into blood vessels, likely to load with IgE. Thus, DC and MC occupy distinct niches and engage in sessile surveillance in the mouse trachea. Little or no access of these cell types to the airway lumen suggests that trans-epithelial transport of proteins in the steady state would be required for them to access luminal antigens.
Thornton, Margaret A; Akasheh, Nadim; Walsh, Marie-Therese; Moloney, Michael; Sheahan, Patrick O; Smyth, Claire M; Walsh, Rory McConn; Morgan, Ross M; Curran, David R; Walsh, Michael T; Gleich, Gerald J; Costello, Richard W
In allergen challenged animal models, eosinophils localize to airway nerves leading to vagally-mediated hyperreactivity. We hypothesized that in allergic rhinitis eosinophils recruited to nasal nerves resulted in neural hyperreactivity. Patients with persistent allergic rhinitis (n=12), seasonal allergic rhinitis (n=7) and controls (n=10) were studied. Inferior nasal turbinate biopsies were obtained before, 8 and 48h after allergen challenge. Eight hours after allergen challenge eosinophils localized to nerves in both rhinitis groups; this was sustained through 48h. Bradykinin challenge, with secretion collection on the contralateral side, was performed to demonstrate nasal nerve reflexes. Twenty fourhours after allergen challenge, bradykinin induced a significant increase in secretions, indicating nasal hyperreactivity. Histological studies showed that nasal nerves expressed both vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 26 (CCL-26). Hence, after allergen challenge eosinophils are recruited and retained at nerves and so may be a mechanism for neural hyperreactivity. Copyright © 2013 Elsevier Inc. All rights reserved.
Kelada, Samir N. P.
Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene–environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design inmore » which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and a consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics.« less
Kelada, Samir N. P.
Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene–environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design in which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and a consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics.
Oseroff, Carla; Sidney, John; Vita, Randi; Tripple, Victoria; McKinney, Denise M.; Southwood, Scott; Brodie, Tess M.; Sallusto, Federica; Grey, Howard; Alam, Rafeul; Broide, David; Greenbaum, Jason A.; Kolla, Ravi; Peters, Bjoern; Sette, Alessandro
A panel of 133 allergens derived from 28 different sources, including fungi, trees, grasses, weeds and indoor allergens, was surveyed utilizing prediction of HLA class II binding peptides and ELISPOT assays with PBMC from allergic donors, resulting in the identification of 257 T cell epitopes. More than 90% of the epitopes were novel, and for 14 allergen sources were the first ever identified. The epitopes identified in the different allergen sources summed up to a variable fraction of the total extract response. In cases of allergens where the identified T cell epitopes accounted for a minor fraction of the extract response, fewer known protein sequences were available, suggesting that for “low epitope coverage” allergen sources, additional allergen proteins remain to be identified. IL-5 and IFN-γresponses were measured as prototype Th2 and Th1 responses, respectively. While in some cases (e.g., Orchard Grass, Alternaria, Cypress, and Russian Thistle) IL-5 production greatly exceeded IFN-γ, in others (e.g., Aspergillus, Penicillum, and Alder) the production of IFN-γ exceeded IL-5. Thus, different allergen sources are associated with variable polarization of the responding T cells. The present study represents the most comprehensive survey to date of human allergen derived T cell epitopes. These epitopes might be used to characterize T cell phenotype/T cell plasticity as a function of seasonality, or as a result of SIT treatment or varying disease severity (asthma or rhinitis). PMID:22786768
Narayanan, Meena; Freidl, Raphaela; Focke-Tejkl, Margarete; Baranyi, Ulrike; Wekerle, Thomas; Valenta, Rudolf; Linhart, Birgit
More than 40% of allergic patients suffer from grass pollen allergy. Phl p 1, the major timothy grass pollen allergen, belongs to the cross-reactive group 1 grass pollen allergens that are thought to initiate allergic sensitization to grass pollen. Repeated allergen encounter boosts allergen-specific IgE production and enhances clinical sensitivity in patients. To investigate immunological mechanisms underlying the boosting of allergen-specific secondary IgE Ab responses and the allergen epitopes involved, a murine model for Phl p 1 was established. A B cell epitope-derived peptide of Phl p 1 devoid of allergen-specific T cell epitopes, as recognized by BALB/c mice, was fused to an allergen-unrelated carrier in the form of a recombinant fusion protein and used for sensitization. This fusion protein allowed the induction of allergen-specific IgE Ab responses without allergen-specific T cell help. Allergen-specific Ab responses were subsequently boosted with molecules containing the B cell epitope-derived peptide without carrier or linked to other allergen-unrelated carriers. Oligomeric peptide bound to a carrier different from that which had been used for sensitization boosted allergen-specific secondary IgE responses without a detectable allergen-specific T cell response. Our results indicate that allergen-specific secondary IgE Ab responses can be boosted by repetitive B cell epitopes without allergen-specific T cell help by cross-linking of the B cell epitope receptor. This finding has important implications for the design of new allergy vaccines.
Narayanan, Meena; Freidl, Raphaela; Focke-Tejkl, Margarete; Baranyi, Ulrike; Wekerle, Thomas; Valenta, Rudolf
More than 40% of allergic patients suffer from grass pollen allergy. Phl p 1, the major timothy grass pollen allergen, belongs to the cross-reactive group 1 grass pollen allergens that are thought to initiate allergic sensitization to grass pollen. Repeated allergen encounter boosts allergen-specific IgE production and enhances clinical sensitivity in patients. To investigate immunological mechanisms underlying the boosting of allergen-specific secondary IgE Ab responses and the allergen epitopes involved, a murine model for Phl p 1 was established. A B cell epitope–derived peptide of Phl p 1 devoid of allergen-specific T cell epitopes, as recognized by BALB/c mice, was fused to an allergen-unrelated carrier in the form of a recombinant fusion protein and used for sensitization. This fusion protein allowed the induction of allergen-specific IgE Ab responses without allergen-specific T cell help. Allergen-specific Ab responses were subsequently boosted with molecules containing the B cell epitope–derived peptide without carrier or linked to other allergen-unrelated carriers. Oligomeric peptide bound to a carrier different from that which had been used for sensitization boosted allergen-specific secondary IgE responses without a detectable allergen-specific T cell response. Our results indicate that allergen-specific secondary IgE Ab responses can be boosted by repetitive B cell epitopes without allergen-specific T cell help by cross-linking of the B cell epitope receptor. This finding has important implications for the design of new allergy vaccines. PMID:28093528
Saw, Sanjay; Arora, Naveen
Protease(s) enhances airway inflammation and allergic cascade. In the present study, effect of a serine protease inhibitor was evaluated in mouse model of airway disease. Mice were sensitized with cockroach extract (CE) or Per a 10 and treated with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) 1 h before or after challenge to measure airway response. Mice were euthanized to collect bronchoalveolar lavage fluid (BALF), blood, and lung to evaluate inflammation. AEBSF treatment significantly reduced the AHR in allergen-challenged mice in dose-dependent manner (p≤ 0.01). IgE (p≤0.05) and Th2 cytokines (p≤0.05) were significantly reduced in treated mice. AEBSF treatment lowered total cell (p≤0.05), eosinophil (p≤0.05), and neutrophil (p≤0.05) in BALF and lung tissue. Oxidative stress parameters were impaired on treatment in allergen-challenged mice (p≤0.05). AEBSF had therapeutic effect in allergen-induced airway resistance and underling inflammation and had potential for combination or as add-on therapy for respiratory diseases.
Maniscalco, M; Sofia, M; Carratù, L; Higenbottam, T
Nitric oxide has been detected by chemiluminescence in the lumen of nasal airway, which is increased in nasal breathing in patients with seasonal rhinitis during a chronic exposure. The purpose of this study was to determinate the effect of a NO-synthase inhibitor NGL-arginine methyl ester (L-NAME) on nasal airway resistance (NAR) in patients with seasonal allergic rhinitis after an acute challenge to the allergen. Nitric oxide levels in the nose were measured by the chemiluminescence method in nine non-atopic volunteers and in seven patients with seasonal rhinitis at rest and after an acute challenge with the allergen. NAR were measured by active anterior rhinomanometry. Basal nasal NO concentration in allergic rhinitis was 496.5 +/- 151.4 parts per billion (ppb). (n = 7) and it was not significantly different from levels found in the control group: 458.4 +/- 105.9 ppb (n = 9). The topical administration of L-NAME in allergic rhinitis reduced the NO concentration (338.6 +/- 99.3 ppb, P < 0.001; n = 7). In the rhinitic patients the challenge with the allergen did not modify the nasal NO levels (504.5 +/- 138.5 ppb). The application of the allergen after the pretreatment with placebo caused a significant increase in NAR (from 0.32 +/- 0.11 Pa s cm-3 to 1.01 +/- 0.12 Pa s cm-3, P < 0.001; n = 7). Pre-treatment with L-NAME did not prevent the increase in NAR induced by allergen challenge (from 0.36 +/- 0.15 Pa s cm-3 to 1.06 +/- 0.26 Pa s cm-3). The results indicate that nasal administration of a NOS inhibitor L-NAME, at doses capable of decreasing nasal NO levels, has no effect on NAR and it does not prevent the NAR increase induced by an acute challenge with allergen in subjects with seasonal rhinitis.
Bossi, R; Banfi, P; Filipazzi, V; Castelli, C; Braga, P C
The antitussive compound Levodropropizine (LD) is active in animal bronchoconstriction induced by histamine and capsaicin and in man protects from bronchoconstriction induced by capsaicin. The primary objective of this study was to evaluate the mechanism of action of LD given at 60 mg t.i.d. as oral drops, for 8 days by means of specific bronchial challenges (allergens) and of aspecific challenges acting via different receptors and fibers (i.e. metacholine via cholinergic receptors and ultrasonically nebulized distilled water (UNDW) via histamine and neuropeptide release). The study design is randomized, double-blind, cross-over versus placebo in 30 allergic asthmatic patients. Baseline bronchial tone and bronchoconstrictor response to metacholine (MCh) were not modified by active treatment nor by placebo. On the contrary, in airway responsiveness to UNDW, the active treatment showed an antagonist effect against induced bronchoconstriction of 59% [activity ratio (AR) as antilog = 0.41; 95% confidence interval 0.35-0.54; p < or = 0.05] in comparison to no effect for placebo. Similarly, in airway responsiveness to specific allergen, active treatment antagonized the bronchoconstrictor effect of grass pollen by 83% and of various allergens (dermatophagoides and grass pollen) by 72%, i.e. AR of 0.17 (95% confidence interval 0.045-0.65; p < 0.01) and of 0.28 (95% confidence interval 0.07-1.04; p < 0.05), respectively. No antagonist effect was evident with placebo at all times. Besides inhibiting cough, LD is also partially effective in inhibiting bronchial hyperreactive response against specific allergen and UNDW bronchoconstriction. Hence, LD might act by partly inhibiting histamine and neuropeptide release.
Radauer-Preiml, Isabella; Andosch, Ancuela; Hawranek, Thomas; Luetz-Meindl, Ursula; Wiederstein, Markus; Horejs-Hoeck, Jutta; Himly, Martin; Boyles, Matthew; Duschl, Albert
Engineered nanomaterials (ENMs) interact with different biomolecules as soon as they are in contact, resulting in the formation of a biomolecule 'corona'. Hence, the 'corona' defines the biological identity of the ENMs and could affect the response of the immune system to ENM exposure. With up to 40 % of the world population suffering from type I allergy, a possible modulation of allergen effects by binding to ENMs is highly relevant with respect to work place and consumer safety. Therefore, the aim of this present study was to gain an insight into the interactions of gold nanoparticles with different seasonally and perennially occurring outdoor and indoor allergens. Gold nanoparticles (AuNPs) were conjugated with the major allergens of birch pollen (Bet v 1), timothy grass pollen (Phl p 5) and house dust mite (Der p 1). The AuNP-allergen conjugates were characterized by means of TEM negative staining, dynamic light scattering (DLS), z-potential measurements and hyperspectral imaging. Furthermore, 3D models were constructed, based on the characterization data, to visualize the interaction between the allergens and the AuNPs surface. Differences in the activation of human basophil cells derived from birch/grass pollen- and house dust mite-allergic patients in response to free allergen and AuNP-allergen conjugates were determined using the basophil activation assay (BAT). Potential allergen corona replacement during BAT was controlled for using Western blotting. The protease activity of AuNP-Der p 1 conjugates compared to free Der p 1 was assessed, by an enzymatic activity assay and a cellular assay pertaining to lung type II alveolar epithelial cell tight junction integrity. The formation of a stable corona was found for all three allergens used. Our data suggest, that depending on the allergen, different effects are observed after binding to ENMs, including enhanced allergic responses against Der p 1 and also, for some patients, against Bet v 1. Moreover elevated
Jackson, H A; Jackson, M W; Coblentz, L; Hammerberg, B
Fourteen dogs with known clinical hypersensitivity to soy and corn were maintained on a limited antigen duck and rice diet until cutaneous manifestations of pruritus were minimal (78 days). Sequential oral challenges with cornstarch, corn and soy were then performed. Subsequently, the dogs were fed a diet containing hydrolysed soy protein and cornstarch. Throughout the study period the dogs were examined for cutaneous manifestations of pruritus and, additionally, serum was collected for measurement of allergen-specific and total immunoglobulin (Ig)E concentrations. Intradermal testing with food antigens was performed prior to entry into the study and after 83 days. A statistically significant clinical improvement was measured between days 0 and 83. Significant pruritus was induced after oral challenge with cornstarch, corn and soy (P = 0.04, 0.002, 0.01, respectively) but not with the hydrolysed diet (P = 0.5). The positive predictive value of the skin test for soy and corn allergy was reduced after feeding a soy and corn free diet. Although increases in soy and corn-specific serum IgE concentrations were measured in individual dogs post challenge they were not statistically significant and could not be used to predict clinical hypersensitivity.
Jung, Kyung-Hwa; Song, Joohyun; Kim, You Ah; Cho, Hi Jae; Min, Byung-Il; Bae, Hyunsu
Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. Viticis Fructus (VF) has long been used in China and Korea as a traditional herbal remedy for treating various inflammatory diseases. Previously, we have isolated a novel phytochemical, pyranopyran-1, 8-dione (PPY), from VF. This study was conducted to evaluate the ability of PPY to prevent airway inflammation and to attenuate airway responses in a cockroach allergen-induced asthma model in mice. The mice sensitized to and challenged with cockroach allergen were treated with oral administration of PPY. The infiltration of total cells, eosinophils and lymphocytes into the BAL fluid was significantly inhibited in cockroach allergen-induced asthma mice treated with PPY (1, 2, or 10 mg/kg). Th2 cytokines and chemokine, such as IL-4, IL-5, IL-13 and eotaxin in BAL fluid were also reduced to normal levels following treatment with PPY. In addition, the levels of IgE were also markedly suppressed after PPY treatment. Histopathological examination demonstrated that PPY substantially inhibited eosinophil infiltration into the airway, goblet cell hyperplasia and smooth muscle hypertrophy. Taken together, these results demonstrate that PPY possesses a potent efficacy on controlling allergic asthma response such as airway inflammation and remodeling. PMID:24489937
Correa da Rosa, Joel; Malajian, Dana; Shemer, Avner; Rozenblit, Mariya; Dhingra, Nikhil; Czarnowicki, Tali; Khattri, Saakshi; Ungar, Benjamin; Finney, Robert; Xu, Hui; Zheng, Xiuzhong; Estrada, Yeriel D; Peng, Xiangyu; Suárez-Fariñas, Mayte; Krueger, James G; Guttman-Yassky, Emma
Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated. We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge. Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber). Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, TH1-subset, and TH2-subset genes in nickel-related AD responses, with increased TH17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD. Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased TH2, TH17, and
Potiwat, Rutcharin; Sitcharungsi, Raweerat
Hypersensitivity reactions caused by ant stings are increasingly recognized as an important cause of death by anaphylaxis. Only some species of ants ( e.g. Solenopsis spp., Myrmecia spp., and Pachycondyla spp.) cause allergic reactions. Ant species are identified by evaluating the morphologic structures of worker ants or by molecular techniques. Ant venom contains substances, including acids and alkaloids, that cause toxic reactions, and those from Solenopsis invicta or the imported fire ant have been widely studied. Piperidine alkaloids and low protein contents can cause local reactions (sterile pustules) and systemic reactions (anaphylaxis). Imported fire ant venoms are cross-reactive; for example, the Sol i 1 allergen from S. invicta has cross-reactivity with yellow jacket phospholipase. The Sol i 3 allergen is a member of the antigen 5 family that has amino acid sequence identity with vespid antigen 5. The clinical presentations of ant hypersensitivity are categorized into immediate and delayed reactions: immediate reactions, such as small local reactions, large local reactions, and systemic reactions, occur within 1-4 hours after the ant stings, whereas delayed reactions, such as serum sickness and vasculitis, usually occur more than 4 hours after the stings. Tools for the diagnosis of ant hypersensitivity are skin testing, serum specific IgE, and sting challenge tests. Management of ant hypersensitivity can be divided into immediate (epinephrine, corticosteroids), symptomatic (antihistamines, bronchodilators), supportive (fluid resuscitation, oxygen therapy), and preventive (re-sting avoidance and immunotherapy) treatments.
Williams, P Brock; Barnes, Charles S; Portnoy, Jay M
Exposure to fungi and their products is practically ubiquitous, yet most of this is of little consequence to most healthy individuals. This is because there are a number of elaborate mechanisms to deal with these exposures. Most of these mechanisms are designed to recognize and neutralize such exposures. However, in understanding these mechanisms it has become clear that many of them overlap with our ability to respond to disruptions in tissue function caused by trauma or deterioration. These responses involve the innate and adaptive immune systems usually through the activation of nuclear factor kappa B and the production of cytokines that are considered inflammatory accompanied by other factors that can moderate these reactivities. Depending on different genetic backgrounds and the extent of activation of these mechanisms, various pathologies with resulting symptoms can ensue. Complicating this is the fact that these mechanisms can bias toward type 2 innate and adaptive immune responses. Thus, to understand what we refer to as allergens from fungal sources, we must first understand how they influence these innate mechanisms. In doing so it has become clear that many of the proteins that are described as fungal allergens are essentially homologues of our own proteins that signal or cause tissue disruptions. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Cockcroft, Donald W
It was only in the late 19th century that specific allergens, pollen, animal antigens and, later, house dust mite, were identified to cause upper and lower airway disease. Early allergen challenge studies, crudely monitored before measurement of forced expiratory volume in 1 s became widespread in the 1950s, focused on the immediate effects but noted in passing prolonged and/or recurrent asthma symptoms. The late asthmatic response, recurrent bronchoconstriction after spontaneous resolution of the early responses occurring 3 h to 8 h or more postchallenge, has been identified and well characterized over the past 50 years. The associated allergen-induced airway hyper-responsiveness (1977) and allergen-induced airway inflammation (1985) indicate that these late sequelae are important in the mechanism of allergen-induced asthma. Allergens are now recognized to be the most important cause of asthma. A standardized allergen inhalation challenge model has been developed and is proving to be a valuable research tool in the investigation of asthma pathophysiology and of potential new pharmacological agents for the treatment of asthma. PMID:24791256
Wüthrich, B; Chen-Walden, H
The protective effect of a new inhaled steroid, fluocortin butyl (FCB), was compared to that of disodium cromoglycate (DSCG) and beclomethasone dipropionate (BDP) in patients with extrinsic asthma by means of the allergen-inhalation challenge test. Three different groups of 12 patients each participated in the study. One group was treated with FCB and BDP, the two others with FCB and DSCG, all in a randomized crossover study plan. After an initial allergen challenge (FEV1 fall greater than 15%), the patients were allocated to either treatment for 7-10 days. A second challenge test was then carried out, followed by a washout period of 4 days. The treatments were then crossed-over, and a third allergen challenge was carried out at the end of the second treatment period. With BDP 5 of 12 patients were protected; with FCB, 6 of 12 in two groups and 8 of 12 patients in a third group. With DSCG 3 of 12 patients were protected in the group in which the last medication was given 12 h before challenge, and 8 of 12 patients in the second group in which medication was given 1-2 h before challenge. In the same groups on FCB no such time-dependent effect was observed. No statistically significant differences were found between either FCB and BDP, or FCB and DSCG in either group.
Tung, Hui-Ying; Landers, Cameron; Li, Evan; Porter, Paul; Kheradmand, Farrah; Corry, David B.
Purpose of review The purpose is to review the important recent advances made in how innate immune cells, microbes, and the environment contribute to the expression of allergic disease, emphasizing the allergen-related signals that drive allergic responses. Recent findings The last few years have seen crucial advances in how innate immune cells such as innate lymphoid cells group 2 and airway epithelial cells and related molecular pathways through organismal proteinases and innate immune cytokines, such as thymic stromal lymphopoietin, IL-25, and IL-33 contribute to allergy and asthma. Simultaneously with these advances, important progress has been made in our understanding of how the environment, and especially pathogenic organisms, such as bacteria, viruses, helminths, and especially fungi derived from the natural and built environments, either promote or inhibit allergic inflammation and disease. Of specific interest are how lipopolysaccharide mediates its antiallergic effect through the ubiquitin modifying factor A20 and the antiallergic activity of both helminths and protozoa. Summary Innate immune cells and molecular pathways, often activated by allergen-derived proteinases acting on airway epithelium and macrophages as well as additional unknown factors, are essential to the expression of allergic inflammation and disease. These findings suggest numerous future research opportunities and new opportunities for therapeutic intervention in allergic disease. PMID:26658015
Background Allergen-specific immunotherapy has been demonstrated to have potential for the treatment of allergic diseases. Transgenic animals are currently the best available bioreactors to produce recombinant proteins, which can be secreted in milk. It has not been clearly demonstrated whether milk from transgenic animals expressing recombinant allergens has immunomodulatory effects on allergic asthma. Methods We aimed to determine whether the oral administration of milk containing a mite allergen can down-regulate allergen-specific airway inflammation. Transgenic CD-1 mice that express a recombinant group 2 allergen from Dermatophagoides pteronyssinus (Dp2) in their milk were generated using an embryonic gene-microinjection technique. Mouse pups were fed transgenic Dp2-containing milk or wild-type milk. Subsequently, these mice were sensitized and challenged with Dp2 to induce allergic airway inflammation. Results Upon sensitization and challenge, mice fed transgenic Dp2 milk had decreased T-helper 2 (Th2) and increased T-helper 1 (Th1) responses in the airway compared with mice fed wild-type milk. Moreover, pre-treatment with transgenic Dp2 milk attenuated airway inflammation and decreased airway hyper-responsiveness. Conclusions This study provides new evidence that oral administration of transgenic milk containing the Dp2 allergen down-regulated and moderately protected against allergic airway inflammation. Milk from transgenic animals expressing allergens may have potential use in the prevention of allergic asthma. PMID:23763898
Jutel, Marek; Solarewicz-Madejek, Katarzyna; Smolinska, Sylwia
Allergen specific immunotherapy (SIT) is the only known causative treatment of allergic diseases. Recombinant allergen-based vaccination strategies arose from a strong need to both to improve safety and enhance efficacy of SIT. In addition, new vaccines can be effective in allergies including food allergy or atopic dermatitis, which poorly respond to the current treatment with allergen extracts. A number of successful clinical studies with both wild-type and hypoallergenic derivatives of recombinant allergens vaccines have been reported for the last decade. They showed high efficacy and safety profile as well as very strong modulation of T and B cell responses to specific allergens. PMID:23095874
Masieri, Simonetta; Trabattoni, Daria; Incorvaia, Cristoforo; De Luca, Maria Cristina; Dell'Albani, Ilaria; Leo, Gualtiero; Frati, Franco
Adenoids, tubal tonsil, palatine tonsil, and lingual tonsil are immunological organs included in the Waldeyer's ring, the basic function of which is the antibody production to common environmental antigens. Adenoidal hypertrophy (AH) is a major medical issue in children, and adenoidectomy is still the most used treatment worldwide. The response of adenoids to allergens is a good model to evaluate their immunological function. This report assessed the immunological changes in adenoid tissues from children with allergic rhinitis (AR) undergoing sublingual immunotherapy (SLIT). Adenoid samples from 16 children (seven males, nine females, mean age 7.12 years) with AH and clinical indication to adenoidectomy were collected. Of them, five children were not allergic and 11 had house dust mite and grass pollen-induced AR. Among allergic children, in four AR was treated by antihistamines while in seven AR was treated by high-dose SLIT during 4-6 months. The evaluation addressed the T helper 1 (Th1), Th2, and Th3 cells by performing a PCR array on mRNA extracted from adenoid samples. In non-allergic children, a typical Th1 pattern was found. SLIT induced a strong down-regulation of genes involved in Th2 and Th1 activation and function. In particular, in SLIT-treated allergic children IL-4, CCR2, CCR3, and PTGDR2 (Th2 related genes) and CD28, IL-2, and INHA (Th1 related genes) expression was reduced, compared with children treated with antihistamines. These preliminary findings warrant investigation in trials including larger numbers of patients, but indicate that hypertrophic adenoids of allergic children have the typical response to the specific allergen administered by SLIT. This should suggest that one should reconsider the immunological role of adenoids.
Becerril Angeles, M H; Pérez López, A; Azuara Pliego, E
This is a method to evaluate both specific sensitivity to allergens in the nasal mucosa, IgE-mediated hypersensitivity, and antiinflammatory and antiallergic drugs efficacy, whose objectives are for research in diagnosis and treatment. The method is based in allergen extracts delivery in the nasal mucosa and the post-challenge measurement of rhinitis symptoms, vasoactive mediators release quantification and nasal obstruction degree evaluated by rhinomanometry. Nasal allergen challenge is a procedure of diagnostic and therapeutic evaluation usefulness, that must be performed in selected patients, in adequate facilities, by experts physicians, with standardised allergen dosages, in an specific nasal area, with objective measurements (rhinomanometry, mediators and secretions of the allergic response) and symptoms scoring that allow get reliable results in patients with allergic rhinitis under study.
Hara, Kenichiro; Iijima, Koji; Elias, Martha K.; Seno, Satoshi; Tojima, Ichiro; Kobayashi, Takao; Kephart, Gail M.; Kurabayashi, Masahiko; Kita, Hirohito
While type 2 immune responses to environmental antigens are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. Here we report that IL-33 and thymic stromal lymphopoietin (TSLP) were produced quickly in the lungs of naïve mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and TSLP sensitized naïve animals to an innocuous airway antigen OVA, which resulted in production of type 2 cytokines and IgE antibody and eosinophilic airway inflammation when mice were challenged with the same antigen. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naïve animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa. PMID:24663677
Hara, Kenichiro; Iijima, Koji; Elias, Martha K; Seno, Satoshi; Tojima, Ichiro; Kobayashi, Takao; Kephart, Gail M; Kurabayashi, Masahiko; Kita, Hirohito
Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa.
Esnault, Stephane; Kelly, Elizabeth A.; Schwantes, Elizabeth A.; Liu, Lin Ying; DeLain, Larissa P.; Hauer, Jami A.; Bochkov, Yury A.; Denlinger, Loren C.; Malter, James S.; Mathur, Sameer K.; Jarjour, Nizar N.
Background The mechanism for the contribution of eosinophils (EOS) to asthma pathophysiology is not fully understood. Genome-wide expression analysis of airway EOS by microarrays has been limited by the ability to generate high quality RNA from sufficient numbers of airway EOS. Objective To identify, by genome-wide expression analyses, a compendium of expressed genes characteristic of airway EOS following an in vivo allergen challenge. Methods Atopic, mild asthmatic subjects were recruited for these studies. Induced sputum was obtained before and 48h after a whole lung allergen challenge (WLAC). Individuals also received a segmental bronchoprovocation with allergen (SBP-Ag) 1 month before and after administering a single dose of mepolizumab (anti-IL-5 monoclonal antibody) to reduce airway EOS. Bronchoalveolar lavage (BAL) was performed before and 48 h after SBP-Ag. Gene expression of sputum and BAL cells was analyzed by microarrays. The results were validated by qPCR in BAL cells and purified BAL EOS. Results A total of 299 transcripts were up-regulated by more than 2-fold in total BAL cells following SBP-Ag. Mepolizumab treatment resulted in a reduction of airway EOS by 54.5% and decreased expression of 99 of the 299 transcripts. 3 of 6 post-WLAC sputum samples showed increased expression of EOS-specific genes, along with the expression of 361 other genes. Finally, the intersection of the 3 groups of transcripts (increased in BAL post SBP-Ag (299), decreased after mepolizumab (99), and increased in sputum after WLAC (365)) was composed of 57 genes characterizing airway EOS gene expression. Conclusion We identified 57 genes that were highly expressed by BAL EOS compared to unseparated BAL cells after in vivo allergen challenge. 41 of these genes had not been previously described in EOS and are thus potential new candidates to elucidate EOS contribution to airway biology. PMID:23844029
Warmbold, Christine; Uliczka, Karin; Rus, Fiorentina; Suck, Roland; Petersen, Arnd; Silverman, Neal; Ulmer, Artur J; Heine, Holger; Roeder, Thomas
Some allergens with relevant protease activity have the potential to directly interact with host structures. It remains to be elucidated whether this activity is relevant for developing their allergenic properties. The major goal of this study was to elucidate whether allergens with a strong protease activity directly interact with modules of the innate immune system, thereby inducing an immune response. We chose Drosophila melanogaster for our experiments to prevent the results from being influenced by the adaptive immune system and used the armamentarium of methods available for the fly to study the underlying mechanisms. We show that Dermatophagoides pteronyssinus major allergen 1 (Der p 1), the major allergen of the house dust mite, efficiently activates various facets of the Drosophila innate-immune system, including both epithelial and systemic responses. These responses depend on the immune deficiency (IMD) pathway via activation of the NF-κB transcription factor Relish. In addition, the major pathogen associated molecular pattern recognizing receptor of the IMD pathway, peptidoglycan recognition protein-LC, was necessary for this response. We showed that Der p 1, which has cysteine protease activity, cleaves the ectodomain of peptidoglycan recognition protein-LC and, thus, activates the IMD pathway to induce a profound immune response. We conclude that the innate immune response to this allergen-mediated proteolytic cleavage represents an ancient type of danger signaling that may be highly relevant for the primary allergenicity of compounds such as Der p 1.
Torjusen, Erika N.; Diette, Gregory B.; Breysse, Patrick N.; Curtin-Brosnan, Jean; Aloe, Charles; Matsui, Elizabeth C.
Home mouse allergen exposure is associated with asthma morbidity, but little is known about the shape of the dose-response relationship or the relevance of location of exposure within the home. Asthma outcome and allergen exposure data were collected every three months for 1 year in 150 urban children with asthma. Participants were stratified by mouse sensitization and relationships between continuous measures of mouse allergen exposure and outcomes of interest were analyzed. Every ten-fold increase in the bed mouse allergen level was associated with an 87% increase in the odds of any asthma-related health care use among mouse sensitized (OR (95% CI): 1.87 (1.21–2.88)), but not non-mouse sensitized participants. Similar relationships were observed for emergency department visit and unscheduled doctor visit among mouse sensitized participants. Kitchen floor and bedroom air mouse allergen concentrations were also associated with greater odds of asthma-related healthcare utilization; however, the magnitude of the association was less than that observed for bed mouse allergen concentrations. In this population of urban children with asthma, there is a linear dose-response relationship between mouse allergen concentrations and asthma morbidity among mouse-sensitized asthmatics. Bed and bedroom air mouse allergen exposure compartments may have a greater impact on asthma morbidity than other compartments. PMID:23067271
Bailey, Michael T; Kierstein, Sonja; Sharma, Satish; Spaits, Matthew; Kinsey, Steven G; Tliba, Omar; Amrani, Yassine; Sheridan, John F; Panettieri, Reynold A; Haczku, Angela
Chronic psychosocial stress exacerbates asthma, but the underlying mechanisms remain poorly understood. We hypothesized that psychosocial stress aggravates allergic airway inflammation by altering innate immune cell function. The effects of stress on airway inflammation, lung function, and glucocorticoid responsiveness were studied in a novel in vivo murine model of combined social disruption stress and allergic sensitization. The effects of corticosterone were assessed on cytokine profile and glucocorticoid receptor activation in LPS-stimulated spleen cell cultures in vitro. Airway inflammation resolved 48 h after a single allergen provocation in sensitized control mice, but not in animals that were repeatedly exposed to stress before allergen challenge. The enhanced eosinophilic airway inflammation 48 h after allergen challenge in these mice was associated with increased levels of IL-5, GM-CSF, IgG1, thymus-activated and regulatory chemokine, TNF-alpha, and IL-6 in the airways and a diminished inhibition of these mediators by corticosterone in LPS-stimulated splenocyte cultures in vitro. Stress-induced reduction of the corticosteroid effects paralleled increased p65 expression and a decreased DNA-binding capability of the glucocorticoid receptor in vitro. Furthermore, glucocorticoid receptor mRNA and protein expression in the lungs of mice exposed to both stress and allergen was markedly reduced in comparison with that in either condition alone or in naive mice. Thus, exposure to repeated social stress before allergen inhalation enhances and prolongs airway inflammation and alters corticosterone responsiveness. We speculate that these effects were mediated at least in part by impaired glucocorticoid receptor expression and function.
Brandt, Eric B.; Biagini Myers, Jocelyn M.; Acciani, Thomas H.; Ryan, Patrick H.; Sivaprasad, Umasundari; Ruff, Brandy; LeMasters, Grace K.; Bernstein, David I.; Lockey, James; LeCras, Timothy D.; Khurana Hershey, Gurjit K.
Background Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEP), increases risk for asthma and asthma exacerbation, however the underlying mechanisms remain poorly understood. Objective To examine the impact of DEP exposure on the generation and persistence of allergen-specific memory T-cells in asthma and translate these findings by determining the impact of early DEP exposure on the prevalence of allergic asthma in children. Methods The impact of DEP on HDM-specific memory responses was determined using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort were analyzed to determine the impact of the DEP exposure on asthma outcomes. Results DEP co-exposure with HDM resulted in persistent Th2/Th17 CD127+ effector/memory cells in the lungs, spleen and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased levels of Th2 cytokines in only mice that had been previously exposed to both HDM and DEP versus HDM alone. Based on these data, we examined whether DEP exposure was similarly associated increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the CCAAPS birth cohort. Early life exposure to high DEP was associated with significantly increased asthma prevalence among allergic children, but not among non-allergic children. Conclusion These findings suggest that DEP exposure results in accumulation of allergen specific Th2/Th17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma. PMID:25748065
Marzban, Gorji; Maghuly, Fatemeh; Herndl, Anita; Katinger, Hermann; Laimer, Margit
Cross-reactive proteins in small fruits of the Rosaceae family like strawberry, raspberry and blackberry revealed an unexpected complex IgE-reactivity pattern. Several copies of PR-10 and PR-14 proteins were detected by Southern blots in strawberry, raspberry and blackberry. In raspberry, the highest similarity at the DNA level for PR-10 and PR-14 (Rub i 1 and Rub i 3) was detected to strawberry sequences of Fra a 1 and Fra a 3. At the protein level, Rub i 1 and Rub i 3 showed more than 70% identity with homologous proteins of rosaceous fruits. Furthermore, raspberries contained additional putative allergens, e.g. class III acidic chitinases and cyclophilins. Blackberries were shown to share at least two well-known major fruit allergens with other rosaceous fruits, namely PR-10s and PR-14s homologous proteins. However the IgE-reactive proteins of small fruits are still not extensively investigated. The main challenges in studying small fruit allergens are the complexity of the fruit matrix, the diversity of physico-chemical properties of fruit proteins, the lack of appropriate protein extraction procedures and the missing information about the influence of processing treatments on food components.
Papazian, D; Hansen, S; Würtzen, P A
The prevalence of allergic diseases such as allergic rhinitis is increasing, affecting up to 30% of the human population worldwide. Allergic sensitization arises from complex interactions between environmental exposures and genetic susceptibility, resulting in inflammatory T helper 2 (Th2) cell-derived immune responses towards environmental allergens. Emerging evidence now suggests that an epithelial dysfunction, coupled with inherent properties of environmental allergens, can be responsible for the inflammatory responses towards allergens. Several epithelial-derived cytokines, such as thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, influence tissue-resident dendritic cells (DCs) as well as Th2 effector cells. Exposure to environmental allergens does not elicit Th2 inflammatory responses or any clinical symptoms in nonatopic individuals, and recent findings suggest that a nondamaged, healthy epithelium lowers the DCs' ability to induce inflammatory T-cell responses towards allergens. The purpose of this review was to summarize the current knowledge on which signals from the airway epithelium, from first contact with inhaled allergens all the way to the ensuing Th2-cell responses, influence the pathology of allergic diseases.
Gimenez-Rivera, Vladimir-Andrey; Siebenhaar, Frank; Zimmermann, Carolin; Siiskonen, Hanna; Metz, Martin; Maurer, Marcus
Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient Kit(W-sh/W-sh) (Sash) and MCPT5-Cre(+)iDTR(+) mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8(+) tissue-resident memory T (TRM) cells. The CD8(+) T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous TRM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8(+) TRM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition.
Background A. fumigatus has been associated with a wide spectrum of allergic disorders such as ABPA or SAFS. It is poorly understood what allergens in particular are being expressed during fungal invasion and which are responsible for stimulation of immune responses. Study of the dynamics of allergen production by fungi may lead to insights into how allergens are presented to the immune system. Methods Expression of 17 A. fumigatus allergen genes was examined in response to various culture conditions and stimuli as well as in the presence of macrophages in order to mimic conditions encountered in the lung. Results Expression of 14/17 allergen genes was strongly induced by oxidative stress caused by hydrogen peroxide (Asp f 1, -2, -4, -5, -6, -7, -8, -10, -13, -17 and -18, all >10-fold and Asp f 11, -12, and -22, 5-10-fold) and 16/17 allergen genes were repressed in the presence of cAMP. The 4 protease allergen genes (Asp f -5, -10, -13 and -18) were expressed at very low levels compared to the comparator (β-tubulin) under all other conditions examined. Mild heat shock, anoxia, lipid and presence of macrophages did not result in coordinated changes in allergen gene expression. Growth on lipid as sole carbon source contributed to the moderate induction of most of the allergen genes. Heat shock (37°C > 42°C) caused moderate repression in 11/17 genes (Asp f 1, -2, -4, -5, -6, -9, -10, -13, -17, -18 and -23) (2- to 9-fold), which was mostly evident for Asp f 1 and -9 (~9-fold). Anaerobic stress led to moderate induction of 13/17 genes (1.1 to 4-fold) with one, Asp f 8 induced over 10-fold when grown under mineral oil. Complex changes were seen in gene expression during co-culture of A. fumigatus with macrophages. Conclusions Remarkable coordination of allergen gene expression in response to a specific condition (oxidative stress or the presence of cAMP) has been observed, implying that a single biological stimulus may play a role in allergen gene regulation
Abelius, Martina Sandberg; Enke, Uta; Varosi, Frauke; Hoyer, Heike; Schleussner, Ekkehard; Jenmalm, Maria C; Markert, Udo R
The immunological milieu in the placenta may be crucial for priming the developing foetal immune system. Early imbalances may promote the establishment of immune-mediated diseases in later life, including allergies. The initial exposure to allergens seems to occur in utero, but little is known about allergen-induced placental cytokine and chemokine release. The release of several cytokines and chemokines from placenta tissue after exposure to mast cell degranulator compound 48/80 or apple allergen in placentas from allergic and healthy mothers was to be analysed. Four placentas from women with apple allergy and three controls were applied in a placental perfusion model with two separate cotyledons simultaneously perfused with and without apple allergen (Mal d 1). Two control placentas were perfused with compound 48/80. In outflow, histamine was quantified spectrophotofluorometrically, IL-2, IL-4, IL-6, IL-10, TNF and IFN-γ by a cytometric multiplex bead array and IL-13 and CXCL10, CXCL11, CCL17 and CCL22 with an in-house multiplex Luminex assay. Compound 48/80 induced a rapid release of histamine, CXCL10, CXCL11, CCL17 and CCL22, but not of the other factors. Apple allergen induced a time-dependent release of IL-6 and TNF, but not of histamine, in placentas of women with apple allergy compared with the unstimulated cotyledon. CCL17 levels were slightly increased after allergen stimulation in control placentas. Allergens can induce placental cytokines and chemokines distinctly in allergic and healthy mothers. These mediators may affect the prenatal development of the immune system and modify the risk of diseases related to immune disorders in childhood such as allergies.
Tworek, Damian; Kuna, Piotr; Młynarski, Wojciech; Górski, Paweł; Pietras, Tadeusz; Antczak, Adam
The role of monokine induced by interferon-γ (IFN-γ, MIG/CXCL9), IFN-γ-inducible protein (IP-10/CXCL10), and IFN-inducible T cell α chemoattractant (I-TAC/CXCL11) in allergic inflammation has not been explored in detail in vivo. The aim of the study was to examine the changes in concentrations of MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 in nasal lavages collected from healthy and allergic subjects during nasal allergen challenge. Subjects allergic to grass pollen and healthy controls were included. Nasal allergen challenge preceded by placebo administration was performed outside the pollen season. Nasal lavages were collected before and 30 min after application of the placebo and 30 min after allergen administration. Concentrations of chemokines were determined using ELISA. We observed significantly higher concentrations of IP-10/CXCL10 in allergic patients compared to the healthy subjects before (354.49 ±329.24 vs. 164.62 ±175.94 pg/ml; p = 0.036), 30 min after placebo (420.3 ±421.28 vs. 246.88 ±353.24 pg/ml; p = 0.021) and 30 min after allergen administration (403.28 ±359.29 vs. 162.68 ±148.69 pg/ml; p = 0.025). IP-10/CXCL10 levels did not change 30 min after allergen provocation. In contrast, MIG/CXCL9 levels were similar in both groups before and after placebo. However, a significant rise in MIG/CXCL9 concentration was noted in allergic patients 30 min after the allergen (138.88 ±109.59 vs. 395.8 ±301.2 pg/ml; p = 0.00026). I-TAC/CXCL11 concentrations increased after placebo as well as the allergen in both groups. IP-10/CXCL10 concentrations are elevated in nasal lavages from allergic patients and this chemokine may play a role in chronic allergic inflammation. MIG/CXCL9 levels increase rapidly after allergen application, which may suggest its role in the early allergic response. Results on I-TAC/CXCL11 concentrations remain inconclusive.
Prichard, M G; Ryan, G; Walsh, B J; Musk, A W
Interrelationships between skin and humoral tests for immediate hypersensitivity to wheat and indicators of respiratory disease were examined in 176 male bakers. Skin tests were assessed by measuring the diameter of the weal resulting from prick innoculation of allergen extract and circulating allergen-specific IgE by radioallergosorbent test (RAST). Fifteen per cent of subjects showed positive skin-prick test responses to wheat extracts. These subjects demonstrated an increased prevalence of respiratory symptoms and of measurable bronchial responsiveness to methacholine. Thirty per cent of subjects had positive skin test responses to common allergens but negative responses to whole wheat. Compared to subjects with no positive skin test responses they had an increased prevalence of bronchial responsiveness to methacholine but a similar prevalence of respiratory symptoms. There was a significant association between skin test responses to whole wheat and skin test responses to common allergens suggesting that bakers with pre-existing sensitivity to common allergens are at increased risk of developing wheat flour sensitization. There was no significant difference between skin-prick test and RAST responses to wheat, water-soluble wheat protein and common allergens. Both tests showed similar relationships with indices of respiratory disease. The associations between skin test and RAST responses to wheat extracts and indices of respiratory disease was stronger for the water-soluble wheat proteins than for other wheat grain extracts. These results suggest that immediate hypersensitivity to wheat flour is important in the development of non-specific bronchial hyperreactivity in bakers and that the water-soluble fractions of wheat flour are the most important allergenic components.(ABSTRACT TRUNCATED AT 250 WORDS)
Hourihane, J. O.; Bedwani, S. J.; Dean, T. P.; Warner, J. O.
OBJECTIVE: To determine the in vivo allergenicity of two grades of peanut oil for a large group of subjects with proved allergy to peanuts. DESIGN: Double blind, crossover food challenge with crude peanut oil and refined peanut oil. SETTING: Dedicated clinical investigation unit in a university hospital. SUBJECTS: 60 subjects allergic to peanuts; allergy was confirmed by challenge tests. OUTCOME MEASURES: Allergic reaction to the tested peanut oils. RESULTS: None of the 60 subjects reacted to the refined oil; six (10%) reacted to the crude oil. Supervised peanut challenge caused considerably less severe reactions than subjects had reported previously. CONCLUSIONS: Crude peanut oil caused allergic reactions in 10% of allergic subjects studied and should continue to be avoided. Refined peanut oil did not pose a risk to any of the subjects. It would be reasonable to recommend a change in labelling to distinguish refined from crude peanut oil. PMID:9133891
Glaumann, Susanne; Nopp, Anna; Johansson, S G O; Borres, Magnus P; Nilsson, Caroline
Double-blind placebo-controlled food challenge, DBPCFC, the gold standard for diagnosing food allergy, is time-consuming and potentially dangerous. A basophil allergen threshold sensitivity test, CD-sens, has shown promising results as a diagnostic tool in food allergy. To evaluate the reproducibility of oral peanut challenge and compare the outcome to CD-sens in peanut-sensitized children. Twenty-seven children (4-19 years) underwent a DBPCFC followed by a single-blind oral food-challenge. The peanut challenges (1 mg to 5 g) were evaluated by severity scoring. Blood samples were drawn for CD-sens before the two first challenges. Thirteen children (48%) did not react at any of the challenges. Fourteen reacted at both peanut challenges but not to placebo. Only two of these children reacted at the same threshold dose and with the same severity score. All other children scored differently or reacted at different doses. For children with a positive challenge the geometric mean of the ratio of the doses was 1.834 (p = 0.307) and the arithmetic mean of the difference between the severity scores was 0.143 (p = 0.952). No association was obtained between the two peanut challenges regarding severity score (r(s) = 0.11, p = 0.71) or threshold dose (r(s) = 0.35, p = 0.22). Among the children positive in peanut challenge, 12 were positive in CD-sens. Two were low-responders and could not be evaluated. Geometric mean of the ratio of CD-sens values in children with a positive challenge was 1.035 (p = 0.505) but unlike for the severity score and the threshold dose the association between the two CD-sens values was strong (r(s) = 0.94, P<0.001). For a positive/negative test the reproducibility is 100% for both peanut challenge and CD-sens. However, a comparison of the degree of allergen threshold sensitivity between the two tests is not possible since the threshold dose and severity scoring is not reproducible.
van der Valk, J P M; Gerth van Wijk, R; Vergouwe, Y; de Jong, N W
One of the purposes to perform an oral food challenge (FC) test is to avoid unnecessary elimination of food allergens. In case of a negative FC test result, the food can be introduced. It is, however, unknown if patients act according to the outcome of the test. This study evaluates the rate of introduction of peanut, hazelnut, cow's milk or hen's egg allergens after a negative FC test. We investigated the introduction rate of children (0-18 years) with a negative FC test visiting the Department of Allergology, Erasmus Medical Centre Rotterdam from 2008 till 2013 and the factors that influence the rate of introduction. Patients were asked to complete a comprehensive questionnaire about their FC test. In total, 157 (38% girls, mean age during challenge 6.9 years) participated in the study. Of these FC tests, 104 (56%) were followed by a successful introduction, 30 (16%) by a partly introduction (traces or processed foods) and 52 (28%) by a failed introduction. Peanut and hazelnut showed a statistically significant lower successful introduction rate. Age, gender, symptoms during FC test, dietary advice and time period to introduction significantly influenced the rate of introduction. One fourth of the children with failure of introducing foods experienced symptoms during the introduction. More than one quarter of all children with a negative FC test result did not introduce the food. The FC test in its current form does not achieve its objective for this group of children.
Background Allergic sensitisation has been ascribed to a dysregulated relationship between allergen-specific Th1, Th2 and regulatory T cells. We sought to utilise our short-term CD154 detection method to further analyse the relationship between these T cell subsets and investigate differences between seasonal and perennial allergens. Using peripheral blood samples from grass-allergic, cat-allergic and healthy non-atopic subjects, we compared the frequencies and phenotype of CD154-positive T helper cells following stimulation with seasonal (grass) and perennial (cat dander) allergens. Results We identified a higher frequency of CD154+ T cells in grass-allergic individuals compared to healthy controls; this difference was not evident following stimulation with cat allergen. Activated Th1, Th2 and Tr1-like cells, that co-express IFNγ, IL4 and IL10, respectively, were identified in varying proportions in grass-allergic, cat-allergic and non-allergic individuals. We confirmed a close correlation between Th1, Th2 and Tr1-like cell frequency in non-allergic volunteers, such that the three parameters increased together to maintain a low Th2: Th1 ratio. This relationship was dysregulated in grass-allergic individuals with no correlation between the T cell subsets and a higher Th2: Th1 ratio. We confirmed previous reports of a late-differentiated T cell phenotype in response to seasonal allergens compared to early-differentiated T cell responses to perennial allergens. Conclusions The findings confirm our existing work illustrating an important balance between Th1, Th2 and Tr1-like responses to allergens in health, where Th2 responses are frequently observed, but balanced by Th1 and regulatory responses. We confirm previous tetramer-based reports of phenotypic differences in T cells responding to seasonal and perennial allergens. PMID:24188324
Tunnicliffe, W S; Evans, D E; Mark, D; Harrison, R M; Ayres, J G
Particulate sulphates, including sulphuric acid (H2SO4), are important components of the ambient aerosol in some areas and are regarded as air pollutants with potentially important human health effects. Challenge studies suggest little or no effect of H2SO4 exposure on lung function in asthmatic adults, although some epidemiological studies demonstrate an effect of acid species on symptoms in subjects with asthma. To date, the effect of H2SO4 on allergen responsiveness has not been studied. The effect of exposure to particulate H2SO4 on the early asthmatic response to grass pollen allergen has been investigated in 13 adults with mild asthma. After establishment of the provocative dose of allergen producing a 15% fall in forced expiratory volume in one second (FEVI) (PD15) for each subject, they were exposed to air, 100 microg m(-3) or 1,000 g x m(-3) H2SO4 for 1 h, double-blind in random order > or =2 weeks apart, through a head dome delivery system 14 h after each exposure subject underwent a fixed-dose allergen challenge (PD15). Ten subjects completed the study. The mean early asthmatic responses (maximum percentage change in FEV1 during the first 2 h after challenge) following air, 100 microg x m(-3) H2SO4, and 1,000 microg m(-3) H2SO4, were -14.1%, -16.7%, and -18.4%, respectively. The difference between 1,000 microg x m(-3) H2SO4 and air was significant (mean difference: -4.3%, 95% confidence interval (CI: -1.2-7.4%, p=0.013). The difference between air and 100 microg m(-3) H2SO4 approached significance (mean difference: -2.6%, 95% CI: 0.0-5.3%, p = 0.051). These results suggest that, at least at high mass concentration, sulphuric acid can potentiate the early asthmatic response of mild asthmatic subjects to grass pollen allergen, although the effect is limited.
Herbert, Cristan; Siegle, Jessica S.; Shadie, Alexander M.; Nikolaysen, Stina; Garthwaite, Linda; Hansbro, Nicole G.; Foster, Paul S.; Kumar, Rakesh K.
SUMMARY Childhood exposure to environmental particulates increases the risk of development of asthma. The underlying mechanisms might include oxidant injury to airway epithelial cells (AEC). We investigated the ability of ambient environmental particulates to contribute to sensitization via the airways, and thus to the pathogenesis of childhood asthma. To do so, we devised a novel model in which weanling BALB/c mice were exposed to both ambient particulate pollutants and ovalbumin for sensitization via the respiratory tract, followed by chronic inhalational challenge with a low mass concentration of the antigen. We also examined whether these particulates caused oxidant injury and activation of AEC in vitro. Furthermore, we assessed the potential benefit of minimizing oxidative stress to AEC through the period of sensitization and challenge by dietary intervention. We found that characteristic features of asthmatic inflammation developed only in animals that received particulates at the same time as respiratory sensitization, and were then chronically challenged with allergen. However, these animals did not develop airway hyper-responsiveness. Ambient particulates induced epithelial injury in vitro, with evidence of oxidative stress and production of both pro-inflammatory cytokines and Th2-promoting cytokines such as IL-33. Treatment of AEC with an antioxidant in vitro inhibited the pro-inflammatory cytokine response to these particulates. Ambient particulates also induced pro-inflammatory cytokine expression following administration to weanling mice. However, early-life dietary supplementation with antioxidants did not prevent the development of an asthmatic inflammatory response in animals that were exposed to particulates, sensitized and challenged. We conclude that injury to airway epithelium by ambient environmental particulates in early life is capable of promoting the development of an asthmatic inflammatory response in sensitized and antigen-challenged mice
Young, R P; Dekker, J W; Wordsworth, B P; Schou, C; Pile, K D; Matthiesen, F; Rosenberg, W M; Bell, J I; Hopkin, J M; Cookson, W O
In order to test for human histocompatibility leucocyte antigens (HLA) class II restriction of IgE responses, 431 subjects from 83 families were genotyped at the HLA-DR and HLA-DP loci and serotyped for IgE responses to six major allergens from common aero-allergen sources. A possible excess of HLA-DR1 was found in subjects who were responsive to Fel d I compared with those who were not (Odds Ratio (OR) = 2, P = 0.002), and a possible excess of HLA-DR4 was found in subjects responsive to Alt a I (OR = 1.9, P = 0.006). Increased sharing of HLA-DR/DP haplotypes was seen in sibling pairs responding to both allergens. Der p I, Der p II, Phl p V and Can f I were not associated with any definite excess of HLA-DR alleles. No significant correlations were seen with HLA-DP genotype and reactivity to any of the allergens. The results suggest class II HLA restriction is insufficient to account for individual differences in reactivity to common allergens.
Panda, R; Ariyarathna, H; Amnuaycheewa, P; Tetteh, A; Pramod, S N; Taylor, S L; Ballmer-Weber, B K; Goodman, R E
Premarket, genetically modified (GM) plants are assessed for potential risks of food allergy. The major risk would be transfer of a gene encoding an allergen or protein nearly identical to an allergen into a different food source, which can be assessed by specific serum testing. The potential that a newly expressed protein might become an allergen is evaluated based on resistance to digestion in pepsin and abundance in food fractions. If the modified plant is a common allergenic source (e.g. soybean), regulatory guidelines suggest testing for increases in the expression of endogenous allergens. Some regulators request evaluating endogenous allergens for rarely allergenic plants (e.g. maize and rice). Since allergic individuals must avoid foods containing their allergen (e.g. peanut, soybean, maize, or rice), the relevance of the tests is unclear. Furthermore, no acceptance criteria are established and little is known about the natural variation in allergen concentrations in these crops. Our results demonstrate a 15-fold difference in the major maize allergen, lipid transfer protein between nine varieties, and complex variation in IgE binding to various soybean varieties. We question the value of evaluating endogenous allergens in GM plants unless the intent of the modification was production of a hypoallergenic crop.
Kelly, MM; King, EM; Rider, CF; Gwozd, C; Holden, NS; Eddleston, J; Zuraw, B; Leigh, R; O'Byrne, PM; Newton, R
BACKGROUND AND PURPOSE Inhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma. EXPERIMENTAL APPROACH Bronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis. KEY RESULTS Compared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects. CONCLUSIONS AND IMPLICATIONS Expression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy
Smit, Joost J; Pennings, Maarten T; Willemsen, Karina; van Roest, Manon; van Hoffen, Els; Pieters, Raymond H
The relative contribution and the relation between individual peanut allergens in peanut allergic responses is still matter of debate. We determined the individual contribution of peanut proteins to B, T cell and allergic effector responses in a mouse model for peanut allergy. Mice were immunized and challenged by oral gavage with peanut protein extract or isolated allergens Ara h 1, 2, 3 and 6 followed by assessment of food allergic manifestations. In addition, T cell responses to the individual proteins were measured by an in vitro dendritic cell-T cell assay. Sensitization with the individual peanut proteins elicited IgE responses with specificity to the allergen used as expected. However, cross reactivity among Ara h 1, 2, 3 and 6 was observed. T cell re-stimulations with peanut extract and individual peanut proteins also showed cross reactivity between Ara h 1, 2, 3 and 6. Despite the cross reactivity at the IgE level, only Ara h 2 and 6 were able to elicit mast cell degranulation after an oral challenge. However, after systemic challenge, Ara h 1, 2 and 6 and to lesser extent Ara h 3 were able to elicit anaphylactic responses. Ara h 1, 2, 3 and 6 sensitize via the intra-gastric route, but differ in their capacity to cause allergic effector responses. Interestingly, extensive cross reactivity at T cell and antibody level is observed among Ara h 1, 2, 3 and 6, which may have important implications for the diagnosis and therapy of peanut allergy. Awareness about the relative contribution of individual peanut allergens and cross reactivity between these allergens is of importance for current research in diagnostics and therapeutics for and the mechanism of peanut allergy.
Zhang, Yifeng; Deng, Yun; Zhao, Yanyun
The secondary, tertiary, and quaternary structures of squid hemocyanin (Hc) were characterised, and the relationship between Hc structure and allergenicity responses to high hydrostatic pressure (HHP) was modelled. The Hc allergenicity varied with its protein structure. Electrophoresis analysis revealed that HHP treatment significantly decreased the band intensity of Hc when increasing pressure from 200 and 400 MPa to 600 MPa. The protein structure analysis of squid Hc showed that while HHP treatment decreased the α-helix content, free sulfhydryl content, and Rg, it increased the random coil content, surface hydrophobicity index (Ho), Guinier aggregation number (〈Nagg〉G) and average aggregation number (〈Nagg〉Q). The α-helix and random coil contents of the 600 MPa treated samples were 23.67% and 37.54%, respectively, compared to 32.37% and 32.02% in the control, respectively. HHP treatment decreased the IgE and IgG-binding capacities, indicating a significant decrease in the allergenicity (P< 0.05) of squid Hc. This study provided meaningful information of applying HHP to reduce allergenicity, and explained the responses of Hc protein structure to HHP for lowering the allergenicity of squid. PMID:28112159
Woodfolk, Judith A; Commins, Scott P; Schuyler, Alexander J; Erwin, Elizabeth A; Platts-Mills, Thomas A E
Allergens are foreign proteins or glycoproteins that are the target of IgE antibody responses in humans. The relationship between subsequent exposure and the allergic symptoms is often or usually obvious; however, there is increasing evidence that in asthma, atopic dermatitis and some forms of food allergy the induction of symptoms is delayed or chronic. The primary exposure to inhaled allergens is to the particles, which are capable of carrying allergens in the air. Thus, the response reflects not only the properties of the proteins, but also the biological properties of the other constituents of the particle. This is best understood in relation to the mite fecal particles in which the contents include many different immunologically active substances. Allergic disease first became a major problem over 100 years ago, and for many years sensitization to pollens was the dominant form of these diseases. The rise in pediatric asthma correlates best with the move of children indoors, which started in 1960 and was primarily driven by indoor entertainment for children. While the causes of the increase are not simple they include both a major increase in sensitization to indoor allergens and the complex consequences of inactivity. Most recently, there has also been an increase in food allergy. Understanding this has required a reappraisal of the importance of the skin as a route for sensitization. Overall, understanding allergic diseases requires knowing about the sources, the particles and the routes of exposure as well as the properties of the individual allergens.
Hauser, Russ; Rice, Timothy M; Krishna Murthy, G G; Wand, Matt P; Lewis, Daniel; Bledsoe, Toni; Paulauskis, Joseph
Although human experimental studies have shown that gaseous pollutants enhance the inflammatory response to allergens, human data on whether combustion particulates enhance the inflammatory response to allergen are limited. Therefore, we conducted a human experimental study to investigate whether combustion particulates enhance the inflammatory response to aeroallergens. "Enhancement" refers to a greater-than-additive response when combustion particulates are delivered with allergen, compared with the responses when particulates and allergen are delivered alone. Eight subjects, five atopic and three nonatopic, participated in three randomized exposure-challenge sessions at least 2 weeks apart (i.e., clean air followed by allergen, particles followed by no allergen, or particles followed by allergen). Each session consisted of nasal exposure to combustion particles (target concentration of 1.0 mg/m3) or clean air for 1 hr, followed 3 hr later by challenge with whole pollen grains or placebo. Nasal lavage was performed immediately before particle or clean air exposure, immediately after exposure, and 4, 18 and 42 hr after pollen challenge. Cell counts, differentials, and measurement of cytokines were performed on each nasal lavage. In atopic but not in nonatopic subjects, when allergen was preceded by particulates, there was a significant enhancement immediately after pollen challenge in nasal lavage leukocytes and neutrophils (29.7 X 10(3) cells/mL and 25.4 X 10(3) cells/mL, respectively). This represents a 143% and 130% enhancement, respectively. The enhanced response for interleukin-4 was 3.23 pg/mL (p = 0.06), a 395% enhancement. In atopic subjects there was evidence of an enhanced response when particulates, as compared to clean air, preceded the allergen challenge.
Stahl, Jessica; Paps, Judy; Bäumer, Wolfgang; Olivry, Thierry
Ceramides are essential stratum corneum (SC) lipids and they play a pivotal role in maintaining effective cutaneous barrier function. The present study aimed at determining the effect of a Dermatophagoides farinae house dust mite (Df-HDM) allergen challenge on SC ceramides of atopic dogs experimentally sensitized to these allergens. Six Df-HDM-sensitized atopic Maltese-beagle dogs were used. Prechallenge SC was obtained by cyanoacrylate stripping. One week later, the dogs were challenged topically with Df-HDM allergens, which resulted in mild to moderate inflammation 24 h later. Two weeks after challenge, SC of lesional and nonlesional skin was obtained. Finally, SC was collected from challenge sites 2 months after lesion resolution. The different SC lipids were quantified blindly by thin-layer chromatography. Significantly lower amounts of ceramides [AH], [AP], [AS], [NP], [EOP], [NS] and [EOS] were observed in lesional SC compared with prechallenge samples, while no significant effect was found on the amount of other lipids, including cholesterol and free fatty acids. The ceramide profile of nonlesional skin generally showed the same postchallenge reduction pattern. Ceramide amounts returned to normal within 2 months after lesion remission. These findings suggest that the allergic reactions caused by Df-HDM allergens lead to a selective reduction of SC ceramides, not only at sites of inflammation but also at sites away from those of allergen application. There is normalization of ceramide amounts after inflammation subsides. These observations suggest that the deficiency of ceramides observed in canine atopic skin occurs, at least in part, secondary to inflammation. © 2012 The Authors. Veterinary Dermatology © 2012 ESVD and ACVD.
Assessment of immune responses to Penicillium chrysogenum and characterization of its allergens
Yongjoo Chung1, Michael E Viana2, Lisa B Copeland3, and MaryJane K Selgrade3, Marsha D W Ward3. 1 UNC, SPH, Chapel Hill, NC, 2NCSU, CVM, Raleigh, NC, 3US EPA, ORD, NHEERL, RTP,...
Assessment of immune responses to Penicillium chrysogenum and characterization of its allergens
Yongjoo Chung1, Michael E Viana2, Lisa B Copeland3, and MaryJane K Selgrade3, Marsha D W Ward3. 1 UNC, SPH, Chapel Hill, NC, 2NCSU, CVM, Raleigh, NC, 3US EPA, ORD, NHEERL, RTP,...
Liccardi, Gennaro; Martín, Santiago; Lombardero, Manuel; D'Amato, Maria; Barber, Domingo; D'Amato, Gennaro; Cazzola, Mario
The relationship between pet ownership and the risk of developing respiratory allergic sensitization to pet allergens is still controversial. To determine the degree of cutaneous immediate hypersensitivity and the levels of specific IgE and IgG4 antibodies to cat allergen in cat sensitized patients directly or indirectly exposed to this animal. We studied 112 adolescents and adults sensitized to cat allergens (43 with and 69 without a cat at home). There were also 52 control subjects, 27 atopic non-sensitized to cat and 25 non-atopic. The degree of immediate hypersensitivity was assessed by using, in duplicate, skin prick test with four five-fold dilutions of cat hair allergen extract with the content of its major allergen Fel d 1 quantified in micrograms plus positive (10 mg/ml histamine chlorhydrate) and negative (saline solution) controls. The resulting wheal areas were analysed by means of Parallel Line Assay. A blood sample was collected from every patient and control subjects for the evaluation of serological cat specific IgE and IgG4 antibodies. Patients with cat at home had a lower cutaneous response than patients without this pet. The difference in the skin sensitivity was estimated in 3.4 times (P<0.01). There was no statistical difference between the levels of cat specific IgE antibodies in the two groups of patients (P=0.065). The levels of Fel d 1 specific IgG4 antibodies showed a statistically significant association with the presence of cat at home, with higher levels in patients owing cat at home than in patients without this pet (P<0.001). The results of this study demonstrate that direct cat exposure in adolescents and adults with respiratory allergy is associated with a lower cutaneous response to cat allergenic extract, assessed by SPT and compared with indirect exposure. In patients with cat at home mean levels of specific IgE are statistically comparable whereas the levels of IgG4 are higher in comparison with subjects not exposed to cats. The
Duez, C; Gras-Masse, H; Hammad, H; Akoum, H; Didierlaurent, A; André, C; Tonnel, A B; Pestel, J
We have previously established a model to study the in vivo human IgE response using humanized SCID mice. Allergic SCID mice were obtained following intraperitoneal injection with mononuclear cells from Dermatophagoides pteronyssinus (Dpt)-sensitive patients, and sensitization by Dpt allergen intraperitoneal injection (immunization) or Dpt aerosol (inhalation). Human serum IgE was measured in allergic SCID mice after administration of human recombinant IFN-gamma or the lipopeptide LP 52-71 (derived from peptide p52-71 from Der p 1, Dpt major allergen, coupled to a lipophilic moiety), during the immunization or the inhalation phase. IFN-gamma inhibited human IgE production when given at the time of immunization, but not during inhalation. This effect was long-lasting as Dpt aerosol, given one month after immunization and IFN-gamma administration, failed to increase IgE levels. Unlike Dpt or p52-71, LP 52-71 failed to induce human IgE production at day 14 and 21 after its injection, but did inhibit the development of the IgE response after a secondary Dpt-challenge. Moreover, LP 52-71 administration 14 days after Dpt inhalation decreased IgE levels, in contrast to peptide 52-71, which increased IgE levels. Thus, taken together these results indicate that the development of the human IgE response in allergic SCID mice can be modulated by modified allergen and a Th1 cytokine.
Eusebius, Nirupama P; Papalia, Lina; Suphioglu, Cenk; McLellan, Susan C; Varney, Michael; Rolland, Jennifer M; O'Hehir, Robyn E
Bermuda grass pollen (BGP) is an increasingly important seasonal aeroallergen in Australia and other subtropical and temperate regions. BGP shares minimal allergenic cross-reactivity with pollens of rye grass or other Pooideae grasses often used for desensitization regimens in grass pollen allergy. Current allergen immunotherapy is seldom used in asthmatic patients due to IgE-mediated side effects. Since clinically effective immunotherapy is linked with altered allergen-specific T cell response, characterisation of human T cell reactivity to Cyn d 1, the major B cell allergen of BGP, should permit the design of effective and safe immunotherapy for BGP allergy. Short-term BGP-specific CD4+ T cell lines were established from peripheral blood of 14 BGP-sensitive patients before and after conventional 50% BGP and 50% 7-grass mix subcutaneous specific allergen immunotherapy (SIT). T cell diversity of antigen specificity and function was assessed by proliferation and cytokine production to BGP, Cyn d 1 and Cyn d 1 peptides. Three highly immunogenic regions of Cyn d 1 were identified in 13/14 patients pre-SIT: Cyn d 1 (109-128), (181-209) and (217-241). The SIT regimen was clinically efficacious. Following SIT, decreased proliferation to BGP, Cyn d 1 and Cyn d 1 peptides was observed with a marked decrease in the IL-5:IFN-gamma ratio. Cyn d 1 is a major T cell allergen of BGP. Decreased Cyn d 1-specific IL-5 dominant T cell responses were observed in association with clinically effective treatment with the 50% BGP and 50% 7-grass mix. Identified dominant T cell regions of Cyn d 1 should facilitate safer vaccine development for BGP-induced asthma in addition to rhinitis. Copyright 2002 S. Karger AG, Basel
Vermani, Maansi; Vijayan, Vannan Kandi; Agarwal, Mahendra Kumar
Aspergillus species (A. flavus and A. niger) are important sources of inhalant allergens. Current diagnostic modalities employ crude Aspergillus extracts which only indicate the source to which the patient has been sensitized, without identifying the number and type of allergens in crude extracts. We report a study on the identification of major and minor allergens of the two common airborne Aspergillus species and heterogeneity of patients' IgE response to them. Skin prick tests were performed on 300 patients of bronchial asthma and/or allergic rhinitis and 20 healthy volunteers. Allergen specific IgE in patients' sera was estimated by enzyme allergosorbent test (EAST). Immunoblots were performed to identify major/minor allergens of Aspergillus extracts and to study heterogeneity of patients'IgE response to them. Positive cutaneous responses were observed in 17% and 14.7% of patients with A. flavus and A. niger extracts, respectively. Corresponding EAST positivity was 69.2% and 68.7%. In immunoblots, 5 allergenic proteins were identified in A. niger extract, major allergens being 49, 55.4 and 81.5 kDa. Twelve proteins bound patients' IgE in A. flavus extract, three being major allergens (13.3, 34 and 37 kDa). The position and slopes of EAST binding and inhibition curves obtained with individual sera varied from patient to patient. The number and molecular weight of IgE-binding proteins in both the Aspergillus extracts varied among patients. These results gave evidence of heterogeneity of patients' IgE response to major/minor Aspergillus allergens. This approach will be helpful to identify disease eliciting molecules in the individual patients (component resolved diagnosis) and may improve allergen-specific immunotherapy.
Isgrò, Mirko; Bianchetti, Lorenza; Marini, Maurizio A; Mattoli, Sabrina
Allergen exposure and rhinovirus infections that propagate from the upper to the lower airways are the most frequent causes of asthma exacerbation. In patients at increased risk of disease exacerbations, chronic airway inflammation is associated with the airway recruitment of circulating fibrocytes, bone marrow-derived CD34(+)CD45RO(+)CD11b(+)CD13(+)HLA-DR(+) progenitors that have antigen-presenting function and fibroblast-like properties. This study demonstrates that allergen-pulsed circulating fibrocytes from patients with allergic asthma are potent inducer of the predominant release of the T helper type (Th)2 cytokines IL-4 and IL-5 from autologous naïve and memory CD4(+) T cells. This study also provides evidence that circulating fibrocytes from allergic asthmatics are susceptible to rhinovirus infection. Infected cells release high amounts of pro-inflammatory cytokines with minimal production of IFN-α/β. Moreover, allergen-pulsed fibrocytes support prolonged rhinovirus replication and release larger quantities of pro-inflammatory cytokines upon rhinovirus infection than unpulsed fibrocytes. Thus, fibrocytes may amplify allergen-induced, Th2 cell-driven inflammatory responses and promote further inflammation by functioning as a reservoir for rhinovirus replication in asthmatic airways. Through these mechanisms, fibrocytes may play an important role in the provocation of disease exacerbations.
Gupta, Rinkesh Kumar; Raghav, Alok; Sharma, Akanksha; Gupta, Kriti; Neelabh; Mandal, Payal; Tripathi, Anurag; Ansari, Irfan Ahmad; Das, Mukul; Dwivedi, Premendra D
Glycation of food allergens may alter their immunological behaviour. We sought to investigate the impact of glycation on the allergenicity of a food protein. Herein, a chickpea protein (≈26kDa) was purified and characterized as lectin. Further, glycation of this purified protein was carried out. Thereafter, allergic behaviour of this glycated protein was compared with its native form, using various allergic parameters in Balb/c mice. The reduced allergenicity of glycated protein was observed as lesser allergic phenotypes, reduced serum immunoglobulins and allergic mediators, lower mast cells and eosinophil counts, lower protein expressions of Th2 cytokines and associated transcription factors. In addition, more Th1 and less Th2 cytokine production in exposed splenocyte, were evident in the glycated protein treated mice as compared to its native protein treatment. Thus, glycation of the chickpea allergen attenuated the sensitizing potential and allergic responses in Balb/c mice significantly and could also be clinically beneficial. Copyright © 2017 Elsevier Ltd. All rights reserved.
Background The eliciting dose (ED) for a peanut allergic reaction in 5% of the peanut allergic population, the ED05, is 1.5 mg of peanut protein. This ED05 was derived from oral food challenges (OFC) that use graded, incremental doses administered at fixed time intervals. Individual patients’ threshold doses were used to generate population dose-distribution curves using probability distributions from which the ED05 was then determined. It is important to clinically validate that this dose is predictive of the allergenic response in a further unselected group of peanut-allergic individuals. Methods/Aims This is a multi-centre study involving three national level referral and teaching centres. (Cork University Hospital, Ireland, Royal Children’s Hospital Melbourne, Australia and Massachusetts General Hospital, Boston, U.S.A.) The study is now in process and will continue to run until all centres have recruited 125 participates in each respective centre. A total of 375 participants, aged 1–18 years will be recruited during routine Allergy appointments in the centres. The aim is to assess the precision of the predicted ED05 using a single dose (6 mg peanut = 1.5 mg of peanut protein) in the form of a cookie. Validated Food Allergy related Quality of Life Questionnaires-(FAQLQ) will be self-administered prior to OFC and 1 month after challenge to assess the impact of a single dose OFC on FAQL. Serological and cell based in vitro studies will be performed. Conclusion The validation of the ED05 threshold for allergic reactions in peanut allergic subjects has potential value for public health measures. The single dose OFC, based upon the statistical dose-distribution analysis of past challenge trials, promises an efficient approach to identify the most highly sensitive patients within any given food-allergic population. PMID:24028324
Lofgren, Jennifer L S; Mazan, Melissa R; Ingenito, Edward P; Lascola, Kara; Seavey, Molly; Walsh, Ashley; Hoffman, Andrew M
The mouse is the most extensively studied animal species in respiratory research, yet the technologies available to assess airway function in conscious mice are not universally accepted. We hypothesized that whole body plethysmography employing noninvasive restraint (RWBP) could be used to quantify specific airway resistance (sRaw-RWBP) and airway responsiveness in conscious mice. Methacholine responses were compared using sRaw-RWBP vs. airway resistance by the forced oscillation technique (Raw-FOT) in groups of C57, A/J, and BALB/c mice. sRaw-RWBP was also compared with sRaw derived from double chamber plethysmography (sRaw-DCP) in BALB/c. Finally, airway responsiveness following allergen challenge in BALB/c was measured using RWBP. sRaw-RWBP in C57, A/J, and BALB/c mice was 0.51 +/- 0.03, 0.68 +/- 0.03, and 0.63 +/- 0.05 cm/s, respectively. sRaw derived from Raw-FOT and functional residual capacity (Raw*functional residual capacity) was 0.095 cm/s, approximately one-fifth of sRaw-RWBP in C57 mice. The intra- and interanimal coefficients of variations were similar between sRaw-RWBP (6.8 and 20.1%) and Raw-FOT (3.4 and 20.1%, respectively). The order of airway responsiveness employing sRaw-RWBP was AJ > BALBc > C57 and for Raw-FOT was AJ > BALB/c = C57. There was no difference between the airway responsiveness assessed by RWBP vs. DCP; however, baseline sRaw-RWBP was significantly lower than sRaw-DCP. Allergen challenge caused a progressive decrease in the provocative concentration of methacholine that increased sRaw to 175% postsaline values based on sRaw-RWBP. In conclusion, the technique of RWBP was rapid, reproducible, and easy to perform. Airway responsiveness measured using RWBP, DCP, and FOT was equivalent. Allergen responses could be followed longitudinally, which may provide greater insight into the pathogenesis of chronic airway disease.
Renand, Amedee; Archila, Luis D; McGinty, John; Wambre, Erik; Robinson, David; Hales, Belinda J; Thomas, Wayne R; Kwok, William W
In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood. We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced. Fel d 1-, Fel d 4-, Fel d 7-, and Fel d 8-specific T-cell responses were characterized by CD154 expression after antigen stimulation. In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)-specific TH2 (sTH2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sTH2 cells, which correlates with higher IgG4 levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG4 are present in allergic subjects and (2) cat allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.
Burton, M D; Papalia, L; Eusebius, N P; O'Hehir, R E; Rolland, J M
Knowledge of dominant T cell epitopes of major allergens recognized by allergic individuals is required to improve efficacy and safety of allergen immunotherapy. Rye grass pollen (RGP) is the most important source of seasonal aeroallergens in temperate climates and Lol p 1 and Lol p 5 are the two major IgE-reactive allergens. This study aimed to characterize the T cell response to these allergens using a large panel of RGP-sensitive individuals. Short-term RGP-specific T cell lines (TCL) were generated from 38 RGP-sensitive subjects and stimulated with Lol p 1 and/or Lol p 5 allergens and synthetic 20-mer peptides. Proliferative responses were determined by 3H-thymidine uptake and IL-5 and IFN-gamma in culture supernatants analysed by ELISA. Of 17 subjects tested for reactivity to both allergens 16 (94%) responded to Lol p 1 and/or Lol p 5, establishing these as major T cell-reactive allergens. Sites of T cell reactivity were spread throughout the allergen molecules but regions of high reactivity were found. For Lol p 1 these spanned residues 19-38, 109-128, 154-173, 190-209, and for Lol p 5 37-56, 100-119, 145-164, 154-173, 190-209, 217-236 and 226-245. IL-5 and IFN-gamma were produced by T cells cultured with proliferation-inducing peptides. T cell responses to RGP major allergens have been extensively characterized, providing fundamental information for developing T cell-targeted immunotherapy for RGP allergy.
KELLY, ERIN L.; AMMONS, SAMANTHA K.; CHERMACK, KELLY; MOEN, PHYLLIS
This article integrates research on gendered organizations and the work-family interface to investigate an innovative workplace initiative, the Results-Only Work Environment (ROWE), implemented in the corporate headquarters of Best Buy, Inc. While flexible work policies common in other organizations “accommodate” individuals, this initiative attempts a broader and deeper critique of the organizational culture. We address two research questions: How does this initiative attempt to change the masculinized ideal worker norm? And what do women's and men's responses reveal about the persistent ways that gender structures work and family life? Data demonstrate the ideal worker norm is pervasive and powerful, even as employees begin critically examining expectations regarding work time that have historically privileged men. Employees' responses to ROWE are also gendered. Women (especially mothers) are more enthusiastic, while men are more cautious. Ambivalence about and resistance to change is expressed in different ways depending on gender and occupational status. PMID:20625518
Kelly, Gail P.; Altbach, Philip G.
Examines research reported in major books and journals of comparative education since 1977, focusing on challenges to established research traditions and the field's responses. Highlights work directing attention to new subjects of inquiry and challenging the nation-state as the exclusive research framework, input-output models and dominant…
Leonardi, A; Busca, F; Tavolato, M; Secchi, A G
To compare the inhibitory effects of a topical combination product, cromolyn sodium (DSCG) 4% with the antihistamine, chlorpheniramine, with those of topical ketotifen 0.05% on the clinical allergic reaction induced by the conjunctival allergen challenge (CAC). Ten allergic but non-active patients were challenged in both eyes with increasing doses of specific allergen to obtain a positive bilateral reaction (visit 1). They were then rechallenged after 1 week to confirm the allergic threshold dose response (visit 2). After 2 weeks, a third CAC was performed bilaterally 30 minutes after topical application of DSCG-chlorpheniramine in one eye and ketotifen in the contralateral eye in a double-masked fashion (visit 3). Clinical signs and symptoms were registered 5, 10, 15, and 20 minutes after challenge using the standard scoring system. Tear cytology was performed 30 minutes after challenge. Comparing the two drug effects at visit 3, DSCG-chlorpheniramine was shown to be superior to ketotifen at all time points for itching (p < 0.01) and at 5 minutes for redness (p < 0.01). For the total signs score, DSCG-chlorpheniramine was shown to be superior to ketotifen at all time points (p < 0.01), and at 10 and 15 minutes for the total symptoms score (p < 0.05). Compared to visit 2, DSCG-chlorpheniramine significantly lowered itching (p < 0.001) and redness (p < 0.05) at 5, 10, 15, and 20 minutes after challenge. Ketotifen significantly lowered itching at 5 and 10 minutes (p < 0.001) and redness at 5, 10, and 15 minutes (p < 0.05). Both drugs reduced the total number of cells evaluated by tear cytology during the early-phase reaction (p < 0.05). DSCG-chlorpheniramine was found to be more effective than ketotifen at preventing itching and redness in the CAC model.
Blaiss, Michael S.; Tort, Maria
Purpose To further assess the prevention of ocular itching with olopatadine hydrochloride ophthalmic solution, 0.2% (OLO) in patients with allergic conjunctivitis. Methods This was a post-hoc analysis of 85 patients participating in 2 prospective, randomized, double-masked bilateral conjunctival allergen challenge (CAC) studies. Patients received OLO in one eye and placebo (vehicle) in the contralateral eye. Ocular itching was self-assessed by patients and rated on a scale of 0 (none) to 4 (severe). To assess onset of action, eligible patients were challenged with antigen 27 minutes after dosing. To assess duration of action, patients were challenged with allergen 16 hours after dosing. The percentage of eyes with zero itching in both studies was assessed at 3 minutes post allergen challenge. Results The percentage of eyes with zero itch at the 3 minutes timepoint after the onset of action allergen challenge was 60.0% for OLO-treated eyes compared with 5.9% for vehicle-treated eyes (P < .0001, OLO vs vehicle). The percentage of eyes with zero itch at 3 minutes post allergen challenge following the 16-hour dosing was 59.8% for OLO-treated eyes compared with 22.0% for vehicle-treated eyes (P < .0001, OLO vs vehicle). Conclusions In bilateral CAC studies, ocular itching was prevented in a higher percentage (P < .0001) of eyes treated with 0.2% olopatadine hydrochloride ophthalmic solution when compared with vehicle as early as 30 minutes and for at least 16 hours post dosing.
Li, Lin-Jing; Zeng, Lu; Li, Xiao-Xi; Mo, Li-Hua; Geng, Xiao-Rui; Zheng, Peng-Yuan; Liu, Zhi-Gang; Feng, Bai-Sui; Yang, Ping-Chang
The pathogenesis of intestinal chronic inflammation is unclear. Food allergy plays an important role in the induction of intestinal inflammation. This study aims to test a hypothesis that food allergy initiates colitis. In this study, BALB/c mice were sensitized to a common food allergen, ovalbumin (OVA) with cholera toxin (CT) as an adjuvant. The colon epithelial barrier function was assessed with Ussing chamber technique. Expression of T cell immunoglobulin mucin domain molecule-4 (TIM4) in dendritic cells was evaluated by flow cytometry, RT-PCR and Western blotting. The results showed that allergen-related colitis was induced in mice as shown by heavy infiltration of inflammatory cells in the colon mucosa, loss of body weight of mice, increases in myeloperoxidase, tumor necrosis factor-α, interleukin-4, OVA-specific IgE in the colon tissue. The colon epithelial barrier function was markedly compromised in colitis group mice, which was mimicked by exposure the colon mucosa to CT in Ussing chamber. High frequency of TIM4+ dendritic cells was detected in the colon mucosa of colitis mice. Exposure of dendritic cells to CT markedly increased the expression of TIM4. We conclude that IBD-like inflammation can be induced in the mouse colon by the food allergen-related immune response. PMID:27604348
Bonefeld, Charlotte M; Geisler, Carsten; Gimenéz-Arnau, Elena; Lepoittevin, Jean-Pierre; Uter, Wolfgang; Johansen, Jeanne D
Allergic contact dermatitis is one of the most frequent forms of skin inflammation. Very often, we are exposed to mixtures of allergens with varying potencies, doses/areas, and exposure times. Therefore, improved knowledge about immune responses to combinations of contact allergens is highly relevant. In this article, we provide a general introduction to immune responses to contact allergens, and discuss the literature concerning immune responses to mixtures of allergens. According to the existing evidence, increased responses are induced following sensitization with combinations of allergens as compared with single allergens. The response to a mixture of allergens can be both additive and synergistic, depending on the dose and combination of allergens. Importantly, sensitization with combinations of either fragrance allergens or metal salts can result in increased challenge responses to specific allergens within the mixture. Taken together, the immune responses to mixtures of allergens are complex, and further studies are required to obtain the necessary knowledge to improve consumer safety. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Hara, Yuko; Shiraishi, Atsushi; Sakane, Yuri; Takezawa, Yuki; Kamao, Tomoyuki; Ohashi, Yuichi; Yasunaga, Sho; Sugahara, Takuya
To evaluate the effects of mandarin orange yogurt containing nobiletin and β-lactoglobulin on the allergic conjunctivitis induced by a conjunctival allergen challenge (CAC). Experiment 1 was performed on 26 asymptomatic patients (age, 25.3 ± 5.3 years) with proven seasonal allergic conjunctivitis due to cedar pollen. We compared the degree of conjunctivitis induced by CAC before and after ingesting mandarin orange yogurt for 2 weeks. Experiment 2 was a double-blind, placebo-controlled trial performed on 31 patients (age, 32.5 ± 12.2 years). A diet containing mandarin orange yogurt was compared to a diet containing yogurt lacking the mandarin orange on the conjunctivitis induced by CAC. The temperature of the inferior bulbar conjunctiva was measured before and 20 minutes after the CAC with an ocular surface thermographer (OST). The degree of conjunctival injection and chemosis was graded by slit-lamp biomicroscopy. The changes in the symptoms were evaluated by a questionnaire. In experiment 1, the scores of redness (3.07 ± 3.03 vs. 1.05 ± 1.70), chemosis (2.84 ± 2.27 vs. 0.81 ± 1.11), itching (4.34 ± 3.05 vs. 1.39 ± 2.12), and temperature (0.73 ± 0.42°C vs. 0.45 ± 0.43°C) were significantly lower (P < 0.001) after a diet of mandarin orange yogurt for 2 weeks. In experiment 2, the scores of redness (1.03 ± 0.18 vs. 1.28 ± 0.52; P = 0.0156), itching (1.93 ± 1.92 vs. 2.82 ± 2.21; P = 0.0133), and surface temperature (0.54 ± 0.21°C vs. 0.31 ± 0.25°C; P < 0.001) were significantly lower in the mandarin orange yogurt group than in the control yogurt group. Mandarin orange yogurt can be an effective nutritional intervention for allergic conjunctivitis.
Spangler, D L; Bensch, G; Berdy, G J
Olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochlofide 0.05% ophthalmic solution are 2 topical antiallergic agents indicated for the treatment of itching of the eye associated with allergic conjunctivitis. Olopatadine has recently received US Food and Drug Administration (FDA) approval for an expanded indication for the treatment of signs and symptoms of allergic conjunctivitis, including itching, tearing, eyelid swelling, redness, and chemosis. The purpose of this study was to compare the efficacy of olopatadine hydrochloride versus azelastine hydrochloride and placebo (artificial tears) in the conjunctival allergen challenge (CAC) model. This was a prospective, randomized, double-masked, contralaterally controlled, multicenter, allergen-challenge study. Itching was chosen as the primary efficacy variable since it is the only FDA-approved indication these 2 agents have in common. Subjects with a history of allergic conjunctivitis who responded to the CAC at screening visits 1 and 2 were randomized to 1 of 3 treatment groups: olopatadine in 1 eye and azelastine in the other eye; olopatadine in 1 eye and placebo in the other eye; or azelastine in 1 eye and placebo in the other eye. At the assessment visit (visit 3), subjects received masked study medication according to the randomization scheme. After 5 minutes, subjects were bilaterally challenged with the allergen concentration that had elicited a positive conjunctival allergic response at visits 1 and 2. Immediately after challenge, subjects gave itching assessments (scale, 0 = no itching to 4 = severe itching) every 30 seconds for a total period of 20 minutes. Mean itching scores for all eyes were compared by treatment. Mean itching scores at each time point were compared between treatments using 2 sample t tests. Of the 180 subjects screened, 111 responded to the CAC at visits 1 and 2 and completed the study; 65% (72/111) of patients were female, 87% (97/111) were white, and 49% (54
Stefan, Schülke; Kirsten, Kuttich; Sonja, Wolfheimer; Nadine, Duschek; Andrea, Wangorsch; Andreas, Reuter; Peter, Briza; Isabel, Pablos; Gabriele, Gadermaier; Fatima, Ferreira; Stefan, Vieths; Masako, Toda; Stephan, Scheurer
Allergies to weed pollen including members of the Compositae family, such as mugwort, ragweed, and feverfew are spreading worldwide. To efficiently treat these newly arising allergies, allergen specific immunotherapy needs to be improved. Therefore, we generated novel vaccine candidates consisting of the TLR5-ligand Flagellin A from Listeria and the major mugwort allergen Art v 1 including either the wild type Art v 1 sequence (rFlaA:Artv1) or a hypoallergenic variant (rFlaA:Artv1(hyp)) with reduced IgE-binding capacity. Immune modulating capacity of these constructs and respective controls was evaluated in vitro and in vivo. Incorporation of hypoallergenic Art v 1 derivative did not interfere with the resulting fusion proteins' immune stimulatory capacity. Both rFlaA:Artv1 and rFlaA:Artv1(hyp) induced a prominent, mTOR-dependent, IL-10 secretion from murine dendritic cells, and suppressed allergen-specific TH2-cytokine secretion in vitro and in vivo. Both conjugates retained the capacity to induce rFlaA-specific antibody responses while efficiently inducing production of Art v 1-specific IgG1 and IgG2a antibodies in mice. Interestingly, only the suppression of TH2-cytokine secretion by rFlaA:Artv1 (but not rFlaA:Artv1(hyp)) was paralleled by a strong secretion of IFN-γ. In summary, we provided evidence that incorporating hypoallergens into flagellin:allergen fusion proteins is a suitable strategy to further improve these promising vaccine candidates.
Wang, H; Mobini, R; Fang, Y; Barrenäs, F; Zhang, H; Xiang, Z; Benson, M
Previously, expression profiling has been used to analyse allergen-challenged T-helper type 2 cells, nasal biopsies and nasal fluid cells from patients with seasonal allergic rhinitis (SAR). Allergen-challenged peripheral blood mononuclear cells (PBMCs) provide a human in vitro model of how antigen-presenting cells, CD4+ T cells and effector cells such as basophils interact in allergic inflammation. To identify novel genes and pathways in allergen-challenged PBMCs from patients with SAR using gene expression profiling and functional studies. PBMCs from 11 patients with SAR and 23 healthy controls were analysed with gene expression profiling. mRNA expression of IL17RB in basophils was evaluated using quantitative real-time PCR. Membrane protein expression and apoptosis of basophils were examined by flow cytometry. Degranulation of basophils was assessed by measuring beta-hexosaminidase release. Cytokine release was measured using ELISA. Gene expression microarray analysis of allergen-challenged PBMCs showed that 209 out of 44000 genes were differentially expressed in patients compared with controls. IL17RB was the gene whose expression increased most in patients (P<0.0001). FACS analysis of PBMCs showed, for the first time, that basophils express IL-17RB. Following allergen challenge, IL-17RB protein increased significantly on basophils from patients compared with controls (P<0.05). IL-3 significantly increased both mRNA and protein expressions of IL17RB. Activation of IL-17RB by its ligand, IL-25, inhibited apoptosis of basophils. Moreover, IgE-mediated degranulation was enhanced by IL-25. Increased expression of IL-17RB on allergen-challenged basophil is regulated by IL-3, inhibits apoptosis and promotes IgE-mediated degranulation of basophils.
Schulten, Véronique; Tripple, Victoria; Aasbjerg, Kristian; Backer, Vibeke; Lund, Gitte; Würtzen, Peter Adler; Sette, Alessandro; Peters, Bjoern
Background Allergen-specific immunotherapy is the only curative treatment for type I allergy. It can be administered subcutaneously (SCIT) or sublingually (SLIT). The clinical efficacy of these two treatment modalities appears to be similar, but potential differences in the immunological mechanisms involved have not been fully explored. Objective To compare changes in the allergen-specific T cell response induced by subcutaneous versus sublingual administration of allergen-specific immunotherapy (AIT). Methods Grass pollen allergic patients were randomized into groups receiving either SCIT injections, or SLIT tablets or neither. PBMC were tested for Timothy grass (TG)-specific cytokine production by ELISPOT after in vitro expansion with TG peptide pools. Phenotypic characterization of cytokine producing cells was performed by FACS. Results In the SCIT group, decreased IL-5 production was observed starting 10 months after treatment was commenced. At 24 months, T cell responses showed IL-5 levels significantly below the before treatment baseline. No significant reduction of IL-5 was observed in the SLIT or untreated group. However, a significant transient increase in IL-10 production after 10 months of treatment compared to baseline was detected in both treatment groups. FACS analysis revealed that IL-10 production was associated with CD4+ T cells that also produced IFNγ, and therefore may be associated with an IL-10-secreting type 1 cell phenotype. Conclusion and clinical relevance The most dominant immunological changes on a cellular level was a decrease in IL-5 in the SCIT group and a significant, transient increase of IL-10 observed after 10 months of treatment in both treated groups. The distinct routes of AIT administration may induce different immune-modulatory mechanisms at the cellular level. PMID:26436865
Salinas, Eva; Quintanar, J Luis; Ramírez-Celis, Nora Alejandra; Quintanar-Stephano, Andrés
Mast cells are immune cells that play a crucial role in inflammatory reactions related to allergic reactions and the defense against certain parasites and bacteria. In allergy, the binding of immunoglobulin E (IgE) to its high-affinity receptor (FcepsilonRI) sensitizes mast cells. Subsequent cross-linking of IgE-FcepsilonRI by multivalent antigen results in cellular activation and the release of proinflammatory mediators. Recent in vivo and in vitro experiments suggest that IgE not only acts as an allergen sensor, but also induces molecular and biological changes in mast cells. In the present study we examined whether allergen-sensitization in vivo could modify the magnitude of mast cells-induced inflammatory responses. Moreover, we studied changes in peritoneal mast cell number and histamine amount during and after sensitization. We provided evidence that sensitization, at the time of the maximum allergen-specific IgE-titer, increases the intensity of a local inflammatory process generated in a cutaneous anaphylactic reaction. Sensitization also supports innate immunity, improving survival and speeding up the resolution of an acute inflammatory reaction induced by polymicrobial sepsis, while decreasing the amount of histamine in peritoneal mast cells. In addition, our results showed that sensitization induces a late increase in the number and histamine amount of peritoneal mast cells. Thus, our findings clearly demonstrated that sensitization induces changes in mast cells which prepare the cell to induce more intense inflammatory responses. This entails an increased detrimental role in subsequent IgE-dependent allergic reactions and an improved protective function in innate defense against pathogens.
The revised nomenclature for allergens is presented together with proposed nomenclatures for (a) allergen genes, mRNAs and cDNAs, and (b) recombinant and synthetic peptides of allergenic interest. PMID:7955031
Penn, Arthur L; Rouse, Rodney L; Horohov, David W; Kearney, Michael T; Paulsen, Daniel B; Lomax, Larry
Fetal stress has been linked to adult atherosclerosis, obesity, and diabetes. Epidemiology studies have associated fetal exposure to maternal smoking and postnatal exposure to environmental tobacco smoke (ETS) with increased asthma risk. We tested the hypothesis, in a mouse model of asthma, that in utero ETS exposure alters airway function and respiratory immune responses in adults. Pregnant Balb/c mice were exposed daily to ETS or HEPA-filtered air (AIR). Offspring inhaled aerosolized ovalbumin (OVA) or saline in weeks 7-8. Regardless of whether they inhaled OVA or saline, mice were sensitized by OVA injections in weeks 11 and 13 followed by OVA aerosol challenge in weeks 14-15. At three time points, we assessed OVA-specific serum immunoglobins, bronchoalveolar lavage cells and cytokines, lung and nasal histopathology, and airway hyperresponsiveness (AHR). At 6 weeks, we found no significant differences between in utero ETS and AIR mice. At 10 weeks, following OVA aerosol, ETS mice displayed greater AHR than AIR mice (alpha = 0.05), unaccompanied by changes in histopathology, cytokine profile, or antibody levels. At 15 weeks, mice that had inhaled saline in weeks 7-8 developed airway inflammation: eosinophilia (alpha = 0.05), interleukin-5 (alpha = 0.05), and AHR (alpha = 0.05) were greater in ETS mice than in AIR mice. Mice that had inhaled OVA in weeks 7-8 demonstrated no airway inflammation after sensitization and challenge. In utero ETS exposure exacerbates subsequent adult responses to initial allergen exposure.
Drake, Li Yin; Iijima, Koji; Hara, Kenichiro; Kobayashi, Takao; Kephart, Gail M; Kita, Hirohito
Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naïve wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naïve wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell-deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re-stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients.
Interleukin (IL)-9 is a pleiotropic T helper 2-type cytokine that has been shown to be up-regulated in allergic airway disease, including asthma. IL-9 has been demonstrated to be a potent stimulus for the production and secretion of mucus from airway epithelial cells via induction of a calcium-activated chloride channel, hCLCA1. The objective of this study was to investigate the expression of IL-9 and hCLCA1 following allergen challenge in the nasal mucosa of allergic rhinitis patients. Nasal biopsies were obtained from allergic rhinitis patients out of allergen season both before (baseline) and after local antigen challenge with either ragweed or diluent (control). Immunohistochemistry and in situ hybridization were used to assess IL-9 protein and hCLCA1 messenger ribonucleic acid. Eosinophils and T cells were detected using immunohistochemistry. IL-9 and hCLCA1 were very low at baseline, and expression was significantly up-regulated following ragweed challenge. Whereas the number of eosinophils increased after allergen challenge, T-cell counts did not change significantly. The results of this study demonstrate the relationship between specific allergen challenge and expression of both IL-9 and hCLCA1, suggesting a possible mechanism for the increased production of mucus from airway epithelial cells in allergic rhinitis. PMID:20525149
Li, Ning; Dong, Xu; Yang, Chang; Liu, Yuli; Ni, Xiuqin
Nerve growth factor (NGF), combined with the high-affinity tyrosine kinase receptor A (TrkA), has been reported to be involved in the pathogenesis of asthma. Ankyrin-rich membrane spanning/transmembrane substrate of protein kinase D (ARMS/Kidins220), a TrkA‑binding protein, modulates the NGF signaling pathway. The aim of the present study was to investigate the expression of Kidins220/ARMS and the effect NGF has on the protein in the spleen and peripheral blood, following airway allergen challenge in mice. BALB/c mice were sensitized and challenged with ovalbumin. The effects of NGF on Kidins220/ARMS in the spleen and peripheral blood of mice were assessed by administering anti-NGF antibody. Expression of ARMS, interleukin (IL)-1β and IL-4 in the spleen and peripheral blood was observed by reverse transcription-polymerase chain reaction, western blot analysis and immunohistochemistry. Pathological changes in the bronchi and lung tissues were examined by hematoxylin and eosin staining. Results showed that Kidins220/ARMS, IL-1β and IL-4 were overexpressed in the spleen and peripheral blood following allergen challenge, compared with the control mice. Moreover, following treatment with anti-NGF, the levels of Kidins220/ARMS, IL-1β and IL-4 in the mice were downregulated. Therefore, the results of the present study showed that Kidins220/ARMS is expressed in the spleen and peripheral blood of normal BALB/c mice and may participate in the immuno-inflammation of asthma through the NGF-mediated signaling pathway.
García-Gavín, Juan; Parente, Joana; Goossens, An
Sulfites, preservatives and antioxidants used in the cosmetic, pharmaceutical and food industry are contact allergens whose relevance seems to be difficult to establish. To perform a retrospective study on patients patch tested with a sulfite. Materials and methods. Between 1990 and 2010, 2763 patients were patch tested with sodium metabisulfite. The reactions were considered to be relevant if there was a clear relationship between the dermatitis and sulfite exposure. One hundred and twenty-four (4.5%) of 2763 patients patch tested positively to sodium metabisulfite. The most frequent localizations of the lesions were the face (40.3%) and the hands (24.2%). Six patients also reported systemic symptoms. Thirteen cases (10.5%) were occupational, 10 of them presenting with hand eczema. Sodium metabisulfite was the single allergen found in 76 cases (61.3%). The reactions were considered to be relevant in 80 cases (64.5%), of which 11 were occupational. Allergic contact dermatitis caused by sulfites is frequent and often relevant. One should be aware of possible relevant sources of exposure, particularly in occupational settings such as hairdressing and the food industry, and in pharmaceutical and cosmetic products. Patch testing with sodium metabisulfite, which seems to be the best indicator for sulfite contact allergy, is also useful in cases of immediate reactions to sulfite-containing products. © 2012 John Wiley & Sons A/S.
Raison-Peyron, Nadia; Bergendorff, Ola; Bourrain, Jean Luc; Bruze, Magnus
Contact dermatitis resulting from the use of shin pads is usually caused by rubber components, dyes, benzoyl peroxide, or formaldehyde resins. To investigate and identify a new allergen in shin pads that was responsible for severe contact dermatitis in a young football player. High-performance liquid chromatography (HPLC) of samples of shin pads was performed. The boy was patch tested with pieces of shin pads and with acetophenone azine, a chemical substance identified by HPLC in the foam of the shin pads. HPLC identified acetophenone azine at concentrations of approximately 20 µg/g of shin pad samples. Patch tests gave strongly positive reactions to pieces of shin pads and to acetophenone azine down to 0.001% in acetone, whereas acetophenone and hydrazine sulfate were both negative. Twenty controls were negative for acetophenone azine 0.01% in acetone. Acetophenone azine is a new, strong allergen of shin pads, and more generally of other sport equipment based on ethylene vinyl acetate. It may be used as a biocide, but this has to be confirmed. Further investigations are needed to understand factors such as exposure, cross-reaction patterns, metabolism, and the optimal patch test preparation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Proud, D; Togias, A; Naclerio, R M; Crush, S A; Norman, P S; Lichtenstein, L M
Using a recently developed model of nasal challenge, we have obtained data that clearly demonstrate, for the first time, kinin generation during a local allergic reaction in vivo. Allergic individuals (n = 8) and matched nonallergic controls (n = 8) were challenged intranasally with the appropriate antigen and nasal washes were taken before and after challenge. Washes were assayed for kinin, histamine, and [3H]-N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity. Increased kinin generation was found by radioimmunoassay (RIA) in the nasal washes of all the allergics (5,560 +/- 1,670 pg/ml) but in none of the controls (38 +/- 16 pg/ml). The presence of kinin was highly correlated with that of histamine and TAME-esterase activity and with the onset of clinical symptoms (P less than 0.001). Serial dilutions of nasal washes produced RIA displacement curves that paralleled the standard curve, and recovery of standard kinins that were added to nasal washes was 100 +/- 4% (n = 14). Kinin recovery was identical in both allergics and controls and did not vary significantly with antigen challenge. The immunoreactive kinin in nasal washes was stable to boiling and not precipitated by ethanol, but completely destroyed by carboxypeptidase B. It was evenly distributed between the sol and gel phases of nasal washes. High performance liquid chromatography analysis of the immunoreactive kinin in nasal washes showed it to be a mixture of lysylbradykinin and bradykinin. We conclude that kinins are produced during local allergic reactions in the nose and may contribute to the symptomatology of the allergic response.
Mauser, Peter J; House, Aileen; Jones, Howard; Correll, Craig; Boyce, Christopher; Chapman, Richard W
Late phase airflow obstruction and reduction in forced vital capacity are characteristic features of human asthma. Airway microvascular leakage and lung edema are also present in the inflammatory phase of asthma, but the impact of this vascular response on lung functions has not been precisely defined. This study was designed to evaluate the role of increased lung microvascular leakage and edema on the late phase changes in forced vital capacity (FVC) and peak expiratory flow (PEF) in allergen-challenged Brown Norway rats using pharmacological inhibitors of the allergic inflammatory response. Rats were sensitized and challenged with ovalbumin aerosol and forced expiratory lung functions (FVC, PEF) and wet and dry lung weights were measured 48 h after antigen challenge. Ovalbumin challenge reduced FVC (63% reduction) and PEF (33% reduction) and increased wet (65% increase) and dry (51% increase) lung weights. The antigen-induced reduction in FVC and PEF was completely inhibited by oral treatment with betamethasone and partially attenuated by inhibitors of arachidonic acid metabolism including indomethacin (cyclooxygenase inhibitor), 7-TM and MK-7246 (CRTH2 antagonists) and montelukast (CysLT1 receptor antagonist). Antagonists of histamine H1 receptors (mepyramine) and 5-HT receptors (methysergide) had no significant effects indicating that these pre-formed mast cell mediators were not involved. There was a highly significant (P < 0.005) correlation for the inhibition of FVC reduction and increase in wet and dry lung weights by these pharmacological agents. These results strongly support the hypothesis that lung microvascular leakage and the associated lung edema contribute to the reduction in forced expiratory lung functions in antigen-challenged Brown Norway rats and identify an important role for the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in these responses.
Marsh, D. G.; Goodfriend, L.; King, T. P.; Lowenstein, H.; Platts-Mills, T. A.
This article presents a nomenclature system for allergens which has been officially recommended by the International Union of Immunological Societies (IUIS). The nomenclature is based on proposals of the IUIS Sub-Committee for Allergen Nomenclature and is applicable to highly purified, well-characterized allergens and to non-purified or partially purified allergenic extracts. PMID:3492310
Simpson, Angela; Lazic, Nevena; Belgrave, Danielle C M; Johnson, Phil; Bishop, Christopher; Mills, Clare; Custovic, Adnan
The relationship between sensitization to allergens and disease is complex. We sought to identify patterns of response to a broad range of allergen components and investigate associations with asthma, eczema, and hay fever. Serum specific IgE levels to 112 allergen components were measured by using a multiplex array (Immuno Solid-phase Allergen Chip) in a population-based birth cohort. Latent variable modeling was used to identify underlying patterns of component-specific IgE responses; these patterns were then related to asthma, eczema, and hay fever. Two hundred twenty-one of 461 children had IgE to 1 or more components. Seventy-one of the 112 components were recognized by 3 or more children. By using latent variable modeling, 61 allergen components clustered into 3 component groups (CG1, CG2, and CG3); protein families within each CG were exclusive to that group. CG1 comprised 27 components from 8 plant protein families. CG2 comprised 7 components of mite allergens from 3 protein families. CG3 included 27 components of plant, animal, and fungal origin from 12 protein families. Each CG included components from different biological sources with structural homology and also nonhomologous proteins arising from the same biological source. Sensitization to CG3 was most strongly associated with asthma (odds ratio [OR], 8.20; 95% CI, 3.49-19.24; P < .001) and lower FEV1 (P < .001). Sensitization to CG1 was associated with hay fever (OR, 12.79; 95% CI, 6.84-23.90; P < .001). Sensitization to CG2 was associated with both asthma (OR, 3.60; 95% CI, 2.05-6.29) and hay fever (OR, 2.52; 95% CI, 1.38-4.61). Latent variable modeling with a large number of allergen components identified 3 patterns of IgE responses, each including different protein families. In 11-year-old children the pattern of response to components of multiple allergens appeared to be associated with current asthma and hay fever but not eczema. Copyright © 2015 The Authors. Published by Elsevier Inc. All
Vaz, A F M; Souza, M P; Medeiros, P L; Melo, A M M A; Silva-Lucca, R A; Santana, L A; Oliva, M L V; Perez, K R; Cuccovia, I M; Correia, M T S
Few chronic food protein models have described the relationship between allergenicity and the molecular structure of food protein after physical processing. The effect of γ-radiation on the structure of food protein was measured by fluorescence, circular dichroism and microcalorimetry. BALB/c mice were intraperitoneally sensitized and then given non-irradiated and irradiated Con-A by daily gavage for 28days. The tendency to form insoluble amorphous aggregates and partially unfolded species was observed after irradiation. The administration of non-irradiated and irradiated samples at low-dose significantly increased weight loss as well as plasma levels of eotaxin in animals repeatedly exposed to Con-A. Significant lymphocytic infiltrate filling completely the stroma of microvilli and tubular glands was observed in the small intestinal of the group given Con-A irradiated at a low dose. This phenotype was not observed in animals treated with Con-A irradiated at a high dose.
Ramos, M V; Aguiar, V C; Melo, V M M; Mesquita, R O; Silvestre, P P; Oliveira, J S; Oliveira, R S B; Macedo, N M R; Alencar, N M N
Immunological and allergenic responses against the latex of Calotropis procera were investigated in mice by oral and subcutaneous routes. The latex was fractionated according to water solubility and molecular size of its components. The fractions were named as non-dialyzable latex (NDL) corresponding to the major latex proteins, dialyzable latex (DL) corresponding to low molecular size substances and rubber latex (RL) which was highly insoluble in water. Anti-sera against these fractions were assayed for total IgG and IgA titration by ELISA and IgE and IgG(1) were quantified by passive cutaneous anaphylaxis (PCA) in rats and mice, respectively. None of the fractions induced antibodies level increases when mice received latex fractions by oral route and thus, did not develop allergy. Nonetheless, anti-sera of mice sensitized with NDL and RL by subcutaneous route displayed considerable immunological response while DL did not. IgG level augmented consistently against NDL and RL while IgA response was detected only to NDL. NDL and RL induced very strong PCA reactions suggesting that both fractions would contain latex substances involved in allergy. Furthermore, protein analysis of NDL and RL suggests that RL still retain residual proteins abundantly found in NDL that could explain its similar allergenic effect. No IgG(1) reaction was detected in any of the anti-sera tested. According to the results, the proteins of latex of Calotropis procera can provoke allergy by subcutaneous route. The NDL has previously shown to display anti-inflammatory and analgesic activities by intraperitoneal injection. It should be relevant to determine whether NDL could induce such activities when assayed by oral route since it was ineffective to induce allergy by this way.
EFFECTS OF ULTRAVIOLET RADIATION (UVR) ON THE RESPIRATORY ALLERGIC RESPONSES OF BALB/C MICE TO A FUNGAL ALLERGEN. M D W Ward, D M Sailstad, D L Andrews, E H Boykin, and MJ K Selgrade. National Health and Environmental Effects Research Laboratory, Office of Research and Developmen...
Hutson, P A; Holgate, S T; Church, M K
We describe the effects of the antiallergic drug cromolyn sodium and the beta 2-selective adrenoceptor agonist albuterol against early and late phase changes in specific airways conductance (sGaw) and leukocyte infiltration into the airways after allergen challenge of nonanesthetized guinea pigs. Inhalation of ovalbumin by sensitized guinea pigs induced three phases of airways obstruction: an early asthmatic response (EAR) peaking at 2 h, a late response (LAR) peaking at 17 h, and a further late response (LLAR) being observed at 72 h. The LAR was accompanied by a 13-fold rise in neutrophils and a four-fold rise in eosinophils recovered by bronchoalveolar lavage (BAL) at 17 h. By 72 h, the BAL content of neutrophils had returned to near normal, whereas eosinophil numbers had risen to 6.7-fold above baseline. Inhalation of an aerosolized solution of cromolyn, 10 mg/ml, 15 min before challenge inhibited both the EAR and LAR and the influx of neutrophils into the airways at 17 h but had no effect on eosinophil accumulation. Inhalation of cromolyn at 6 h, i.e., after the completion of the EAR, inhibited the LAR, the LLAR, and the rise in eosinophils at 72 h but did not reduce the influx of neutrophils at 17 h. Administration of cromolyn at both 15 min before and 6 h after challenge inhibited all changes in sGaw and reduced the accumulation of neutrophils at 17 h and the influx of eosinophils at 72 h. In contrast, inhalation of albuterol, 0.1 mg/ml, 15 min before allergen provocation blocked the EAR and the rise in BAL neutrophils at 17 h but did not inhibit the LAR. Inhalation of albuterol at 6 h partially reversed the LAR but had no effect on either the LLAR or cellular changes. Given at both times, albuterol inhibited the EAR and neutrophil accumulation at 17 h and partially reversed the LAR but produced no other effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Hourihane, Jonathan O'B; Allen, Katrina J; Shreffler, Wayne G; Dunngalvin, Gillian; Nordlee, Julie A; Zurzolo, Giovanni A; Dunngalvin, Audrey; Gurrin, Lyle C; Baumert, Joseph L; Taylor, Steve L
Eliciting doses (EDs) of allergenic foods can be defined by the distribution of threshold doses for subjects within a specific population. The ED05 is the dose that elicits a reaction in 5% of allergic subjects. The predicted ED05 for peanut is 1.5 mg of peanut protein (6 mg of whole peanut). We sought to validate the predicted peanut ED05 (1.5 mg) with a novel single-dose challenge. Consecutive eligible children with peanut allergy in 3 centers were prospectively invited to participate, irrespective of previous reaction severity. Predetermined criteria for objective reactions were used to identify ED05 single-dose reactors. Five hundred eighteen children (mean age, 6.8 years) were eligible. No significant demographic or clinical differences were identified between 381 (74%) participants and 137 (26%) nonparticipants or between subjects recruited at each center. Three hundred seventy-eight children (206 male) completed the study. Almost half the group reported ignoring precautionary allergen labeling. Two hundred forty-five (65%) children experienced no reaction to the single dose of peanut. Sixty-seven (18%) children reported a subjective reaction without objective findings. Fifty-eight (15%) children experienced signs of a mild and transient nature that did not meet the predetermined criteria. Only 8 (2.1%; 95% CI, 0.6%-3.4%) subjects met the predetermined criteria for an objective and likely related event. No child experienced more than a mild reaction, 4 of the 8 received oral antihistamines only, and none received epinephrine. Food allergy-related quality of life improved from baseline to 1 month after challenge regardless of outcome (η(2) = 0.2, P < .0001). Peanut skin prick test responses and peanut- and Ara h 2-specific IgE levels were not associated with objective reactivity to peanut ED05. A single administration of 1.5 mg of peanut protein elicited objective reactions in fewer than the predicted 5% of patients with peanut allergy. The novel
Mah, Francis S; Rosenwasser, Lanny J; Townsend, William D; Greiner, Jack V; Bensch, George
Olopatadine 0.2% (Pataday, Alcon Laboratories Inc., Fort Worth, Texas, USA) and epinastine 0.05% (Elestat, Inspire Pharmaceuticals, Inc., Durham, NC, USA) are topical ocular anti-allergic agents. Both are H(1) antihistamine/mast cell stabilizers indicated for the treatment of ocular itching associated with allergic conjunctivitis. To compare the efficacy and comfort of olopatadine 0.2% with epinastine 0.05%, in the prevention of ocular itching associated with allergic conjunctivitis following conjunctival allergen challenge (CAC). This was a 7 week, four visit, double-masked, randomized, placebo-controlled CAC study. Visit 1 screened subjects for positive ocular allergic responses and Visit 2 confirmed those responses. At Visit 3, 92 subjects were randomized into one of four treatment groups to receive one drop of study medication in each eye: (1) olopatadine 0.2%/placebo, (2) epinastine 0.05%/placebo, (3) olopatadine 0.2%/epinastine 0.05%, (4) placebo/placebo. Subjects were challenged 12 h after drop instillation to evaluate duration of action. At Visit 4, subjects were challenged 5 min after drop instillation to evaluate onset of action. Drop comfort was assessed at Visit 4. MAIN OUTCOME MEASURES; This article focuses on the results of the onset-of-action challenge (Visit 4). At Visit 4, ocular itching was assessed at 3, 5, and 7 min and redness was assessed at 7, 15, and 20 min post-challenge. Drop comfort was assessed upon instillation, at 30s, and at 1, 2, and 5 min post-instillation. Olopatadine 0.2%-treated eyes exhibited significantly lower mean ocular itching scores versus epinastine 0.05%-treated eyes at 5 (p = 0.024) and 7 min (p = 0.003) post-challenge. Olopatadine 0.2%-treated eyes exhibited significantly lower mean redness scores versus epinastine 0.05%-treated eyes at all time points post-challenge (ciliary: p < or = 0.013, conjunctival: p < or = 0.015, episcleral: p < or = 0.006). Olopatadine 0.2% was rated as significantly more comfortable than
Walnut is one of the most frequently involved foods in anaphylactic reactions. We investigated changes in walnut allergenicity after physical treatments by in vitro techniques and physiologically relevant assays. Changes in the allergenicity of walnut subjected to high pressure and thermal/pressur...
Renz, H; Saloga, J; Bradley, K L; Loader, J E; Greenstein, J L; Larsen, G; Gelfand, E W
T and B cell responses after sensitization to ragweed (RW) were examined in a mouse model in which BALB/c mice were exposed to the allergen by ultrasonic nebulization. Sensitization resulted in the stimulation of an IgE anti-RW response and was paralleled by a rise in IgG1 anti-RW titers. Skin testing for immediate cutaneous hypersensitivity revealed the presence of allergic type I reactions to RW. Sensitization to RW in this way was also associated with the development of increased airways responsiveness as determined by electrical field stimulation of preparations of tracheal smooth muscle. Histologic examination of the airways and the lung indicated the presence of a mononuclear cell infiltrate in the mucosa and submucosa of the airways that was accompanied by an enlargement of local draining lymph nodes of the airways and the lung. T cell populations were analyzed for the frequency of V beta-expressing T cells. Such analysis indicated that RW sensitization stimulated the expression of V beta 8.1+, V beta 8.2+, and V beta 13+ T cells in the local lymphoid tissue and of V beta 8.1+, V beta 8.2+, V beta 8.3+, V beta 9+ and V beta 14+ T cells in the spleen. Co-culture of these T cell populations with RW-primed B cells indicated that in the presence of RW, V beta 8.2 T cells stimulated IgE and IgG1 production, whereas the other T cell populations showed a different stimulation profile for Ig isotypes and IgG subclasses. The transfer of V beta 8.2 T cells from sensitized but not from nonsensitized control mice stimulated an allergen-specific IgE and IgG1 response and increased airways responsiveness in naive recipients. These data provide additional support for the pivotal role of specific V beta-expressing T cell subpopulations in the stimulation of IgE/IgG1 production and increased airways responsiveness.
Sheller, James R.; Polosukhin, Vasiliy V.; Mitchell, Daphne; Cheng, D-S.; Peebles, R. Stokes; Blackwell, Timothy S.
NF-kB is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kB activation in allergic inflammation we generated transgenic mouse lines that allowed for the inducible stimulation of NF-kB in airway epithelial cells. After allergic sensitization with ovalbumin and alum, mice were challenged daily with ovalbumin aerosols and NF-kB was activated in airway epithelium by administration of doxycycline. Enhancement of airway epithelial NF-kB expression alone did not lead to increased airway responsiveness to methacholine. However induction of epithelial NF-kB during allergic inflammation caused airway hyperresponsiveness, increased airway neutrophilic and lymphocytic inflammation and goblet cell hyperplasia. Accompanying the exaggerated inflammation was an increase in the cytokines, G-CSF, IL-15, and KC. Interestingly, the counter regulatory interleukin, IL-10, was suppressed by NF-kB activation. The epithelial NF-kB dependent modulation of these cytokines provides a plausible explanation for the increased inflammation seen with overexpression of NF-kB. Modulation of airway epithelial NF-kB activation enhances the airway hyperresponsiveness and mucus secretion found in the mouse lung during allergic inflammation. NF-kB represents a potential target for pharmacologic intervention in human asthma. PMID:19995280
Santiago, Helton da Costa; Ribeiro-Gomes, Flávia L; Bennuru, Sasisekhar; Nutman, Thomas B
Immunological cross-reactivity between environmental allergens and helminth proteins has been demonstrated, although the clinically related implications of this cross-reactivity have not been addressed. To investigate the impact of molecular similarity among allergens and cross-reactive homologous helminth proteins in IgE-based serologic assessment of allergic disorders in a helminth-infected population, we performed ImmunoCAP tests in filarial-infected and noninfected individuals for IgE measurements to allergen extracts that contained proteins with high levels of homology with helminth proteins as well as IgE against representative recombinant allergens with and without helminth homologs. The impact of helminth infection on the levels and function of the IgE to these specific homologous and nonhomologous allergens was corroborated in an animal model. We found that having a tissue-invasive filarial infection increased the serological prevalence of ImmunoCAP-identified IgE directed against house dust mite and cockroach, but not against timothy grass, the latter with few allergens with homologs in helminth infection. IgE ELISA confirmed that filaria-infected individuals had higher IgE prevalences to those recombinant allergens that had homologs in helminths. Mice infected with the helminth Heligmosomoides polygyrus displayed increased levels of IgE and positive skin tests to allergens with homologs in the parasite. These results show that cross-reactivity among allergens and helminth proteins can have practical implications, altering serologic approaches to allergen testing and bringing a new perspective to the "hygiene hypothesis."
Benichou, Annie-Claude; Armanet, Marion; Bussière, Anthony; Chevreau, Nathalie; Cardot, Jean-Michel; Tétard, Jan
Occasional rhinitis symptoms caused by exposure to pollution or allergens is a growing concern. Based first on empirical observation of a lesser occurrence of allergies in quail farmers and then scientific works on ovomucoids properties, we developed a dietary supplement for the relief of such occasional rhinitis symptoms. The objective of the study was to determine whether one acute oral dose of the study product attenuates nasal provocation and other allergy-related symptoms after exposure to a standardized allergenic challenge as compared to placebo. Healthy subjects were recruited to participate in a randomized, double-blind, two-arm crossover, placebo-controlled, clinical trial. One acute dose of either the active study product (proprietary blend of quail egg) or placebo was given concomitantly to the standardized allergenic challenge. The primary endpoint was peak nasal inspiratory flow (PNIF) measurement and the secondary endpoints were subjects' perceived feelings of well-being based on Visual Analog Scale (VAS) scores for allergy-related symptoms, as well as immunoglobulin E count. Forty-three healthy subjects were enrolled and evaluable in a per protocol analysis. A gradual increase in PNIF from nadir up to Time 120 reflected the normal, gradual recovery from nasal obstruction induced by allergenic challenge for both the active and the placebo groups. At all postchallenge time points, the active group had higher PNIF values compared to the placebo group, indicating that the active product was associated with fewer symptoms and reduced intensity of these symptoms. The active product resulted also in statistically significant improvements of most of the subjects' perceived feelings of well-being based on VAS scores. No adverse events occurred during the study. In conclusion, the dietary supplement consisting of proprietary blend made of quail eggs provides fast and efficient relief of allergic rhinitis symptoms caused by the most common outdoor and indoor
Benichou, Annie-Claude; Armanet, Marion; Bussière, Anthony; Chevreau, Nathalie; Cardot, Jean-Michel; Tétard, Jan
Occasional rhinitis symptoms caused by exposure to pollution or allergens is a growing concern. Based first on empirical observation of a lesser occurrence of allergies in quail farmers and then scientific works on ovomucoids properties, we developed a dietary supplement for the relief of such occasional rhinitis symptoms. The objective of the study was to determine whether one acute oral dose of the study product attenuates nasal provocation and other allergy-related symptoms after exposure to a standardized allergenic challenge as compared to placebo. Healthy subjects were recruited to participate in a randomized, double-blind, two-arm crossover, placebo-controlled, clinical trial. One acute dose of either the active study product (proprietary blend of quail egg) or placebo was given concomitantly to the standardized allergenic challenge. The primary endpoint was peak nasal inspiratory flow (PNIF) measurement and the secondary endpoints were subjects' perceived feelings of well-being based on Visual Analog Scale (VAS) scores for allergy-related symptoms, as well as immunoglobulin E count. Forty-three healthy subjects were enrolled and evaluable in a per protocol analysis. A gradual increase in PNIF from nadir up to Time 120 reflected the normal, gradual recovery from nasal obstruction induced by allergenic challenge for both the active and the placebo groups. At all postchallenge time points, the active group had higher PNIF values compared to the placebo group, indicating that the active product was associated with fewer symptoms and reduced intensity of these symptoms. The active product resulted also in statistically significant improvements of most of the subjects' perceived feelings of well-being based on VAS scores. No adverse events occurred during the study. In conclusion, the dietary supplement consisting of proprietary blend made of quail eggs provides fast and efficient relief of allergic rhinitis symptoms caused by the most common outdoor and indoor
Liu, Cuiqing; Yavar, Zubin
A growing number of extreme climate events are occurring in the setting of ongoing climate change, with an increase in both the intensity and frequency. It has been shown that ambient temperature challenges have a direct and highly varied impact on cardiovascular health. With a rapidly growing amount of literature on this issue, we aim to review the recent publications regarding the impact of cold and heat on human populations with regard to cardiovascular disease (CVD) mortality/morbidity while also examining lag effects, vulnerable subgroups, and relevant mechanisms. Although the relative risk of morbidity/mortality associated with extreme temperature varied greatly across different studies, both cold and hot temperatures were associated with a positive mean excess of cardiovascular deaths or hospital admissions. Cause-specific study of CVD morbidity/mortality indicated that the sensitivity to temperature was disease-specific, with different patterns for acute and chronic ischemic heart disease. Vulnerability to temperature-related mortality was associated with some characteristics of the populations, including sex, age, location, socioeconomic condition, and comorbidities such as cardiac diseases, kidney diseases, diabetes, and hypertension. Temperature-induced damage is thought to be related to enhanced sympathetic reactivity followed by activation of the sympathetic nervous system, renin-angiotensin system, as well as dehydration and a systemic inflammatory response. Future research should focus on multidisciplinary adaptation strategies that incorporate epidemiology, climatology, indoor/building environments, energy usage, labor legislative perfection, and human thermal comfort models. Studies on the underlying mechanism by which temperature challenge induces pathophysiological response and CVD await profound and lasting investigation. PMID:26432837
Liu, Cuiqing; Yavar, Zubin; Sun, Qinghua
A growing number of extreme climate events are occurring in the setting of ongoing climate change, with an increase in both the intensity and frequency. It has been shown that ambient temperature challenges have a direct and highly varied impact on cardiovascular health. With a rapidly growing amount of literature on this issue, we aim to review the recent publications regarding the impact of cold and heat on human populations with regard to cardiovascular disease (CVD) mortality/morbidity while also examining lag effects, vulnerable subgroups, and relevant mechanisms. Although the relative risk of morbidity/mortality associated with extreme temperature varied greatly across different studies, both cold and hot temperatures were associated with a positive mean excess of cardiovascular deaths or hospital admissions. Cause-specific study of CVD morbidity/mortality indicated that the sensitivity to temperature was disease-specific, with different patterns for acute and chronic ischemic heart disease. Vulnerability to temperature-related mortality was associated with some characteristics of the populations, including sex, age, location, socioeconomic condition, and comorbidities such as cardiac diseases, kidney diseases, diabetes, and hypertension. Temperature-induced damage is thought to be related to enhanced sympathetic reactivity followed by activation of the sympathetic nervous system, renin-angiotensin system, as well as dehydration and a systemic inflammatory response. Future research should focus on multidisciplinary adaptation strategies that incorporate epidemiology, climatology, indoor/building environments, energy usage, labor legislative perfection, and human thermal comfort models. Studies on the underlying mechanism by which temperature challenge induces pathophysiological response and CVD await profound and lasting investigation. Copyright © 2015 the American Physiological Society.
Tagawa, Yoshiaki; Namba, Kenichi; Nakazono, Yumi; Iwata, Daiju; Ishida, Susumu
The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
... Basics Facts and Statistics NIAID Resources Allergens Peanut Tree Nuts Milk Egg Wheat Soy Fish Shellfish Sesame ... Basics Facts and Statistics NIAID Resources Allergens Peanut Tree Nuts Milk Egg Wheat Soy Fish Shellfish Sesame ...
Pomés, Anna; Mueller, Geoffrey A; Randall, Thomas A; Chapman, Martin D; Arruda, L Karla
This review addresses the most recent developments on cockroach allergen research in relation to allergic diseases, especially asthma. The number of allergens relevant to cockroach allergy has recently expanded considerably up to 12 groups. New X-ray crystal structures of allergens from groups 1, 2, and 5 revealed interesting features with implications for allergen standardization, sensitization, diagnosis, and therapy. Cockroach allergy is strongly associated with asthma particularly among children and young adults living in inner-city environments, posing challenges for disease control. Environmental interventions targeted at reducing cockroach allergen exposure have provided conflicting results. Immunotherapy may be a way to modify the natural history of cockroach allergy and decrease symptoms and asthma severity among sensitized and exposed individuals. The new information on cockroach allergens is important for the assessment of allergen markers of exposure and disease, and for the design of immunotherapy trials.
Jung, Kyung-Hwa; Choi, Hei-Lim; Park, Soojin; Lee, Geunhyeog; Kim, Miran; Min, Joon-Ki; Min, Byung-Il; Bae, Hyunsu
PM014 is a modified form of the Chung-Sang-Bo-Ha-Tang (CSBHT) herbal formula that has been used to treat chronic pulmonary diseases in Korea for centuries. Previously, we developed a formulation of PM014 based on a series of in vitro and in vivo screening efforts that comprises seven herbal extracts. The PM014 formula includes the root of Rehmannia glutinosa, the cortex of Paeonia suffruticosa, the fruit of Schizandra chinensis, the root of Asparagus cochinchinensis, seeds of Prunus armeniaca, the root of Scutellaria baicalensis and the root of Stemona sessilifolia. Asthma is a chronic inflammatory disease of the lungs that is characterized by wheezing, bronchial contraction, and chest tightness. In addition, the airway becomes hypersensitive and narrows through an inflammatory reaction mediated by Th2 cells. The present study was conducted to evaluate the ability of PM014 to prevent allergic airway inflammation and to attenuate airway responses in a cockroach allergen-induced mouse model. Mice sensitized to and challenged with cockroach allergen were treated with oral administration of PM014. Airway resistance was determined by whole body plethysmography. In addition, Th2 cytokines and immune cell profiles of bronchoalveolar lavage (BAL) fluid and inflammatory mediators in serum were analyzed by ELISA. A series of histological examinations were also conducted to demonstrate the effects of PM014 on airway remodeling, goblet cell hyperplasia and inflammatory responses in the lung. PM014 significantly inhibited the number of total cells, eosinophils, neutrophils, macrophages and lymphocytes in the BAL fluid of mice that were challenged with cockroach allergen. In addition, PM014 reduced the levels of Th2 cytokines (IL-4, IL-5 and IL-13) in the BAL fluid and inflammatory mediators such as IgE in the serum, as measured by enzyme-linked immunosorbent assay (ELISA). Histopathological analysis also showed that PM014 substantially inhibited eosinophil infiltration into the
Van Gramberg, Jenna L; Bischof, Robert J; O'Hehir, Robyn E; de Veer, Michael J; Meeusen, Els N
The innate response generated after initial allergen exposure is crucial for polarising adaptive immunity, but little is known about how it drives an atopic or type-2 immune response. The present study characterises the response of skin-draining afferent lymph in sheep following injection with peanut (PN) extract in the presence or absence of aluminium hydroxide (AlOH) adjuvant. Lymph was collected and innate cell populations characterised over an 84 h time period. The innate response to PN extract in afferent lymph displayed an early increase in neutrophils and monocytes without any changes in the dendritic cell (DC) population. PN antigen was transported by neutrophils and monocytes for the first 36 h, after which time DCs were the major antigen trafficking cells. AlOH adjuvant gradually increased antigen uptake by DCs at the later time points. Following lymphatic characterisation, sheep were sensitised with PN extract by three subcutaneous injections of PN in AlOH, and the level of PN-specific immunoglobulin E (IgE) was determined. Sheep with higher levels of steady-state DCs in afferent lymph showed increased monocytic recruitment in afferent lymph and reduced PN-specific IgE following sensitisation. In addition, DCs from afferent lymph that had ingested PN antigen increased the expression of monocyte chemoattractant mRNA. The results of this study show that the innate response to PN extract involves a dynamic change in cell populations in the afferent lymph over time. In addition, DCs may determine the strength of the initial inflammatory cell response, which in turn may determine the nature of the antigen-specific adaptive response.
Bashir, Mohamed Elfatih H; Lui, Jan Hsi; Palnivelu, Ravishankar; Naclerio, Robert M; Preuss, Daphne
Pollen grains are the male gametophytes that deliver sperm cells to female gametophytes during sexual reproduction of higher plants. Pollen is a major source of aeroallergens and environmental antigens. The pollen coat harbors a plethora of lipids that are required for pollen hydration, germination, and penetration of the stigma by pollen tubes. In addition to proteins, pollen displays a wide array of lipids that interact with the human immune system. Prior searches for pollen allergens have focused on the identification of intracellular allergenic proteins, but have largely overlooked much of the extracellular pollen matrix, a region where the majority of lipid molecules reside. Lipid antigens have attracted attention for their potent immunoregulatory effects. By being in close proximity to allergenic proteins on the pollen surface when they interact with host cells, lipids could modify the antigenic properties of proteins. We performed a comparative pollen lipid profiling of 22 commonly allergenic plant species by the use of gas chromatography-mass spectroscopy, followed by detailed data mining and statistical analysis. Three experiments compared pollen lipid profiles. We built a database library of the pollen lipids by matching acquired pollen-lipid mass spectra and retention times with the NIST/EPA/NIH mass-spectral library. We detected, identified, and relatively quantified more than 106 lipid molecular species including fatty acids, n-alkanes, fatty alcohols, and sterols. Pollen-derived lipids stimulation up-regulate cytokines expression of dendritic and natural killer T cells co-culture. Here we report on a lipidomic analysis of pollen lipids that can serve as a database for identifying potential lipid antigens and/or novel candidate molecules involved in allergy. The database provides a resource that facilitates studies on the role of lipids in the immunopathogenesis of allergy. Pollen lipids vary greatly among allergenic species and contain many molecules
Bashir, Mohamed Elfatih H.; Lui, Jan Hsi; Palnivelu, Ravishankar; Naclerio, Robert M.; Preuss, Daphne
lipids vary greatly among allergenic species and contain many molecules that have stimulatory or regulatory effects on immune responses. PMID:23469025
Mahajan, Avanika; Youssef, Lama A; Cleyrat, Cédric; Grattan, Rachel; Lucero, Shayna R; Mattison, Christopher P; Erasmus, M Frank; Jacobson, Bruna; Tapia, Lydia; Hlavacek, William S; Schuyler, Mark; Wilson, Bridget S
Ag-mediated crosslinking of IgE-FcεRI complexes activates mast cells and basophils, initiating the allergic response. Of 34 donors recruited having self-reported shrimp allergy, only 35% had significant levels of shrimp-specific IgE in serum and measurable basophil secretory responses to rPen a 1 (shrimp tropomyosin). We report that degranulation is linked to the number of FcεRI occupied with allergen-specific IgE, as well as the dose and valency of Pen a 1. Using clustered regularly interspaced palindromic repeat-based gene editing, human RBL(rαKO) cells were created that exclusively express the human FcεRIα subunit. Pen a 1-specific IgE was affinity purified from shrimp-positive plasma. Cells primed with a range of Pen a 1-specific IgE and challenged with Pen a 1 showed a bell-shaped dose response for secretion, with optimal Pen a 1 doses of 0.1-10 ng/ml. Mathematical modeling provided estimates of receptor aggregation kinetics based on FcεRI occupancy with IgE and allergen dose. Maximal degranulation was elicited when ∼2700 IgE-FcεRI complexes were occupied with specific IgE and challenged with Pen a 1 (IgE epitope valency of ≥8), although measurable responses were achieved when only a few hundred FcεRI were occupied. Prolonged periods of pepsin-mediated Pen a 1 proteolysis, which simulates gastric digestion, were required to diminish secretory responses. Recombinant fragments (60-79 aa), which together span the entire length of tropomyosin, were weak secretagogues. These fragments have reduced dimerization capacity, compete with intact Pen a 1 for binding to IgE-FcεRI complexes, and represent a starting point for the design of promising hypoallergens for immunotherapy. Copyright © 2017 by The American Association of Immunologists, Inc.
Kawano, K; Oumi, K; Ashida, Y; Horiuchi, Y; Mizuno, T
The aim of the present study was to examine the correlation between the results of lymphocyte proliferative test (LPT) specific to food allergens and allergic skin diseases in dogs. Investigations were performed in 138 dogs with allergic skin diseases diagnosed in a private animal hospital. Of the 138 animals, 97 cases had positive reactions in LPT specific to food allergens. Of these 97 dogs, 67 animals were diagnosed with canine atopic dermatitis (CAD), but 30 dogs did not have IgE antibodies to environmental allergens. As 14 dogs out of 30 animals showed a positive result, 12 dogs underwent elimination diet trial based on the test results and all of them showed improvement in the pruritus score. Therefore, we conclude that LPT is an effective diagnostic test for allergic skin disease. Results of the lymphocyte test are useful in the identification of food allergens for the elimination diet trial.
Joad, Jesse P. Kott, Kayleen S.; Bric, John M.; Schelegle, Edward S.; Gershwin, Laurel J.; Plopper, Charles G.; Peake, Janice L.; Pinkerton, Kent E.
Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA) + ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA + ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.
Renand, Amedee; Archila, Luis D.; McGinty, John; Wambre, Erik; Robinson, David; Hales, Belinda J.; Thomas, Wayne R.; Kwok, William W.
Background In human subjects, allergen-tolerance has been observed after high dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T cell response that leads to the induction of IgG4 during chronic allergen exposure remains poorly understood. Objective To evaluate the relationship between cat allergen-specific T cell frequency, cat allergen-specific IgE and IgG4 titers and clinical status in cat allergic adults with and without cat ownership and the cellular mechanism by which IgG4 is produced. Methods Fel d 1, Fel d 4, Fel d 7 and Fel d 8- specific T cell responses were characterized by CD154 expression after antigen stimulation. Results In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4) specific TH2 cells (sTH2 cells) correlates with IgE level and is linked to asthma. Paradoxically, we observed that cat allergic subjects with chronic cat exposure maintain high frequency of sTH2 cells, which correlates with IgG4 level and low-sensitization. B cells from allergic, but not from non-allergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones, and Fel d 1 peptide or the Fel d 1 recombinant protein. Conclusion These experiments suggest that 1) allergen-experienced B cells with capacity to produce IgG4 are present in allergic subjects; and 2) cat-allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus, IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization. PMID:26371841
Jutel, Marek; Akdis, Mübeccel; Budak, Ferah; Aebischer-Casaulta, Carmen; Wrzyszcz, Maria; Blaser, Kurt; Akdis, Cezmi A
The regulation of normal and allergic immune responses to airborne allergens in the mucosa is still poorly understood, and the mechanism of specific immunotherapy (SIT) in normalizing the allergic response to such allergens is currently not clear. Accordingly, we have investigated the immunoregulatory mechanism of both normal and allergic responses to the major house-dust mite (HDM) and birch pollen allergens--Dermatophagoides pteroynyssinus (Der p)1 and Bet v 1, respectively--as well as the immunologic basis of SIT to HDM in rhinitis and asthma patients. In normal immunity to HDM and birch pollen, an allergen-specific peripheral T cell suppression to Der p 1 and Bet v 1 was observed. The deviated immune response was characterized by suppressed proliferative T cell and Th1 (IFN-gamma) and Th2 (IL-5, IL-13) cytokine responses, and increased IL-10 and TGF-beta secretion by allergen-specific T cells. Neutralization of cytokine activity showed that T cell suppression was induced by IL-10 and TGF-beta during SIT and in normal immunity to the mucosal allergens. In addition, SIT induced an antigen-specific suppressive activity in CD4(+) CD25(+) T cells of allergic individuals. Together, these results demonstrate a deviation towards a regulatory/suppressor T cell response during SIT and in normal immunity as a key event for the healthy immune response to mucosal antigens.
Rimmer, Janet; Santos, Conceição; Yli-Panula, Eija; Noronha, Virginia; Viander, Markku
Background The precise way in which allergen is handled by the nose is unknown. The objective of this study was to determine recovery of Der p 1 allergen following nasal administration and to determine whether Der p 1 can be detected in nasal biopsies after natural exposure and nasal challenge to allergen. Methods (1) 20 nonatopic non-rhinitics were challenged with Der p 1 and recovery was measured by ELISA in the nasal wash, nasal mucus and induced sputum up to 30 minutes. Particulate charcoal (<40 μm) served as control. (2) In 8 subjects (5 atopics), 30 to 60 minutes after challenge histological localisation of Der p 1 in the nasal mucosal epithelium, subepithelial mucous glands and lamina propria was performed. Co-localisation of Der p 1 with macrophages and IgE-positive cells was undertaken. Results (1) Less than 25% of total allergen was retrievable after aqueous or particulate challenge, most from the nasal mucus during 1-5 min after the challenge. The median of carbon particles recovered was 9%. (2) Prechallenge Der p 1 staining was associated with the epithelium and subepithelial mucous glands. After challenge there was a trend for greater Der p 1 deposition in atopics, but both atopics and nonatopics showed increases in the number of Der p 1 stained cells and stained tissue compartments. In atopics, increased eosinophils, macrophages and IgE positive cells co-localized with Der p 1 staining. Conclusions Der p 1 allergen is detected in nasal tissue independent of atopic status after natural exposure. After challenge the nose effectively retains allergen, which remains mucosally associated; in atopics there is greater Der p 1 deposition and inflammatory response than in nonatopics. These results support the hypothesis that nasal mucus and tissue act as a reservoir for the inhaled Der p 1 allergen leading to a persistent allergic inflammatory response in susceptible individuals. PMID:25969994
Oseroff, Carla; Sidney, John; Tripple, Victoria; Grey, Howard; Wood, Robert; Broide, David H; Greenbaum, Jason; Kolla, Ravi; Peters, Bjoern; Pomés, Anna; Sette, Alessandro
Bla g allergens are major targets of IgE responses associated with cockroach allergies. However, little is known about corresponding T cell responses, despite their potential involvement in immunopathology and the clinical efficacy of specific immunotherapy. Bioinformatic predictions of the capacity of Bla g 1, 2, 4, 5, 6, and 7 peptides to bind HLA-DR, -DP, and -DQ molecules, and PBMC responses from 30 allergic donors, identified 25 T cell epitopes. Five immunodominant epitopes accounted for more than half of the response. Bla g 5, the most dominant allergen, accounted for 65% of the response, and Bla g 6 accounted for 20%. Bla g 5 induced both IL-5 and IFN-γ responses, whereas Bla g 6 induced mostly IL-5, and, conversely, Bla g 2 induced only IFN-γ. Thus, responses to allergens within a source are independently regulated, suggesting a critical role for the allergen itself, and not extraneous stimulation from other allergens or copresented immunomodulators. In comparing Ab with T cell responses for several donor/allergen combinations, we detected IgE titers in the absence of detectable T cell responses, suggesting that unlinked T cell-B cell help might support development of IgE responses. Finally, specific immunotherapy resulted in IL-5 down modulation, which was not associated with development of IFN-γ or IL-10 responses to any of the Bla g-derived peptides. In summary, the characteristics of T cell responses to Bla g allergens appear uncorrelated with IgE responses. Monitoring these responses may therefore yield important information relevant to understanding cockroach allergies and their treatment.
Fujimura, Masato; Masuda, Kenichi; Hayashiya, Makio; Okayama, Taro
Two different allergy tests, antigen-specific immunoglobulin E quantification (IgE test) and flow cytometric analysis of antigen-specific proliferation of peripheral lymphocytes (lymphocyte proliferation test), were performed to examine differences in allergic reactions to food allergens in dogs with food allergy (FA). Thirteen dogs were diagnosed as FA based on clinical findings and elimination diet trials. Seven dogs clinically diagnosed with canine atopic dermatitis (CAD) were used as a disease control group, and 5 healthy dogs were used as a negative control group. In the FA group, 19 and 33 allergen reactions were identified using the serum IgE test and the lymphocyte proliferation test, respectively. Likewise, in the CAD group, 12 and 6 allergen reactions and in the healthy dogs 3 and 0 allergen reactions were identified by each test, respectively. A significant difference was found between FA and healthy dogs in terms of positive allergen detection by the lymphocyte proliferation test, suggesting that the test can be useful to differentiate FA from healthy dogs but not from CAD. Both tests were repeated in 6 of the dogs with FA after a 1.5- to 5-month elimination diet trial. The IgE concentrations in 9 of 11 of the positive reactions decreased by 20-80%, whereas all the positive reactions in the lymphocyte proliferation test decreased to nearly zero (P<0.05), suggesting that lymphocytes against food allergens may be involved in the pathogenesis of canine FA.
Anand, Setty Balakrishnan; Gnanasekar, Munirathinam; Thangadurai, Mani; Prabhu, Prince R.; Kaliraj, Perumal
A homologue of Brugia malayi venom allergen (BmVAH) was cloned from the infective stages (L3) of Wuchereria bancrofti. Sequence analysis showed 90% sequence identity between WbVAH and BmVAH. Recombinant WbVAH was then expressed and purified. VAH from other nematode parasites is being evaluated as potential vaccine candidates. Because W. bancrofti infections are more prevalent than B. malayi, it will significantly benefit using W. bancrofti antigens for vaccine development. In this study, we have evaluated the human immune responses to rWbVAH in putatively immune individuals who live in the endemic regions (endemic normal, EN) to determine the vaccine potential of WbVAH. These responses were then compared to those in infected individuals (microfilaraemic, MF and chronic pathology, CP). Results show that EN subjects carry WbVAH-specific IgG1, IgG2, and IgG3 circulating antibodies. It is interesting to note that CP patients also carried antibodies against WbVAH that was mainly of the IgG3 isotype. Peripheral blood mononuclear cells (PBMC) from EN individuals responded strongly to rWbVAH by proliferating and secreting IFN-γ. PBMC from MF patients also proliferated in response to rWbVAH but secreted mainly IL-10. Thus, there was a clear dichotomy in the cytokine production by infected patients vs individuals who are putatively immune (EN). Although vaccine potential of WbVAH has not been established yet, our findings suggest that WbVAH mediated immune responses in EN individuals is primarily Th1-biased. Further vaccination studies are underway in animal models to determine the role of WbVAH in protective immunity against W. bancrofti and B. malayi infections. PMID:17558521
Toomer, Ondulla T; Ferguson, Martine; Pereira, Marion; Do, Andrew; Bigley, Elmer; Gaines, Dennis; Williams, Kristina
Neonatal to early childhood is the critical period for establishing a balance of T helper 1 (Th1) versus T helper 2 (Th2) cellular immunity within the gut, which is strongly influenced by the source and establishment of gut microflora. Probiotic administration has been shown to attenuate Th2-biased cellular immunity and predisposition to food allergies. To test this hypothesis we provided ad libitum a probiotic-supplemented (Primalac 454 Feed Grade Microbials) or control diet to lactating dams with suckling pups and weaned pups until 10 weeks of age. Weaned mice were sensitized/challenged with egg allergen ovalbumin, saline or adjuvant at 6, 8 and 10 weeks of age. At 3, 6, 8 and 10 weeks, fecal samples were collected for microbial analysis, while blood samples were analyzed for ovalbumin-IgE and total plasma IgE levels. At termination, splenic T helper cell lymphocyte population subtypes were determined using FACS analysis and Th1/Th2/Th17 gene expression by PCR array. At 21 days of age, pups suckled by lactating dams fed the probiotic supplemented diet had significantly enhanced Lactobacillus acidophilus fecal counts compared to controls. Moreover, mice fed the probiotic supplemented diet had enhanced splenic naturally occurring and induced regulatory T cell populations, enhanced TGFβ gene expression and reduced expression of allergic mediator IL13 compared to controls. These results provide evidence that early probiotic supplementation may provide host protection from hypersensitivity reactions to food allergens by attenuating food allergen inflammatory responses. Published by Elsevier GmbH.
Shandilya, Umesh Kumar; Kapila, Rajeev; Haq, Raies M; Kapila, Suman; Kansal, V K
Heat treatment is the most common method for reducing pathogen load, but it remains controversial in reducing the incidence of hyperimmune reactions. The aim of this study was to compare the allergenicity of caseins (CSN) and whey proteins (WP) of thermally processed cow and buffalo milk in a mouse model. Swiss albino mice were sensitised by intraperitoneal injections (administered in three doses at weekly intervals) of CSN or WP from cow or buffalo milk for the evaluation of humoral response and splenocyte stimulation index. After 3 weeks of intraperitoneal stimulation of mice with milk proteins, the sterilised milk protein group displayed significantly lowered (P ≤ 0.05) serum IgG and IgE levels, while considerably increased cow milk protein-specific responses (IgE) were shown by proteins of pasteurised milk compared with those of raw milk. The stimulation index of splenocytes induced by CSN or WP of boiled and sterilised milk was also lower (P ≤ 0.05) than that of raw milk of both cow and buffalo. The experiment showed that boiling and sterilisation of cow and buffalo milk clearly affect the allergenicity by decreasing the humoral and cell-mediated responses in mice. All results indicated that CSN and WP of sterilised milk are less allergenic than those of raw milk in mice. © 2013 Society of Chemical Industry.
Oh, Ji Eun; Oh, Dong Sun; Jung, Hi Eun
The genital mucosa is a barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. Although both allergen exposure and parasite infections frequently occur in the genital area, the mechanism by which immune responses—particularly type 2 immunity—are induced has rarely been studied in the genital mucosa. Here, we demonstrate the induction of T helper type 2 (Th2) immunity in the genital mucosa in response to a model allergen, the protease papain. Intravaginal papain immunization induced type 2 immunity in a manner that was dependent on protease activity and the estrous phase of the mice. In addition, IL-33 was released from the vaginal epithelia after intravaginal papain immunization, leading to the activation of type 2 innate lymphoid cells (ILC2s). Moreover, the IL-33–MyD88 (myeloid differentiation primary response gene 88) signaling pathway was critical for the induction of type 2 immunity. We also found that Th2 differentiation in response to intravaginal papain treatment requires a specific dendritic cell (DC) subset that is controlled by interferon regulatory factor 4 (IRF4). These findings suggest that type 2 immunity is induced by a unique mechanism in the genital tract, which is an important, but often overlooked, barrier surface. PMID:28137851
Tulic, Meri K; Christodoulopoulos, Pota; Fiset, Pierre Olivier; Vaillancourt, Patrice; Lavigne, Francois; Marshall, Jason D; Van Nest, Gary; Eiden, Joseph J; Hamid, Qutayba
Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS. Tissue from ragweed-sensitive patients (n = 12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, -5, -13, TNF-alpha and IFN-gamma mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry. RW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA+ cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNgamma-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA+ cells, T cells, B cells and neutrophils remained unchanged. AIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals.
Weichel, M; Vergoossen, N J; Bonomi, S; Scibilia, J; Ortolani, C; Ballmer-Weber, B K; Pastorello, E A; Crameri, R
Food allergy to wheat and maize is an increasing factor of deterioration of life quality, especially childhood and can, in rare cases, even induce anaphylaxis. Although omega-5 gliadin from wheat and maize lipid transfer protein have been characterized as major cereal allergens on the molecular level, the list of food allergens is far to be complete. To identify the IgE-binding repertoires of wheat and maize we screened respective cDNA libraries displayed on phage surface with sera from patients with a confirmed food allergy. The study included six patients with a positive double-blind, placebo-controlled food challenge (DBPCFC) to wheat, nine patients with a positive DBPCFC to maize, and six patients with anaphylactic reactions after ingestion of wheat. The enriched sequences encoding IgE-binding proteins showed heterogeneous repertoires for both, wheat and maize. The selected wheat repertoire yielded 12, the maize repertoire 11 open reading frames. Among these we identified allergens belonging to already characterized allergens families, such as gliadin, profilin and beta-expansin. Besides, we found novel proteins with high cross-reactive potential, such as thioredoxins, as well as sequences that had so far not been related to cereal allergy at all. The IgE-binding capacity of some selected proteins was evaluated in vitro and cross-reactivity was demonstrated by competition ELISA. With regard to the heterogeneity of the characterized sequences as well as to the biochemical nature of the new allergens detected we conclude that wheat and maize-related food allergy is more complex than so far anticipated.
Peters, Rachel L; Allen, Katrina J; Dharmage, Shyamali C; Tang, Mimi L K; Koplin, Jennifer J; Ponsonby, Anne-Louise; Lowe, Adrian J; Hill, David; Gurrin, Lyle C
Ninety-five percent positive predictive values (PPVs) provide an invaluable tool for clinicians to avoid unnecessary oral food challenges. However, 95% PPVs specific to infants, the age group most likely to present for diagnosis of food allergy, are limited. We sought to develop skin prick test (SPT) and allergen-specific IgE (sIgE) thresholds with 95% PPVs for challenge-confirmed food allergy in a large population-based cohort of 1-year-old infants with challenges undertaken irrespective of SPT wheal size or previous history of ingestion. HealthNuts is a population-based, longitudinal food allergy study with baseline recruitment of 1-year-old infants. Infants were recruited from council-run immunization sessions during which they underwent SPTs to 4 allergens: egg, peanut, sesame, and cow's milk/shrimp. Any infant with a detectable SPT response was invited to undergo oral food challenge and sIgE testing. Five thousand two hundred seventy-six infants participated in the study. Peanut SPT responses of 8 mm or greater (95% CI, 7-9 mm), egg SPT responses of 4 mm or greater (95% CI, 3-5 mm), and sesame SPT responses of 8 mm or greater (95% CI, 5-9 mm) had 95% PPVs for challenge-proved food allergy. Peanut sIgE levels of 34 kUA/L or greater (95% CI, 14-48 kUA/L) and egg sIgE levels of 1.7 kUA/L or greater (95% CI, 1-3 kUA/L) had 95% PPVs for challenge-proved food allergy. Results were robust when stratified on established risk factors for food allergy. Egg SPT responses and sIgE levels were poor predictors of allergy to egg in baked goods. These 95% PPVs, which were generated from a unique dataset, are valuable for the diagnosis of food allergy in young infants and were robust when stratified across a number of different risk factors. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Spiric, Jelena; Engin, Anna M; Karas, Michael; Reuter, Andreas
Allergy against birch pollen is among the most common causes of spring pollinosis in Europe and is diagnosed and treated using extracts from natural sources. Quality control is crucial for safe and effective diagnosis and treatment. However, current methods are very difficult to standardize and do not address individual allergen or isoallergen composition. MS provides information regarding selected proteins or the entire proteome and could overcome the aforementioned limitations. We studied the proteome of birch pollen, focusing on allergens and isoallergens, to clarify which of the 93 published sequence variants of the major allergen, Bet v 1, are expressed as proteins within one source material in parallel. The unexpectedly complex Bet v 1 isoallergen composition required manual data interpretation and a specific design of databases, as current database search engines fail to unambiguously assign spectra to highly homologous, partially identical proteins. We identified 47 non-allergenic proteins and all 5 known birch pollen allergens, and unambiguously proved the existence of 18 Bet v 1 isoallergens and variants by manual data analysis. This highly complex isoallergen composition raises questions whether isoallergens can be ignored or must be included for the quality control of allergen products, and which data analysis strategies are to be applied.
Ansari, A A; Freidhoff, L R; Marsh, D G
Lol p II and III are each about 11-kD protein allergens from the pollen of Lolium perenne (rye grass). We have found that human immune responses (IgE and IgG antibodies) to both proteins are significantly associated with HLA-DR3. In addition, the two proteins are cross-reactive with the antibodies in many human sera (about 84% human sera showed the cross-reactivity). We have determined greater than 90% of the amino acid sequences of the two proteins and found that they are at least 54% homologous. Berzofsky found that 75% of the 23 known T cell sites in various proteins had an amphipathic structure. Our analysis by the same method showed that both Lol p II and III have a major region of amphipathicity (at residues 61-67, Lol p III numbering) which might contain sites for binding to an Ia molecule and a T cell receptor. This region is identical between Lol p II and III, except for an Arg-Lys substitution, and could account, in part, for the DR3 association with responsiveness to both molecules. An interesting difference between the two proteins is that immune response to Lol p III is associated with DR5 (in addition to DR3), whereas no DR5 association is found in the case of Lol p II. One possibility is that Lol p III has an additional site which binds to the DR5 Ia molecule. Lol p III indeed has a second highly amphiphathic peptide, 24-30 (Lol p III 24 R P G D T L A 30), which is different and not amphipathic in Lol p II.(ABSTRACT TRUNCATED AT 250 WORDS)
Toomer, Ondulla T; Ferguson, Martine; Pereira, Marion; Do, Andrew; Bigley, Elmer; Gaines, Dennis; Williams, Kristina
Neonatal to early childhood is the critical period for establishing a balance of T helper 1 (Th1) versus T helper 2 (Th2) cellular immunity within the gut, which is strongly influenced by the source and establishment of gut microflora. Probiotic administration has been shown to attenuate Th2-biased cellular immunity and predisposition to food allergies. To test this hypothesis we provided ad libitum a probiotic-supplemented (Primalac 454 Feed Grade Microbials) or control diet to lactating dams with suckling pups and weaned pups until 10 weeks of age. Weaned mice were sensitized/challenged with peanut extract, saline or adjuvant at 6, 8 and 10 weeks of age. At 3, 6, 8 and 10 weeks, fecal samples were collected for microbial analysis, while blood samples were analyzed for total plasma IgE levels. At termination (10 weeks of age), splenic T lymphocyte population subtypes were determined using FACS analysis and Th1/Th2/Th17 gene expression by PCR array. Mice given the probiotic-supplemented diet had significantly enhanced probiotic fecal counts compared to controls at 3, 6, 8 and 10 weeks. Moreover, mice fed the probiotic-supplemented diet had enhanced splenic naturally occurring T regulatory cell populations, and reduced splenic gene expression of allergic mediator IL-13 compared to controls. These results provide evidence that early probiotic supplementation may provide host protection to hypersensitivity reactions to food allergens by attenuating food allergen inflammatory responses. Published by Elsevier GmbH.
Burian, Barbara K.
Emergency and abnormal situations in aviation present flight crews with a number of challenges. Checklists are essential tools that have been developed to assist them to meet these challenges. However, in order for checklists to be most effective in these situations they must be designed with the operational and situational demands of emergencies and abnormal conditions in mind as well as human performance capabilities and limitations under high stress and workload.
Food allergy has become a major public health concern in westernized countries, and allergic reactions to peanuts are particularly common and severe. Allergens are defined as antigens that elicit an IgE response, and most allergenic materials (e.g., pollens, danders, and foods) contain multiple allergenic proteins. This has led to the concept that there are “major” allergens and allergens of less importance. “Major allergens” have been defined as allergens that bind a large amount of IgE from the majority of patients and have biologic activity. However, the ability of an allergen to cross-link complexes of IgE and its high-affinity receptor FcεRI (IgE/FcεRI), which we have termed its allergic effector activity, does not correlate well with assays of IgE binding. To identify the proteins that are the most active allergens in peanuts, we and others have employed in vitro model assays of allergen-mediated cross-linking of IgE/FcεRI complexes and have demonstrated that the most potent allergens are not necessarily those that bind the most IgE. The importance of a specific allergen can be determined by measuring the allergic effector activity of that allergen following purification under non-denaturing conditions and by specifically removing the allergen from a complex allergenic extract either by chromatography or by specific immunodepletion. In our studies of peanut allergens, our laboratory has found that two related allergens, Ara h 2 and Ara h 6, together account for the majority of the effector activity in a crude peanut extract. Furthermore, murine studies demonstrated that Ara h 2 and Ara h 6 are not only the major elicitors of anaphylaxis in this system, but also can effectively desensitize peanut-allergic mice. As a result of these observations, we propose that the definition of a major allergen should be based on the potency of that allergen in assays of allergic effector activity and demonstration that removal of that allergen from an extract
Akdis, Mübeccel; Verhagen, Johan; Taylor, Alison; Karamloo, Fariba; Karagiannidis, Christian; Crameri, Reto; Thunberg, Sarah; Deniz, Günnur; Valenta, Rudolf; Fiebig, Helmut; Kegel, Christian; Disch, Rainer; Schmidt-Weber, Carsten B.; Blaser, Kurt; Akdis, Cezmi A.
The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-γ–, interleukin (IL)-4–, and IL-10–producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1–like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4–secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-β as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy. PMID:15173208
Xu, Ting; Zhou, Yufeng; Qiu, Lipeng; Do, Danh C; Zhao, Yilin; Cui, Zhuang; Wang, Heng; Liu, Xiaopeng; Saradna, Arjun; Cao, Xu; Wan, Mei; Gao, Peisong
Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen-treated AhR-deficient (AhR(-/-)) mice showed exacerbation of lung inflammation when compared with wild-type (WT) mice. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen-challenged AhR(-/-) mice as compared with WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR, and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes cyp1a1 and cyp1b1. Furthermore, we tracked the migration of i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-β1-neutralizing Ab. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity.
Xu, Ting; Zhou, Yufeng; Qiu, Lipeng; Do, Danh C; Zhao, Yilin; Cui, Zhuang; Wang, Heng; Liu, Xiaopeng; Saradna, Arjun; Cao, Xu; Wan, Mei; Gao, Peisong
Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen treated AhR-deficient (AhR−/−) mice showed exacerbation of lung inflammation when compared to wild-type (WT) mice. In contrast, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen challenged AhR−/− mice as compared to WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes, cyp1a1 and cyp1b1. Furthermore, we tracked the migration of intravenously injected GFP+ MSCs and found that cockroach allergen-challenged AhR−/− mice displayed less migration of MSCs to the lungs compared to WT. The AhR mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium (ECM) prepared from CRE-challenged epithelial cells significantly induced MSC migrations, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGFβ1 neutralizing antibody. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity. PMID:26561548
Pizzolla, Angela; Oh, Ding Yuan; Luong, Suzanne; Prickett, Sara R.; Henstridge, Darren C.; Febbraio, Mark A.; O’Hehir, Robyn E.; Rolland, Jennifer M.; Hardy, Charles L.
The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a ‘western’ diet high in fat and low in fibre. Although non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation. PMID:27483441
Ying, S; Meng, Q; Taborda-Barata, L; Kay, A B
The allergen-induced cutaneous late-phase response serves as a model of allergic inflammation and is associated with infiltration of neutrophils, eosinophils, T cells, and macrophages. The mechanisms controlling the resolution of allergic inflammatory processes and the fate of infiltrating cells are uncertain. We observed that both the magnitude of the late-phase response and the numbers of infiltrating neutrophils and eosinophils peaked at 6 hr, persisted for 48 hr, but resolved completely by 7 days. In contrast, T-cell and macrophage numbers peaked between 24 and 72 hr after allergen challenge and persisted for up to 7 days. By using the techniques of terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine 5'-triphosphate (dUTP) nickend-labeling (TUNEL) and by combining TUNEL with immunohistochemistry, we tested the hypothesis that the resolution of the late-phase response is associated with apoptosis of neutrophils and eosinophils, with subsequent engulfment of apoptotic cells and apoptotic bodies by tissue macrophages. As the cutaneous late-phase response resolved, there was a progressive increase (peaking at 72 hr) in the total numbers of TUNEL-positive (TUNEL+) cells and in the numbers of macrophages that had engulfed apoptotic cells and bodies. The majority of TUNEL+ cells were identified as neutrophils and eosinophils. In contrast, very little apoptosis was associated with T cells or macrophages. These experiments represent a novel demonstration of cell type-specific apoptosis in vivo in human allergic inflammatory tissue and suggest that phagocytosis by macrophages of apoptotic neutrophils and eosinophils may be a mechanism that regulates resolution of the atopic allergic inflammatory response.
Ming, Mei; Zhao, Baozhong; Shea, Christopher R; Shah, Palak; Qiang, Lei; White, Steven R; Sims, Diane M; He, Yu-Ying
Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin (FLG). Mutational loss of the skin barrier protein FLG predisposes subjects to the development of atopic dermatitis (AD). We sought to determine the role of sirtuin 1 (SIRT1) in skin barrier function, FLG expression, and development of AD. Skin histology of mice with skin-specific SIRT1 deletion and wild-type control animals was examined by using hematoxylin and eosin staining. Protein and mRNA abundance was analyzed by means of immunoblotting, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by means of ELISA. Here we show that FLG is regulated by the protein deacetylase SIRT1 and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin SIRT1 knockdown or genetic deletion downregulates FLG, and regulation of FLG expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes activation of the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor ligand restores FLG expression in SIRT1-inhibited cells. Compared with normal human skin, SIRT1 is downregulated in both AD and non-AD lesions. Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacologic target, and might facilitate the development of mechanism-based agents for AD prevention and therapy. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Ming, Mei; Zhao, Baozhong; Shea, Christopher R.; Shah, Palak; Qiang, Lei; White, Steven R.; Sims, Diane M.; He, Yu-Ying
Background Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin. Mutational loss of the skin barrier protein filaggrin predisposes individuals to the development of atopic dermatitis (AD). Objective to determine the role of SIRT1 in skin barrier function, filaggrin expression, and the development of AD. Methods Skin histology of mice with skin-specific SIRT1 deletion and wild-type controls was examined by Hematoxyline and Eosin (H&E). Protein and mRNA abundance was analyzed by immunoblot, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by ELISA. Results Here we show that filaggrin is regulated by the protein deacetylase SIRT1, and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin, SIRT1 knockdown or genetic deletion down-regulates filaggrin, and regulation of filaggrin expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes the activation of the aryl hydrocarbon receptor (AhR), and the AhR ligand restores filaggrin expression in SIRT1-inhibited cells. As compared with normal human skin, SIRT1 is down-regulated in the lesions of atopic dermatitis as well as non-atopic dermatitis. Conclusion Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacological target, and may facilitate the development of mechanism-based agents for AD prevention and therapy. PMID:25445829
Gebe, John A; Yadava, Koshika; Ruppert, Shannon M; Marshall, Payton; Hill, Paul; Falk, Ben A; Sweere, Johanna M; Han, Hongwei; Kaber, Gernot; Medina, Carlos; Mikecz, Katalin; Ziegler, Steven F; Balaji, Swathi; Keswani, Sundeep G; Perez, Vinicio A de Jesus; Butte, Manish J; Nadeau, Kari; Altemeier, William A; Fanger, Neil; Bollyky, Paul L
The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-κB signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.
Hoseini-Alfatemi, Seyedeh Mahsan; Bayry, Jagadeesh; Sharifi-Rad, Javad
A number of allergens from eggplant (Solanum melongena L.) have been previously identified. In this study, we could detect IgE reactivity of two allergic subjects' sera towards two protein bands of molecular mass of about 35 and 15 kDa. As IgE were reactive to both raw and cooked eggplant extracts, a heat-stable nature of these novel allergens is apparent. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
Carneiro, Raquel; Reefer, Amanda; Wilson, Barbara; Hammer, Juergen; Platts-Mills, Thomas; Custis, Natalie; Woodfolk, Judith
Atopic dermatitis (AD) is often associated with high titer IgE antibodies (ab) to allergens, and IL-10-mediated regulation of IFN-gamma has been proposed to contribute to this IgE ab production. However, the relevance of IL-10 and IFN-gamma to IgE associated with AD has not been examined in the context of an allergen-specific system. Analysis of PBMC responses in vitro showed deficient T cell proliferation to overlapping IL-10- (peptide (P) 2:1) and IFN-gamma- (P2:2) inducing chain 2 major epitopes of cat allergen (Fel d 1) in cultures from sensitized AD patients (mean IgE to cat=20.9 IU/ml). Diminished IFN-gamma induction by Fel d 1 and P2:2, along with elevated peptide-induced IL-10 (except for P2:1) was observed in PBMC cultures from AD subjects compared with non-AD (sensitized and non-sensitized) subjects. Neither T cell proliferation nor IFN-gamma production to chain 2 epitopes could be restored by anti-IL-10 mAb in cultures from sensitized AD subjects. Moreover, allergen avoidance was associated with a paradoxical decrease in both IL-10 and IFN-gamma in peptide-stimulated PBMC from these subjects. Control of IFN-gamma production to chain 2 epitopes by IL-10 may be relevant to sensitization status. Development of high titer IgE ab in AD could reflect a failure of this mechanism.
Xie, Qiang-min; Wu, Ximei; Wu, Hui-min; Deng, Yang-mei; Zhang, Shui-juan; Zhu, Jian-ping; Dong, Xin-wei
Clinically sublingual immunotherapy (SLIT) by using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. Supposed that oral administration of high-dose of allergen extracts imitates SLIT and may prevent IgE-related responses in allergic diseases, we investigated the effects of oral administration of allergen extracts from Dermatophagoides farinae (Derf) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in a model of asthmatic rat. After administration to the specific Derf-sensitized rats with Derfdrop solution containing Derf1 and Derf2 extracts derived from Derf, the effects of Derfdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, as well as serum IgE and IgG levels were investigated. Results indicated that Derfdrop not only dose-dependently prevented the AHR in response to methacholine, but also significantly reduced the serum total and allergen-specific IgE levels, all the maximal effects were achieved at dose of 5 mg/kg/d, and were as comparable as those of dexamethasone at dose of 1.0 mg/kg/d. Furthermore, oral administration of Derfdrop not only dose-dependently elevated allergen-specific serum IgG levels and reduced total and allergen-specific IgE levels, but also normalized the imbalance between the Th1 cytokine, IFN-gamma and Th2 cytokine, IL-4. Finally, oral administration of Derfdrop significantly reduced Goblet cell hyperplasia and eosinophilia in the Derf-sensitized allergic rat model. These data suggest that Derfdrop effectively improves specific allergen-induced inflammation and AHR in Derf-sensitized and -challenged rats and provide with the rationale for clinical SLIT by using Derfdrop in a specific allergen-induced asthma.
Wheat IgE-mediated food allergy in European patients: alpha-amylase inhibitors, lipid transfer proteins and low-molecular-weight glutenins. Allergenic molecules recognized by double-blind, placebo-controlled food challenge.
Pastorello, Elide A; Farioli, Laura; Conti, Amedeo; Pravettoni, Valerio; Bonomi, Simona; Iametti, Stefania; Fortunato, Donatella; Scibilia, Joseph; Bindslev-Jensen, Carsten; Ballmer-Weber, Barbara; Robino, Anna M; Ortolani, Claudio
Three main problems hamper the identification of wheat food allergens: (1) lack of a standardized procedure for extracting all of the wheat protein fractions; (2) absence of double-blind, placebo-controlled food challenge studies that compare the allergenic profile of Osborne's three protein fractions in subjects with real wheat allergy, and (3) lack of data on the differences in IgE-binding capacity between raw and cooked wheat. Sera of 16 wheat-challenge-positive patients and 6 patients with wheat anaphylaxis, recruited from Italy, Denmark and Switzerland, were used for sodium dodecyl sulfate-polyacrylamide gel electrophoresis/immunoblotting of the three Osborne's protein fractions (albumin/globulin, gliadins and glutenins) of raw and cooked wheat. Thermal sensitivity of wheat lipid transfer protein (LTP) was investigated by spectroscopic approaches. IgE cross-reactivity between wheat and grass pollen was studied by blot inhibition. The most important wheat allergens were the alpha-amylase/trypsin inhibitor subunits, which were present in all three protein fractions of raw and cooked wheat. Other important allergens were a 9-kDa LTP in the albumin/globulin fraction and several low-molecular-weight (LMW) glutenin subunits in the gluten fraction. All these allergens showed heat resistance and lack of cross-reactivity to grass pollen allergens. LTP was a major allergen only in Italian patients. The alpha-amylase inhibitor was confirmed to be the most important wheat allergen in food allergy and to play a role in wheat-dependent exercise-induced anaphylaxis, too. Other important allergens were LTP and the LMW glutenin subunits.
Dutkiewicz, Jacek; Skórska, Czesława; Krysińska-Traczyk, Ewa; Cholewa, Grazyna; Sitkowska, Jolanta; Milanowski, Janusz; Góra, Anna
Serum samples from 61 potato processing workers and 30 urban dwellers not exposed to organic dusts (as a reference group) were examined in agar-gel precipitation test performed by Ouchterlony double diffusion method with the antigens of 12 microorganisms associated with organic dusts. Each serum was tested twice: not concentrated, and three-fold concentrated, for the detection of low levels of precipitins. The antibody response of workers to the antigen of coryneform bacterium Agromyces ramosus was high, at both not concentrated and 3-fold concentrated sera (respectively 29.5% and 45.9%)--significantly greater than in reference group (p < 0.001). Workers' response to the antigens of Gram-negative bacterium Alcaligenes faecalis and thermophilic actinomycete Thermoactinomyces vulgaris was lower (respectively 13.1% and 13.1% at not concentrated sera, 24.6% and 29.5% at 3-fold concentrated sera) but in all cases significantly greater than in reference group (p < 0.05 at not concentrated sera, p < 0.01 and p < 0.001 at 3-fold concentrated sera). The frequency of positive precipitin reactions of potato workers to antigen of Penicillium citrinum was high only at 3-fold concentrated sera (55.7%)--significantly higher compared to reference group (p < 0.001). The antibody response of potato workers to other antigens was either unspecific or low, showing no significant difference compared to reference group. Twenty eight out of 61 examined potato processing workers (45.9%) reported the occurrence of the work-related pulmonary symptoms. The frequency of positive precipitin reactions to Agromyces ramosus, Alcaligenes faecalis, Thermoactinomyces vulgaris, Penicillium citrinum and Acinetobacter calcoaceticus was significantly greater in the subgroup of 28 workers reporting work-related pulmonary symptoms compared to 33 asymptomatic workers (p < 0.05). Study results suggest that antigens of Agromyces ramosus, Alcaligenes faecalis, Thermoactinomyces vulgaris and Penicillium
Ansari, A A; Shinomiya, N; Zwollo, P; Marsh, D G
The grass pollen allergen Lol p III (Mr 11,000) is a well-characterized antigen that has been found useful in immunogenetic studies of human immune responsiveness. Since immune responsiveness to this allergen is associated with HLA-DR3, we investigated whether there was any sequence in the HLA-D region that would render a person "susceptible" [antibody (Ab)-positive] to the allergen. By sequence-specific oligonucleotide (SSO) slot-blot and sequence analyses of polymerase chain reaction (PCR)-amplified genomic DNA from Lol p III responder and nonresponder subjects, Ab responsiveness was found to be strongly associated with the sequence Glu-Tyr-Ser-Thr-Ser (EYSTS), present in the first polymorphic regions of DR beta I polypeptide chains of DR3, DR11 (split of DR5), and DRw6. Of the 41 grass-allergic subjects investigated, 19 had the EYSTS sequence, of whom 18 (95%) were Lol p III immunoglobulin G (IgG) Ab responders; among the 22 EYSTS- subjects, ten were Lol p III responders (P = 0.001, relative risk = 21.6). No such association was found with any polymorphic sequences in other DR beta chains, or in DQ alpha I and DQ beta I chains. These findings suggest that the EYSTS sequence is important in the presentation of an epitope of Lol p III; other sequence(s) may be involved in the presentation of other epitope(s). To our knowledge, this is the first demonstration of a strong association between a specific HLA sequence and immune responsiveness to a well-defined antigen. The paper shows that presence of the EYSTS sequence classifies subjects as Lol p III responders in 18/19 cases.
Rindsjö, E; Joerink, M; Johansson, C; Bremme, K; Malmström, V; Scheynius, A
It is hypothesized that the in utero environment in allergic mothers can affect the neonatal immune responses. The aim of this study was to analyse the effect of maternal allergic disease on cord blood mononuclear cell (CBMC) phenotype and proliferative responses upon allergen stimulation. Peripheral blood mononuclear cells (PBMC) from 12 allergic and 14 nonallergic mothers and CBMC from their children were analysed. In the mothers, we determined cell proliferation, production of IL-4 and expression of FOXP3 in response to allergen stimulation. In the children, we evaluated cell proliferation and FOXP3 expression following allergen stimulation. Furthermore, expression of different homing markers on T cells and regulatory T cells and maturity of the T cells and B cell subsets were evaluated directly ex vivo. The timothy- and birch-allergic mothers responded with increased proliferation and/or IL-4 production towards timothy and birch extract, respectively, when compared to nonallergic mothers. This could not be explained by impairment of FOXP3(+) regulatory T cells in the allergic mothers. CBMC proliferation and FOXP3 expression in response to allergens were not affected by the allergic status of the mother. Also, phenotype of T cells, FOXP3(+) regulatory T cells and B cells was not affected by the allergic status of the mother. Our results suggest that maternal allergic disease has no effect on the neonatal response to allergens or the phenotype of neonatal lymphocytes. The factors studied here could, however, still affect later development of allergy.
Lucae, S; Schmid-Grendelmeier, P; Wüthrich, B; Kraft, D; Valenta, R; Linhart, B
Atopic dermatitis (AD) patients mount IgE antibody responses to a variety of environmental allergens and also to autoantigens. We analyzed serum samples from four AD patients who had received oral cyclosporine A (CyA) treatment for up to 17 months regarding IgE autoreactivity to nitrocellulose-blotted human epithelial cell extracts and IgE levels to environmental allergens by quantitative ImmunoCap measurements. Skin inflammation was assessed by SCORAD. During full-dose treatment, a strong reduction in T-cell-mediated skin symptoms was observed which reappeared when CyA treatment was reduced or stopped. The intensity of IgE autoreactivity seemed to follow skin inflammation as it was reduced during full-dose treatment and increased upon inflammation. Interestingly, IgE levels to exogenous allergens were boosted by allergen exposure, declined thereafter, and seemed to be unaffected by CyA. Our data thus indicate that allergen-specific IgE production is boosted by allergen contact and cannot be reduced by CyA-mediated T-cell suppression. © 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.
Madouri, Fahima; Chenuet, Pauline; Beuraud, Chloé; Fauconnier, Louis; Marchiol, Tiffany; Rouxel, Nathalie; Ledru, Aurélie; Gallerand, Margaux; Lombardi, Vincent; Mascarell, Laurent; Marquant, Quentin; Apetoh, Lionel; Erard, François; Le Bert, Marc; Trovero, Fabrice; Quesniaux, Valérie F J; Ryffel, Bernhard; Togbe, Dieudonnée
Protein kinase C (PKC) θ, a serine/threonine kinase, is involved in TH2 cell activation and proliferation. Type 2 innate lymphoid cells (ILC2s) resemble TH2 cells and produce the TH2 cytokines IL-5 and IL-13 but lack antigen-specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct TH2 responses in patients with allergic lung inflammation remains unknown. We hypothesized that PKC-θ contributes to ILC2 activation and might be necessary for ILC2s to instruct the TH2 response. PRKCQ gene expression was assessed in innate lymphoid cell subsets purified from human PBMCs and mouse lung ILC2s. ILC2 activation and eosinophil recruitment, TH2-related cytokine and chemokine production, lung histopathology, interferon regulatory factor 4 (IRF4) mRNA expression, and nuclear factor of activated T cells (NFAT1) protein expression were determined. Adoptive transfer of ILC2s from wild-type mice was performed in wild-type and PKC-θ-deficient (PKC-θ(-/-)) mice. Here we report that PKC-θ is expressed in both human and mouse ILC2s. Mice lacking PKC-θ had reduced ILC2 numbers, TH2 cell numbers and activation, airway hyperresponsiveness, and expression of the transcription factors IRF4 and NFAT1. Importantly, adoptive transfer of ILC2s restored eosinophil influx and IL-4, IL-5 and IL-13 production in lung tissue, as well as TH2 cell activation. The pharmacologic PKC-θ inhibitor (Compound 20) administered during allergen challenge reduced ILC2 numbers and activation, as well as airway inflammation and IRF4 and NFAT1 expression. Therefore our findings identify PKC-θ as a critical factor for ILC2 activation that contributes to TH2 cell differentiation, which is associated with IRF4 and NFAT1 expression in allergic lung inflammation. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Leemans, Jérôme; Kirschvink, Nathalie; Clercx, Cécile; Cambier, Carole; Gustin, Pascal
Knowledge about the use of inhaled bronchodilators in cats with so-called 'feline asthma' is limited and relies on the experience of clinicians treating these patients. A randomised controlled four-way crossover study was therefore designed to compare the effects of salbutamol (SAL, 100 μg), ipratropium bromide (IB, 20 μg) and a combination of both (SAL/IB, 100 μg/20 μg), delivered through a pressurised metered-dose inhaler (pMDI) connected to a spacing chamber, on allergen-induced bronchospasms in five Ascaris suum (AS)-sensitised cats. Four AS bronchial provocation challenges were carried out at 1 week intervals, followed by one of four treatment protocols: SAL, IB, SAL/IB or control (untreated). Enhanced pause (Penh), an estimator of airflow limitation measured by barometric whole-body plethysmography, was repeatedly assessed within 120 min following the administration of each treatment protocol. Responses to inhaled medications were evaluated by calculating the area under the time-response curves (AUC) from 0 to 60 or 120 min after drug administration (AUC(0-60), AUC(0-120)), as well as the times required for half-recovery (T(50%)) or for returning to nearly basal conditions (T(20%)). No significant differences were found among the four study groups, with reference to the mean AUC(0-60), T(20%) and T(50%) values of Penh (P>0.05). Mean AUC(0-120) values of Penh were similar between the bronchodilators tested, but were significantly lower than those in the untreated group. It was concluded that inhalation of SAL, IB and SAL/IB via pMDI failed to improve most Penh-derived parameters, which suggested that these bronchodilators were of limited efficacy in reversing allergen-induced bronchospasm in cats. However, further studies using a larger number of animals are warranted to investigate if different drugs or delivery devices or higher dosages may be more effective.
Horner, W E; Helbling, A; Salvaggio, J E; Lehrer, S B
Airborne fungal spores occur widely and often in far greater concentrations than pollen grains. Immunoglobulin E-specific antigens (allergens) on airborne fungal spores induce type I hypersensitivity (allergic) respiratory reactions in sensitized atopic subjects, causing rhinitis and/or asthma. The prevalence of respiratory allergy to fungi is imprecisely known but is estimated at 20 to 30% of atopic (allergy-predisposed) individuals or up to 6% of the general population. Diagnosis and immunotherapy of allergy to fungi require well-characterized or standardized extracts that contain the relevant allergen(s) of the appropriate fungus. Production of standardized extracts is difficult since fungal extracts are complex mixtures and a variety of fungi are allergenic. Thus, the currently available extracts are largely nonstandardized, even uncharacterized, crude extracts. Recent significant progress in isolating and characterizing relevant fungal allergens is summarized in the present review. Particularly, some allergens from the genera Alternaria, Aspergillus, and Cladosporium are now thoroughly characterized, and allergens from several other genera, including some basidiomycetes, have also been purified. The availability of these extracts will facilitate definitive studies of fungal allergy prevalence and immunotherapy efficacy as well as enhance both the diagnosis and therapy of fungal allergy. PMID:7621398
Cabanillas, Beatriz; Maleki, Soheila J; Rodríguez, Julia; Cheng, Hsiaopo; Teuber, Suzanne S; Wallowitz, Mikhael L; Muzquiz, Mercedes; Pedrosa, Mercedes M; Linacero, Rosario; Burbano, Carmen; Novak, Natalija; Cuadrado, Carmen; Crespo, Jesús F
The aim of this study was to investigate changes in walnut allergenicity after processing treatments by in vitro techniques and physiologically relevant assays. The allergenicity of walnuts subjected to high hydrostatic pressure and thermal/pressure treatments was evaluated by IgE-immunoblot and antibodies against walnut major allergen Jug r 4. The ability of processed walnut to cross-link IgE on effector cells was evaluated using a rat basophil leukaemia cell line and by skin prick testing. Susceptibility to gastric and duodenal digestion was also evaluated. The results showed that walnuts subjected to pressure treatment at 256 kPa, 138 °C, were able to diminish the IgE cross-linking capacity on effector cells more efficiently than high pressure treated walnuts. IgE immunoblot confirmed these results. Moreover, higher susceptibility to digestion of pressure treated walnut proteins was observed. The use of processed walnuts with decreased IgE binding capacity could be a potential strategy for walnut tolerance induction.
Kamijo, Seiji; Takeda, Haruna; Tokura, Tomoko; Suzuki, Mayu; Inui, Kyoko; Hara, Mutsuko; Matsuda, Hironori; Matsuda, Akira; Oboki, Keisuke; Ohno, Tatsukuni; Saito, Hirohisa; Nakae, Susumu; Sudo, Katsuko; Suto, Hajime; Ichikawa, Saori; Ogawa, Hideoki; Okumura, Ko; Takai, Toshiro
How the innate and adaptive immune systems cooperate in the natural history of allergic diseases has been largely unknown. Plant-derived allergen, papain, and mite allergens, Der f 1 and Der p 1, belong to the same family of cysteine proteases. We examined the role of protease allergens in the induction of Ab production and airway inflammation after repeated intranasal administration without adjuvants and that in basophil/mast cell stimulation in vitro. Papain induced papain-specific IgE/IgG1 and lung eosinophilia. Der f 1 induced Der f 1-specific IgG1 and eosinophilia. Although papain-, Der f 1-, and Der p 1-stimulated basophils expressed allergy-inducing cytokines, including IL-4 in vitro, basophil-depleting Ab and mast cell deficiency did not suppress the papain-induced in vivo responses. Protease inhibitor-treated allergens and a catalytic site mutant did not induce the responses. These results indicate that protease activity is essential to Ab production and eosinophilia in vivo and basophil activation in vitro. IL-33-deficient mice lacked eosinophilia and had reduced papain-specific IgE/IgG1. Coadministration of OVA with papain induced OVA-specific IgE/IgG1, which was reduced in IL-33-deficient mice. We demonstrated IL-33 release, subsequent IL-33-dependent IL-5/IL-13 release, and activation of T1/ST2-expressing lineage(-)CD25(+)CD44(+) innate lymphoid cells in the lung after papain inhalation, suggesting the contribution of the IL-33-type 2 innate lymphoid cell-IL-5/IL-13 axis to the papain-induced airway eosinophilia. Rag2-deficient mice, which lack adaptive immune cells, showed significant, but less severe, eosinophilia. Collectively, these results suggest cooperation of adaptive immune cells and IL-33-responsive innate cells in protease-dependent allergic airway inflammation.
Hegewald, Jana; Gantin, Richard G; Lechner, Christian J; Huang, Xiangsheng; Agosssou, Abram; Agbeko, Yvon F; Soboslay, Peter T; Köhler, Carsten
In sub-Saharan Africa poly-parasite infections are frequently observed in children, and with poly-parasitism modulating immune mechanisms, mediated by cytokines and chemokines, are required to prevent overwhelming inflammation and host tissue damage. We analyzed in children co-infected with helminthes and protozoan parasites their cellular production of regulatory and pro-inflammatory cytokines and chemokines in response to parasite antigens and allergens. Intestinal and intravascular parasite infections were detected in stool and urines samples. The in vitro cellular cytokine and chemokine responses of peripheral blood mononuclear cells (PBMC) to parasite antigens and allergens were analysed in children (n = 87) with single and poly-parasite infection, and skin prick test reactivity to fungus and mite allergens was determined in singly and poly-parasitized children (n = 509). In children Entamoeba histolytica/dispar (62%), Necator americanus (31%), Schistosoma haematobium (28%), S. mansoni (21%), Hymenolepis nana (2%) and Strongyloides stercoralis (1%) were diagnosed. Singly infected were 37%, 47% were positive for 2 or more parasite species and 16% were infection-free. When PBMC were stimulated in vitro with parasite antigens and allergens, regulatory-type cytokine IL-27 and alarmin-type IL-33 enhanced with poly-parasite infections whilst IL-10 and pro-inflammatory MIP3-α/CCL20 and MIG/CXCL9 were produced in similar amounts in singly or poly-parasitized children. The co-stimulation in vitro of PBMC with mite allergens and Ascaris lumbricoides antigens depressed the allergen-induced pro-inflammatory IL-27, IL-33 and MIP3-α/CCL20 responses while regulatory IL-10 remained unaffected. Post albendazole and/or praziquantel treatment, the cellular release of IL-10, IL-33, MIP3-α/CCL20 and MIG/CXCL9 lessened significantly in all children infection groups. Skin prick test (SPT) reactivity to fungus Aspergillus fumigatus and mite Dermatophagoides pteronyssinus
Niederberger, Verena; Niggemann, Bodo; Kraft, Dietrich; Spitzauer, Susanne; Valenta, Rudolf
The formation of IgE antibodies against environmental allergens represents the hallmark of type I allergy. Data from in vitro cultured cells and experimental animal models provide controversial evidence for isotype switching from IgM to IgE production via sequential as well as non-sequential (i.e. direct) class switch. We analyzed the evolution of IgE responses in 11 children developing birch pollen and/or grass pollen allergy during the first 7 years of life using purified recombinant allergen molecules (major birch pollen allergen, Bet v 1; major timothy grass pollen allergens, Phl p 1, Phl p 2, Phl p 5). Demographic, clinical and serological data indicated a postnatal sensitization to pollen allergens. A parallel development of IgG(1-4) and IgE responses to recombinant allergen molecules compatible with a strictly sequential class switch to IgE was observed only in one child. The only partly synchronized and dissociated development of allergen-specific antibody responses found in all other cases can be best explained by a partly sequential class switch involving few switch stations or, more likely, by direct class switching. Kinetics and courses of allergen-specific antibody responses (IgM, IgG(1-4), IgE) during the first years of life suggest that, once established, allergen-specific IgE responses are driven by antigen contact rather than by cytokines controlling class switch to IgE.
Kurup, Viswanath P; Sussman, Gordon L; Yeang, Hoong Y; Elms, Nancy; Breiteneder, Heimo; Arif, Siti AM; Kelly, Kevin J; Bansal, Naveen K; Fink, Jordan N
Background In recent years, allergy to natural rubber latex has emerged as a major allergy among certain occupational groups and patients with underlying diseases. The sensitization and development of latex allergy has been attributed to exposure to products containing residual latex proteins. Although improved manufacturing procedures resulted in a considerable reduction of new cases, the potential risk for some patient groups is still great. In addition the prevalent cross-reactivity of latex proteins with other food allergens poses a major concern. A number of purified allergens and a few commercial kits are currently available, but no concerted effort was undertaken to evaluate them. Methods We studied 11 purified latex allergens, Hev b 1 to Hev b 10, and Hev b 13 along with several crude allergen extracts and two commercial ImmunoCAP assays to evaluate specific IgE antibody in the sera from latex allergic patients and controls. Health care workers and spina bifida patients with clinical symptoms of latex allergy, spina bifida patients without latex allergy, and non-atopic health care workers have been studied. Results The results suggest that Hev b 2, 5, 6, and 13 together identified over 80 percent health care workers with latex allergy, while Hev b 6 along with Hev b 1 or 3 detected specific IgE antibody in all sera studied from patients with spina bifida and latex allergy. The ImmunoCAP results using both Hev b 5 amplified and non-amplified closely agreed with the clinical diagnosis of latex allergy in health care workers and in spina bifida. Conclusion Although the purified allergens and crude extracts reacted diversely with IgE from different patient groups, the results indicated that use of certain combinations of purified recombinant antigens will be useful in commercial kits or in in-house assays for detecting specific IgE antibody in the sera. The results suggest that a combination of Hev b 2, 3, 5, 6, and 13 together detected specific IgE in 80% of
Batista, Rita; Martins, Isabel; Jeno, Paul; Ricardo, Cândido Pinto; Oliveira, Maria Margarida
In spite of being among the main foods responsible for allergic reactions worldwide, soybean (Glycine max)-derived products continue to be increasingly widespread in a variety of food products due to their well-documented health benefits. Soybean also continues to be one of the elected target crops for genetic modification. The aim of this study was to characterize the soya proteome and, specifically, IgE-reactive proteins as well as to compare the IgE response in soya-allergic individuals to genetically modified Roundup Ready soya versus its non-transgenic control. We performed two-dimensional gel electrophoresis of protein extracts from a 5% genetically modified Roundup Ready flour sample and its non-transgenic control followed by Western blotting with plasma from 5 soya-sensitive individuals. We used peptide tandem mass spectrometry to identify soya proteins (55 protein matches), specifically IgE-binding ones, and to evaluate differences between transgenic and non-transgenic samples. We identified 2 new potential soybean allergens--one is maturation associated and seems to be part of the late embryogenesis abundant proteins group and the other is a cysteine proteinase inhibitor. None of the individuals tested reacted differentially to the transgenic versus non-transgenic samples under study. Soybean endogenous allergen expression does not seem to be altered after genetic modification. Proteomics should be considered a powerful tool for functional characterization of plants and for food safety assessment. Copyright (c) 2007 S. Karger AG, Basel.
Burge, H A; Rogers, C A
Outdoor allergens are an important part of the exposures that lead to allergic disease. Understanding the role of outdoor allergens requires a knowledge of the nature of outdoor allergen-bearing particles, the distributions of their source, and the nature of the aerosols (particle types, sizes, dynamics of concentrations). Primary sources for outdoor allergens include vascular plants (pollen, fern spores, soy dust), and fungi (spores, hyphae). Nonvascular plants, algae, and arthropods contribute small numbers of allergen-bearing particles. Particles are released from sources into the air by wind, rain, mechanical disturbance, or active discharge mechanisms. Once airborne, they follow the physical laws that apply to all airborne particles. Although some outdoor allergens penetrate indoor spaces, exposure occurs mostly outdoors. Even short-term peak outdoor exposures can be important in eliciting acute symptoms. Monitoring of airborne biological particles is usually by particle impaction and microscopic examination. Centrally located monitoring stations give regional-scale measurements for aeroallergen levels. Evidence for the role of outdoor allergens in allergic rhinitis is strong and is rapidly increasing for a role in asthma. Pollen and fungal spore exposures have both been implicated in acute exacerbations of asthma, and sensitivity to some fungal spores predicts the existence of asthma. Synergism and/or antagonism probably occurs with other outdoor air particles and gases. Control involves avoidance of exposure (staying indoors, preventing entry of outdoor aerosols) as well as immunotherapy, which is effective for pollen but of limited effect for spores. Outdoor allergens have been the subject of only limited studies with respect to the epidemiology of asthma. Much remains to be studied with respect to prevalence patterns, exposure and disease relationships, and control. PMID:10931783
Gendel, Steven M
The efficacy of any specific bioinformatic analysis of the potential allergenicity of new food proteins depends directly on the nature and content of the databases that are used in the analysis. A number of different allergen-related databases have been developed, each designed to meet a different need. These databases differ in content, organization, and accessibility. These differences create barriers for users and prevent data sharing and integration. The development and application of appropriate semantic web technologies, (for example, a food allergen ontology) could help to overcome these barriers and promote the development of more advanced analytic capabilities.
Roux, Kenneth H; Teuber, Suzanne S; Sathe, Shridhar K
Allergic reactions to tree nuts can be serious and life threatening. Considerable research has been conducted in recent years in an attempt to characterize those allergens that are most responsible for allergy sensitization and triggering. Both native and recombinant nut allergens have been identified and characterized and, for some, the IgE-reactive epitopes described. Some allergens, such as lipid transfer proteins, profilins, and members of the Bet v 1-related family, represent minor constituents in tree nuts. These allergens are frequently cross-reactive with other food and pollen homologues, and are considered panallergens. Others, such as legumins, vicilins, and 2S albumins, represent major seed storage protein constituents of the nuts. The allergenic tree nuts discussed in this review include those most commonly responsible for allergic reactions such as hazelnut, walnut, cashew, and almond as well as those less frequently associated with allergies including pecan, chestnut, Brazil nut, pine nut, macadamia nut, pistachio, coconut, Nangai nut, and acorn. Copyright 2003 S. Karger AG, Basel
Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides lacking allergen-specific T cell epitopes reduces Bet v 1-specific T cell responses via blocking antibodies in a murine model for birch pollen allergy
Linhart, B; Narayanan, M; Focke-Tejkl, M; Wrba, F; Vrtala, S; Valenta, R
Background Vaccines consisting of allergen-derived peptides lacking IgE reactivity and allergen-specific T cell epitopes bound to allergen-unrelated carrier molecules have been suggested as candidates for allergen-specific immunotherapy. Objective To study whether prophylactic and therapeutic vaccination with carrier-bound peptides from the major birch pollen allergen Bet v 1 lacking allergen-specific T cell epitopes has influence on Bet v 1-specific T cell responses. Methods Three Bet v 1-derived peptides, devoid of Bet v 1-specific T cell epitopes, were coupled to KLH and adsorbed to aluminium hydroxide to obtain a Bet v 1-specific allergy vaccine. Groups of BALB/c mice were immunized with the peptide vaccine before or after sensitization to Bet v 1. Bet v 1- and peptide-specific antibody responses were analysed by ELISA. T cell and cytokine responses to Bet v 1, KLH, and the peptides were studied in proliferation assays. The effects of peptide-specific and allergen-specific antibodies on T cell responses and allergic lung inflammation were studied using specific antibodies. Results Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides induced a Bet v 1-specific IgG antibody response without priming/boosting of Bet v 1-specific T cells. Prophylactic and therapeutic vaccination of mice with the peptide vaccine induced Bet v 1-specific antibodies which suppressed Bet v 1-specific T cell responses and allergic lung inflammation. Conclusion and Clinical Relevance Vaccination with carrier-bound allergen-derived peptides lacking allergen-specific T cell epitopes induces allergen-specific IgG antibodies which suppress allergen-specific T cell responses and allergic lung inflammation. PMID:24447086
Casani, John R.
The Galileo mission to Jupiter will make the first direct sampling of the atmosphere of the solar system's largest planet and will spend as long as 22 months orbiting Jupiter. Launch date, trajectory, Jupiter arrival, and number of orbits of that planet depend on NASA's flight schedules since destruction of the Space Shuttle Challenger on Jan. 28, 1986. Galileo's responses to the schedule changes caused by the Challenger explosion are discussed.
Casani, John R.
The Galileo mission to Jupiter will make the first direct sampling of the atmosphere of the solar system's largest planet and will spend as long as 22 months orbiting Jupiter. Launch date, trajectory, Jupiter arrival, and number of orbits of that planet depend on NASA's flight schedules since destruction of the Space Shuttle Challenger on Jan. 28, 1986. Galileo's responses to the schedule changes caused by the Challenger explosion are discussed.
Horak, Friedrich; Zieglmayer, Petra; Zieglmayer, René; Lemell, Patrick
This double-blind cross-over study compared the potential of bilastine, cetirizine, and fexofenadine to relieve the symptoms of allergic rhinitis. Seventy-five allergic volunteers were challenged with grass pollen in the Vienna Challenge Chamber (VCC) on two consecutive days of allergen provocation; 6 h on day 1 and 4 h day 2. Bilastine 20 mg, cetirizine 10 mg, fexofenadine 120 mg, or placebo were taken orally 2 h after the start of provocation on day 1 only. Total nasal symptom scores, the global symptom scores, nasal secretions, and eye symptoms were assessed on both day 1 and day 2. Bilastine had a rapid onset of action, within 1 h, and a long duration of action, greater than 26 h. Cetirizine was similar. Fexofenadine was similar on day 1 but less effective on day 2, indicating a shorter duration of action. Bilastine, like cetirizine and fexofenadine, was safe and well tolerated in this study.
Stelmaszczyk-Emmel, Anna; Zawadzka-Krajewska, Anna; Głodkowska-Mrówka, Eliza; Demkow, Urszula
Over the last decades allergic diseases has become a major health problem worldwide. The only specific treatment to date is allergen specific immunotherapy (ASIT). Although it was shown that ASIT generates allergen-tolerant T cells, detailed mechanism underlying its activity is still unclear and there is no reliable method to monitor its effectiveness. The aim of our study was to evaluate ASIT influence on the frequency of forkhead box P3 (FoxP3) Tregs in allergic children with various clinical manifestations. The relative number of FoxP3 Tregs in 32 blood samples from allergic children at baseline and/or after 1 year of ASIT was assessed by flow cytometry. In the entire studied group, the percentage of FoxP3 Tregs did not increase 1 year after ASIT. Nevertheless, the percentage of FoxP3 Tregs after ASIT significantly increased in children with respiratory allergy (conjunctivitis, asthma, and rhinitis) coexisting with nonrespiratory manifestations (food allergy and/or atopic dermatitis), whereas, in patients with respiratory allergy only, the percentage of FoxP3 Tregs decreased. To the best of our knowledge, this is the first report showing various differential FoxP3 Tregs response to ASIT in allergic children. FoxP3 Tregs number could be useful in treatment monitoring. Further studies are warranted to confirm these observations.
Stern, Debra A; Riedler, Josef; Nowak, Dennis; Braun-Fahrlander, Charlotte; Swoboda, Ines; Balic, Nadja; Chen, Kuan-Wei; Vrtala, Susanne; Grönlund, Hans; van Hage, Marianne; Valenta, Rudolf; Spitzauer, Susanne; Von Mutius, Erika; Vercelli, Donata
IgE synthesis by human B cells results from allergen-dependent, T(H)2-mediated isotype switching. Exposure to a farming environment protects against IgE responses. We reconstructed allergen-dependent switching patterns in vivo to identify the level or levels at which farm exposure acts to protect against atopy. Serum IgG1 to IgG4 and IgE to grass (rPhl p 1 and rPhl p 5), cat (rFel d 1), and mite (rDer p 2) were assessed by means of ELISA in the Allergy and Endotoxin study population (812 children). Farm exposure was defined as currently living on a farm, exposure to stables/farm milk in the first year of life, or both. Farm exposure did not affect allergen-specific IgG2 and IgG3 levels but had complex allergen-specific effects on IgG1, IgG4, and IgE levels. Exposure protected against grass-specific responses at every step along the IgG1/IgG4/IgE switching pathway but had no significant effect on mite responses. Protection from cat responses was concentrated at the IgG1 level. For all allergens, failure to express IgG1 was associated with low prevalence of IgG4 or IgE responses. Notably, coexpression of IgG1, IgG4, and IgE to grass was associated with increased risk of allergic disease and higher IgE levels compared with production of IgG1 and IgE without IgG4, suggesting IgG4 coexpression marks stronger activation of T(H)2-dependent events. The protective effects of farm exposure were confined to T(H)2-dependent IgG1, IgG4, and IgE expression and were allergen and switch stage specific, suggesting that distinct mechanisms regulate individual steps within allergen-induced class switching in vivo. Environmental interventions to prevent IgE expression might need to be tailored to specific allergens.
Liu, Zhenyu; Hu, Youtian; Yu, Xiaoyun; Xi, Jiefeng; Fan, Xiaoming; Tse, Chung-Ming; Myers, Allen C; Pasricha, Pankaj J; Li, Xingde; Yu, Shaoyong
Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE.
Liu, Zhenyu; Hu, Youtian; Yu, Xiaoyun; Xi, Jiefeng; Fan, Xiaoming; Tse, Chung-Ming; Myers, Allen C.; Pasricha, Pankaj J.; Li, Xingde
Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE. PMID:25591867
Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo
Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma.
Lobaton, P; Moreno, F; Coulie, P
Thirty patients suffering from perennial allergic rhinitis took astemizole and cetirizine, 10 mg/d, under double-blind, crossover randomized conditions for 4 weeks. Four weeks washout separated the two periods. Nasal condition was improved, histamine and allergen-induced wheal responses were inhibited by both treatments with a slight advantage for cetirizine. Both treatments were well tolerated.
Heurung, Ashley R; Raju, Srihari I; Warshaw, Erin M
Sunscreen is a key component in the preventive measures recommended by dermatologists and public health campaigns aimed at reducing sunburn, early skin aging, and skin cancer. To maximize compliance, adverse reactions to sunscreens should be minimized. Although inactive ingredients cause many of these reactions, it is important for dermatologists to be aware of reactions to active ultraviolet filters. There are approximately 120 chemicals that can function as ultraviolet (UV) filters. This review focuses on the 36 most common filters in commercial and historical use. Of these, 16 are approved for use by the US Food and Drug Administration. The benzophenones and dibenzoylmethanes are the most commonly implicated UV filters causing allergic and photoallergic contact dermatitis (PACD) reactions; benzophenone-3 is the leading allergen and photoallergen within this class. When clinically indicated, patch and photopatch testing should be performed to common UV filters.
Jeong, Kyoung Yong; Hong, Chein-Soo; Lee, Joo-Shil; Park, Jung-Won
Preparation of high quality allergen extracts is essential for the diagnosis and immunotherapy of allergic disorders. Standardization of allergen extracts concerns determination of the allergen unit, development of reference material and measurement of the overall IgE binding capacity of an allergen extract. Recently, quantification of individual allergens has been the main focus of allergen standardization because the allergenicity of most allergen extracts is known to be mainly dependent on the content of a small number of allergen molecules. Therefore, characterization of major allergens will facilitate the standardization of allergens. In this article, we review the current state of allergen standardization. In addition, we briefly summarize the components of allergen extracts that should be under control for the optimization of allergen standardization, since its adjuvant-like activities could play an important role in allergic reactions even though the molecule itself does not bind to the IgE antibodies from subjects.
Zhang, Zhonghua; Xiao, Chang; Gibson, Aaron M; Bass, Stacey A; Khurana Hershey, Gurjit K
Despite the important role for epidermal growth factor (EGF) in epithelial homeostasis and wound healing, it has not been investigated in atopic dermatitis (AD). We used AD animal models to explore the role of EGF in AD. In an acute AD model, skin transepidermal water loss was significantly attenuated in EGF-treated mice. Blockade of EGFR signaling genetically or pharmacologically confirms a protective role for EGFR signaling in AD. In a chronic/relapsing AD model, EGF treatment of mice with established AD resulted in an attenuation of AD exacerbation (skin epithelial thickness, cutaneous inflammation, and total and allergen specific IgE) following cutaneous allergen rechallenge. EGF treatment did not alter expression of skin barrier junction proteins or antimicrobial peptides in the AD model. However, EGF treatment attenuated allergen-induced expression of IL-17A, CXCL1, and CXCL2 and neutrophil accumulation in AD skin following cutaneous allergen exposure. IL-17A production was decreased in the in vitro restimulated skin-draining lymph node cells from the EGF-treated mice. Similarly, IL-17A was increased in waved-2 mice skin following allergen exposure. Whereas IL-6 and IL-1β expression was attenuated in the skin of EGF-treated mice, EGF treatment also suppressed allergen-induced IL-6 production by keratinocytes. Given the central role of IL-6 in priming Th17 differentiation in the skin, this effect of EGF on keratinocytes may contribute to the protective roles for EGFR in AD pathogenesis. In conclusion, our study provides evidence for a previously unrecognized protective role for EGF in AD and a new role for EGF in modulating IL-17 responses in the skin.
Torkildsen, Gail; Narvekar, Abhijit; Bergmann, Mark
Background Symptom relief for the duration of 24 hours after treatment would benefit patients with allergic conjunctivitis. Objective To compare the safety and efficacy of olopatadine 0.77% with vehicle or olopatadine 0.2% in patients with allergic conjunctivitis in a conjunctival allergen-challenge clinical study. Patients and methods In this Phase III, multicenter, double-masked, parallel-group, randomized trial, patients with allergic conjunctivitis received olopatadine 0.77%, its vehicle, or olopatadine 0.2%, administered once at visits 3A (day 0), 4A (day 14 ±2), and 5 (day 21 +3). Allergic conjunctivitis-associated sign and symptom assessments included ocular itching, conjunctival redness, total redness, chemosis, and tearing scores. Adverse events and ocular safety parameters were also assessed. Results A total of 202 qualifying patients were randomized. Olopatadine 0.77% was superior (P<0.001) to vehicle for treatment of ocular itching at 3, 5, and 7 minutes postchallenge at onset of action and 16- and 24-hour duration of action. Conjunctival redness mean scores were significantly lower for olopatadine 0.77% versus vehicle at all three post-conjunctival allergen-challenge time points: onset (−1.52 to −1.48; P<0.001), 16 hours (−1.50 to −1.38; P<0.01), and 24 hours (−1.58 to −1.38; P<0.05). At 24 hours, olopatadine 0.77% was superior to olopatadine 0.2% at all three postchallenge time points for ocular itching (P<0.05), conjunctival redness (P<0.05), and total redness (P<0.05). No clinically relevant differences in safety parameters or adverse events were observed between the treatment groups. Conclusion Olopatadine 0.77% is superior to both its vehicle and olopatadine 0.2% for the treatment of allergen-mediated ocular itching and conjunctival redness. Ocular itching symptom relief is maintained over 24 hours, supporting once-daily dosing and demonstrating a comparable safety profile to olopatadine 0.2%. PMID:26392751
Torkildsen, Gail; Narvekar, Abhijit; Bergmann, Mark
Symptom relief for the duration of 24 hours after treatment would benefit patients with allergic conjunctivitis. To compare the safety and efficacy of olopatadine 0.77% with vehicle or olopatadine 0.2% in patients with allergic conjunctivitis in a conjunctival allergen-challenge clinical study. In this Phase III, multicenter, double-masked, parallel-group, randomized trial, patients with allergic conjunctivitis received olopatadine 0.77%, its vehicle, or olopatadine 0.2%, administered once at visits 3A (day 0), 4A (day 14 ±2), and 5 (day 21 +3). Allergic conjunctivitis-associated sign and symptom assessments included ocular itching, conjunctival redness, total redness, chemosis, and tearing scores. Adverse events and ocular safety parameters were also assessed. A total of 202 qualifying patients were randomized. Olopatadine 0.77% was superior (P<0.001) to vehicle for treatment of ocular itching at 3, 5, and 7 minutes postchallenge at onset of action and 16- and 24-hour duration of action. Conjunctival redness mean scores were significantly lower for olopatadine 0.77% versus vehicle at all three post-conjunctival allergen-challenge time points: onset (-1.52 to -1.48; P<0.001), 16 hours (-1.50 to -1.38; P<0.01), and 24 hours (-1.58 to -1.38; P<0.05). At 24 hours, olopatadine 0.77% was superior to olopatadine 0.2% at all three postchallenge time points for ocular itching (P<0.05), conjunctival redness (P<0.05), and total redness (P<0.05). No clinically relevant differences in safety parameters or adverse events were observed between the treatment groups. Olopatadine 0.77% is superior to both its vehicle and olopatadine 0.2% for the treatment of allergen-mediated ocular itching and conjunctival redness. Ocular itching symptom relief is maintained over 24 hours, supporting once-daily dosing and demonstrating a comparable safety profile to olopatadine 0.2%.
Chapman, Martin D; Pomés, Anna; Breiteneder, Heimo; Ferreira, Fatima
Purified allergens are named using the systematic nomenclature of the Allergen Nomenclature Sub-Committee of the World Health Organization and International Union of Immunological Societies. The system uses abbreviated Linnean genus and species names and an Arabic number to indicate the chronology of allergen purification. Most major allergens from mites, animal dander, pollens, insects, and foods have been cloned, and more than 40 three-dimensional allergen structures are in the Protein Database. Allergens are derived from proteins with a variety of biologic functions, including proteases, ligand-binding proteins, structural proteins, pathogenesis-related proteins, lipid transfer proteins, profilins, and calcium-binding proteins. Biologic function, such as the proteolytic enzyme allergens of dust mites, might directly influence the development of IgE responses and might initiate inflammatory responses in the lung that are associated with asthma. Intrinsic structural or biologic properties might also influence the extent to which allergens persist in indoor and outdoor environments or retain their allergenicity in the digestive tract. Analyses of the protein family database suggest that the universe of allergens comprises more than 120 distinct protein families. Structural biology and proteomics define recombinant allergen targets for diagnostic and therapeutic purposes and identify motifs, patterns, and structures of immunologic significance.
Papazian, D; Wagtmann, V R; Hansen, S; Würtzen, P A
Airway epithelial cells (AECs) form a polarized barrier along the respiratory tract. They are the first point of contact with airborne antigens and are able to instruct resident immune cells to mount appropriate immune responses by either soluble or contact-dependent mechanisms. We hypothesize that a healthy, polarized epithelial cell layer inhibits inflammatory responses towards allergens to uphold homeostasis. Using an in-vitro co-culture model of the airway epithelium, where a polarized cell layer of bronchial epithelial cells can interact with dendritic cells (DCs), we have investigated recall T cell responses in allergic patients sensitized to house dust mite, grass and birch pollen. Using allergen extract-loaded DCs to stimulate autologous allergen-specific T cell lines, we show that AEC-imprinted DCs inhibit T cell proliferation significantly of Bet v 1-specific T cell lines as well as decrease interleukin (IL)-5 and IL-13 production, whereas inhibition of Phl p 5-specific T cells varied between different donors. Stimulating autologous CD4(+) T cells from allergic patients with AEC-imprinted DCs also inhibited proliferation significantly and decreased production of both T helper type 1 (Th1) and Th2 cytokines upon rechallenge. The inhibitory effects of AECs' contact with DCs were absent when allergen extract-loaded DCs had been exposed only to AECs supernatants, but present after direct contact with AECs. We conclude that direct contact between DCs and AECs inhibits T cell recall responses towards birch, grass and house dust mite allergens in vitro, suggesting that AECs-DC contact in vivo constitute a key element in mucosal homeostasis in relation to allergic sensitisation.
Zhu, Zheng; Xie, Yanqing; Guan, Weijie; Gao, Yi; Huang, Rongquan; Xia, Shu; Jian, Wenhua; Liang, Zhiyu
challenge, LTD4 nasal provocation tests do not confer any major effect on BHR. LTD4 might not play a vital role in eliciting bronchial responsiveness induced by nasal allergen challenge. PMID:28275474
Calus, L; Devuyst, L; Van Zele, T; De Ruyck, N; Derycke, L; Bachert, C; Gevaert, P
The majority of grass pollen-sensitized rhinitis patients develops allergic symptoms when exposed to the causal allergen and shows a positive nasal allergen provocation test (NAPT). Chronic rhinosinusitis with nasal polyposis (CRSwNP) patients, also characterized by eosinophilic inflammation and local IgE production, can suffer from comorbid inhalant allergy, but may show a different response to allergens. We aimed to explore the allergic response to grass pollen allergens by NAPT in grass pollen-sensitized CRSwNP patients. Twelve grass pollen-sensitized CRSwNP patients underwent NAPT with grass pollen and were compared with 12 grass pollen allergic rhinitis patients, 12 control patients and 12 CRSwNP patients without grass pollen sensitization. A positive NAPT was based on change in nasal airflow and symptoms. Further, VAS scores of different symptoms were noted before and after NAPT. Biomarkers such as total IgE, grass pollen-specific IgE and tryptase were measured in serum and nasal secretions. NAPT was positive in 6 of 12 of the grass pollen-sensitized CRSwNP patients, and another four patients developed allergic symptoms not fulfilling the criteria of positivity. In contrast, all patients with allergic rhinitis developed a positive provocation test, whereas in the control group one of the patients and in the non-sensitized CRSwNP group two of the patients developed a positive provocation test. These results show that allergen exposure induces an attenuated clinical response in patients with CRSwNP and sensitization to grass pollen as compared with grass pollen allergic rhinitis patients. © 2015 John Wiley & Sons Ltd.
Bourke, C D; Mutapi, F; Nausch, N; Photiou, D M F; Poulsen, L K; Kristensen, B; Arnved, J; Rønborg, S; Roepstorff, A; Thamsborg, S; Kapel, C; Melbye, M; Bager, P
Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied. The aim was to investigate whether infection with the nematode parasite Trichuris suis alters systemic cytokine levels, cellular cytokine responses to parasite antigens and pollen allergens and/or the cytokine profile of allergic individuals. In a randomized double-blinded placebo-controlled clinical trial (UMIN trial registry, Registration no. R000001298, Trial ID UMIN000001070, URL: http://www.umin.ac.jp/map/english), adults with grass pollen-induced allergic rhinitis received three weekly doses of 2500 Trichuris suis ova (n = 45) or placebo (n = 44) over 6 months. IFN-γ, TNF-α, IL-4, IL-5, IL-10 and IL-13 were quantified via cytometric bead array in plasma. Cytokines, including active TGF-β, were also quantified in supernatants from peripheral blood mononuclear cells cultured with parasite antigens or pollen allergens before, during and after the grass pollen season for a sub-cohort of randomized participants (T. suis ova-treated, n = 12, Placebo-treated, n = 10). Helminth infection induced a Th2-polarized cytokine response comprising elevated plasma IL-5 and parasite-specific IL-4, IL-5 and IL-13, and a global shift in the profile of systemic cytokine responses. Infection also elicited high levels of the regulatory cytokine IL-10 in response to T. suis antigens. Despite increased production of T. suis-specific cytokines in T. suis ova-treated participants, allergen-specific cytokine responses during the grass pollen season and the global profile of PBMC cytokine responses were not affected by T. suis ova treatment. This study suggests that cytokines induced by Trichuris suis ova treatment do not alter allergic reactivity to pollen during the peak of allergic rhinitis
Pastorello, Elide A; Farioli, Laura; Pravettoni, Valerio; Scibilia, Joseph; Conti, Amedeo; Fortunato, Donatella; Borgonovo, Linda; Bonomi, Simona; Primavesi, Laura; Ballmer-Weber, Barbara
Italian patients with maize anaphylaxis have been shown to have IgE toward two major maize allergens: an alpha-amylase inhibitor and a 9-kDa LTP. A complete study on maize food allergens in patients with positive maize double-blind, placebo-controlled food challenge (DBPCFC) is lacking. The objective was to utilize the three maize protein fractions to identify and characterize the most relevant IgE-binding proteins recognized by the sera of Italian and Swiss patients with either a positive maize-DBPCFC or a history of maize-induced anaphylaxis. Osborne's protein fractions of maize were extracted to obtain water-soluble, total zein, and total protein fractions. Protein IgE-binding capacity was investigated by SDS-PAGE immunoblotting using the sera from DBPCFC-positive patients and from patients with maize-induced anaphylaxis. Purified maize LTP was used to inhibit the IgE immunoblotting of the three protein fractions. IgE immunoblotting demonstrated that the 9-kDa LTP was recognized by all the Italian patients and by none of the Swiss patients. Other allergens were: 14-kDa alpha-amylase inhibitor, 30-kDa endochitinases A and -B, 19 kDa zein-beta precursor, and 26 kDa zein-alpha precursor; a newly described allergen, the globulin-2 precursor, identified in the total protein fraction. It is noteworthy that maize LTP and endochitinase were cross-reactive with grape LTP and one grape endochitinase. LTP was found to be the only major allergen in Italian patients with either positive maize challenge or a history of maize-induced anaphylaxis. We have identified other maize allergens in subjects with maize food allergy, as grape cross-reactive endochitinase, however, the clinical significance of these proteins needs to be investigated in larger groups of patients with allergy to these food items.
Ackerman, Stacey; D’Ambrosio, Francis; Greiner, Jack V; Villanueva, Linda; Ciolino, Joseph B; Hollander, David A
Background The purpose of this study was to evaluate the efficacy and duration of action of once-daily dosing with alcaftadine 0.25% ophthalmic solution and olopatadine 0.2% ophthalmic solution as compared with placebo in the prevention of ocular itching, and to directly compare the efficacy of alcaftadine 0.25% with olopatadine 0.2% in the prevention of ocular itching associated with allergic conjunctivitis using the conjunctival allergen challenge model. Methods Subjects with allergic conjunctivitis (n = 127) were enrolled in a multicenter, double-masked, randomized, active-controlled and placebo-controlled clinical trial. Using the conjunctival allergen challenge model, this study was conducted over the course of approximately 5 weeks. Subjects were randomized into one of three treatment arms: alcaftadine 0.25% ophthalmic solution, olopatadine 0.2% ophthalmic solution, or placebo. Study medications were administered twice over the course of the trial. The primary efficacy measure for the study was ocular itching evaluated by the subject at 3, 5, and 7 minutes post challenge. Secondary endpoints, measured at 7, 15, and 20 minutes post challenge, included conjunctival, ciliary, and episcleral redness, lid swelling, chemosis, and tearing. Duration of action was measured at 16 and 24 hours post-instillation of the study medication at visits 3 and 4, respectively. Results For the primary measure of ocular itching, both actives, alcaftadine 0.25% and olopatadine 0.2%, were statistically superior to placebo at all three measured time points for both the 16-hour and 24-hour measures (P < 0.0001). Eyes treated with alcaftadine 0.25% had numerically lower mean ocular itching scores than eyes treated with olopatadine 0.2% at every time point, and this difference was statistically significant at the 3-minute time point 16 hours post instillation (P = 0.026). Eyes treated with alcaftadine 0.25% and with olopatadine 0.2% displayed significantly less lid swelling relative to
Witting Christensen, S K; Kortekaas Krohn, I; Thuraiaiyah, J; Skjold, T; Schmid, J M; Hoffmann, H J H
Sequential allergen desensitization provides temporary tolerance for allergic patients. We adapted a clinical protocol to desensitize human blood basophils ex vivo and investigated the mechanism and allergen specificity. We included 28 adult, grass allergic subjects. The optimal, activating allergen concentration was determined by measuring activated CD63(+) CD193(+) SS(Low) basophils in a basophil activation test with 8 log-dilutions of grass allergen. Basophils in whole blood were desensitized by incubation with twofold to 2.5-fold increasing allergen doses in 10 steps starting at 1 : 1000 of the optimal dose. Involvement of p38 mitogen-activated protein kinase (MAPK) was assessed after 3 min of allergen stimulation (n = 7). Allergen specificity was investigated by desensitizing cells from multi-allergic subjects with grass allergen and challenging with optimal doses of grass, birch, recombinant house dust mite (rDer p2) allergen or anti-IgE (n = 10). Desensitization reduced the fraction of blood basophils responding to challenge with an optimal allergen dose from a median (IQR) 81.0% (66.3-88.8) to 35.4% (19.8-47.1, P < 0.0001). CD63 MFI expression was reduced from 68 248 (29 336-92 001) to 30 496 (14 046-46 179, P < 0.0001). Basophils from multi-allergic subjects were desensitized with grass allergen. Challenge with grass allergen resulted in 39.6% activation (15.8-58.3). An unrelated challenge (birch, rDer p2 or anti-IgE) resulted in 53.4% activation (30.8-66.8, P = 0.16 compared with grass). Desensitization reduced p38 MAPK phosphorylation from a median 48.1% (15.6-92.8) to 26.1% (7.4-71.2, P = 0.047) and correlated with decrease in CD63 upregulation (n = 7, r > 0.79, P < 0.05). Desensitization attenuated basophil response rapidly and non-specifically at a stage before p38 MAPK phosphorylation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
An, Su; Chen, Lingling; Long, Chengbo; Liu, Xiaoyu; Xu, Xuemei; Lu, Xingre; Rong, Mingqiang; Liu, Zhigang; Lai, Ren
The most important indoor allergens for humans are house dust mites (HDM). Fourteen Dermatophagoides farinae allergens (Der f 1-3, 6, 7, 10, 11, 13-18, and 22) are reported although more than 30 allergens have been estimated in D. farinae. Seventeen allergens belonging to 12 different groups were identified by a procedure of proteomics combined with two-dimensional immunoblotting from D. farina extracts. Their sequences were determined by Edman degradation, mass spectrometry analysis, and cDNA cloning. Their allergenicities were assayed by enzyme-linked immunosorbent assay inhibition tests, immunoblots, basophil activation test, and skin prick tests. Eight of them are the first report as D. farinae allergens. The procedure of using a proteomic approach combined with a purely discovery approach using sera of patients with broad IgE reactivity profiles to mite allergens was an effective method to investigate a more complete repertoire of D. farinae allergens. The identification of eight new D. farinae allergens will be helpful for HDM allergy diagnosis and therapy, especially for patients without response for HDM major allergens. In addition, the current work significantly extendedthe repertoire of D. farinae allergens.
Takeda, K; Miyahara, N; Kodama, T; Taube, C; Balhorn, A; Dakhama, A; Kitamura, K; Hirano, A; Tanimoto, M; Gelfand, E W
S-carboxymethylcysteine (S-CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S-CMC on allergic airway inflammation has not yet been defined. In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S-CMC (5-100 mg.kg-1) was administered from 2 days before the secondary challenge through to the day of assay. Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S-CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S-CMC. In BAL fluid, increased levels of interferon-gamma, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected. In conclusion, the data indicate that S-carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.
Armentia, A; Rodríguez, R; Callejo, A; Martín-Esteban, M; Martín-Santos, J-M; Salcedo, G; Pascual, C; Sánchez-Monge, R; Pardo, M
Cereals are among the major foods that account for food hypersensitivity reactions. Salt-soluble proteins appear to be the most important allergens contributing to the asthmatic response. In contrast, very limited information is available regarding cereal allergens responsible for allergic reactions after ingestion of cereal proteins. The aim of this study was to evaluate the allergenic reactivity of ingested and inhaled cereal allergens in different ages, in order to investigate if the response to different allergens would depend on the sensitization route. We included 66 patients in three groups. Group 1: 40 children aged 3 to 6 months who suffered from diarrhoea, vomiting, eczema or weight loss after the introduction of cereal formula in their diet and in which a possibility of coeliac disease was discarded. Group 2: 18 adults with food allergy due to cereals tested by prick tests, specific IgE and food challenge. Group 3: eight patients previously diagnosed as having baker's asthma. Sera pool samples were collected from each group of patients and IgE immunoblotting was performed. We found an important sensitization to cereal in the 40 children. The most important allergens were wheat followed by barley and rye. Among the adults with cereal allergy, sensitization to other allergens was common, especially to Lolium perenne (rye grass) pollen. Immunoblotting showed similar allergenic detection in the three groups. Clinically significant reactivity to cereal may be observed in early life. Inhalation and ingestion routes causing cereal allergy seem to involve similar allergens. The diet control was more effective in children. The possibility of cereal allergy after the introduction of cereal formula during the lactation period should not be underestimated.
Arbes, Samuel J; Gergen, Peter J; Elliott, Leslie; Zeldin, Darryl C
Allergy skin tests were administered in the second and third National Health and Nutrition Examination Surveys (NHANES II and III) conducted in the United States from 1976 through 1980 and 1988 through 1994, respectively. This study estimated positive skin test response rates in NHANES III and identified predictors of one or more positive test responses. Comparisons with NHANES II were also made. In NHANES III, 10 allergens and 2 controls were tested in all subjects aged 6 to 19 years and a random half-sample of subjects aged 20 to 59 years. A wheal-based definition of a positive test response was used. In NHANES III, 54.3% of the population had positive test responses to 1 or more allergens. Prevalences were 27.5% for dust mite, 26.9% for perennial rye, 26.2% for short ragweed, 26.1% for German cockroach, 18.1% for Bermuda grass, 17.0% for cat, 15.2% for Russian thistle, 13.2% for white oak, 12.9% for Alternaria alternata, and 8.6% for peanut. Among those with positive test responses, the median number of positive responses was 3.0. Adjusted odds of a positive test response were higher for the following variables: age of 20 to 29 years, male sex, minority race, western region, old homes, and lower serum cotinine levels. For the 6 allergens common to NHANES II and III, prevalences were 2.1 to 5.5 times higher in NHANES III. The majority of the US population represented in NHANES III was sensitized to 1 or more allergens. Whether the higher prevalences observed in NHANES III reflect true changes in prevalence or methodological differences between the surveys cannot be determined with certainty.
Inam, Muhammad; Shafique, Rubaba Hamid; Roohi, Nabila; Irfan, Muhammad; Abbas, Shahid; Ismail, Muhammad
In this study, we estimated the prevalence of food allergy in the adult allergic patients of Rawalpindi and Islamabad , Pakistan, based on self-report, skin prick test (SPT) and oral food challenge test (OFC). SPT was used for the estimation of sensitization to wheat, egg, milk, beef, chicken, mutton, fish, corn, lentils, rice, soya, peanut and banana. Among 689 patients, 39.19 % showed sensitivity to one or more foods, where, sensitization to wheat (156; 22.6 %) was highest, followed by egg (148; 21.48 %) and milk (138; 20.03 %). Sensitization to various proteins ranged between 15.53-15.97 %, while lentils, corn, rice, soya and peanut sensitization was 15.4, 16, 12.5, 12 and 11.5 % respectively. Only 7.1 % patients were SPT positive for banana allergen. SPT was performed in patients with self-reported food allergy (341/689) and also with no self-reported history of food allergy (348/689). SPT results were positive in 69.8 % of the self-report group, whereas, in the patients with no self-reported food allergy 9.2 % were found sensitized to one or more tested food allergens. 101 patients were recruited for OFC, 61 % of these were confirmed of food allergy. The prevalence of food allergy in the study population was 9 %. Food specific OFC results show that wheat allergy is affecting 1.6 % (95 % CI 0.9-2.84 %) of the total allergy patients, followed by egg allergy 1.31 % (95 % CI 0.70-2.47 %). Furthermore, corn allergy, rice allergy and peanut allergy were 1.02, 0.87 and 0.73 %, respectively. In conclusion, wheat allergy is the most prevalent, followed by egg, chicken, beef and fish allergy, respectively.
Vidal-Quist, J C; Ortego, F; Lombardero, M; Castañera, P; Hernández-Crespo, P
House dust mites are a major source of allergy worldwide. While diagnosis and treatment based on mite extracts have remarkably advanced, little information exists on the expression of allergens in mites. We have studied gene expression of eight Dermatophagoides pteronyssinus (Trouessart) (Acari: Pyroglyphidae) allergens (Der p 1, 2, 3, 4, 5, 7, 10 and 21). All allergens showed higher transcription in nymphs compared with larvae or adults, with the only exception of Der p 10. The transcription of Der p 4 and Der p 10, together with the transcription and protein ratios Der p 1 to Der p 2, were higher in males than in females. One-week exposure of mite cultures to 16 or 35 °C (versus 24 °C) or low RH (44% versus 76%) significantly influenced the allergen gene transcription profile. Our results demonstrate that allergen expression is quantitatively and/or qualitatively influenced by mite development and sex, as well as by the environment. We suggest that monitoring allergen gene expression may be a useful tool to assist the optimization of mite cultures in the production of standardized allergenic extracts for clinical use.
Kanagawa, Yoshiyuki; Matsumoto, Shinya; Koike, Soichi; Imamura, Tomoaki
Food allergy patients are known to present with allergic reactions to multiple allergens, but extrapolating these associations is difficult. Data mining, a procedure that analyzes characteristic combinations among large amounts of information, is often used to analyze and predict consumer purchasing behaviour. We applied this technique to the extrapolation of food allergen associations in allergy patients. We sent 1510 families our 'Questionnaire survey for the prevention of food allergies'. Responses noting 6549 allergens came from 878 families with 1383 patients, including 402 with anaphylaxis. Some results of the survey have already been published and here we presented the results of our association analysis of combinations of food allergens. Egg, milk, wheat, peanuts, and buckwheat are the most common food allergens. The most common simultaneous combinations of these allergens were 'egg-milk', 'egg-wheat', and 'milk-wheat'. The occurrence probability of a combination (i.e. one person suffering from a certain allergen also suffers from another) is called 'confidence'. Confidence was higher for 'chicken-egg', 'abalone-salmon eggs', and 'matsutake mushroom-milk'. As well, the combinations of 'crab-shrimp', 'squid-shrimp', and 'squid-crab' also indicated higher values in a statistical examination of the occurrence probabilities of these allergen combinations (Z-score). From the results of the association analysis, we speculated that some food allergens, such as abalone, orange, salmon, chicken, pork, matsutake mushroom, peach and apple did not independently induce food allergies. We also found that combinations, such as 'crab-shrimp', 'squid-shrimp', 'squid-crab', 'chicken-beef', and 'salmon-mackerel' had strong associations.
Rudzki, E; Grzywa, Z; Krajewska, D; Kozłowska, A; Czerwińska-Dihm, I
In the report new contact allergens and allergen sources detected in Warsaw in the period 1975-1977 are described. They are divided into 3 groups: industrial allergens, remaining occupational allergens and cosmetics. There are given some data concerning the substances present in industrial oils, hardeners and epoxy resin solvents, drugs sensitizing nurses, several new sources of chromium allergens, essential oils and synthetic flavours. Results obtained with various star anise oil samples are described. Essential oils and synthetic flavours. Results obtained with various star anise oil samples are described. Essential oils and synthetic flavours are discussed as the main allergens in cosmetics.
Belz, Regina G; Hurle, Karl; Duke, Stephen O
The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.
Sugimoto, Mayumi; Kamemura, Norio; Nagao, Mizuho; Irahara, Makoto; Kagami, Shoji; Fujisawa, Takao; Kido, Hiroshi
Oral immunotherapy (OIT) induces desensitization and/or tolerance in patients with persistent food allergy, but the biomarkers of clinical outcomes remain obscure. Although OIT-induced changes in serum allergen-specific IgE and IgG4 levels have been investigated, the response of other allergen-specific IgG subclasses and IgA during OIT remains obscure. A pilot study was conducted to investigate egg OIT-induced changes in allergen-specific IgE, IgG subclasses, and IgA levels and search for possible prediction biomarkers of desensitization. We measured serum levels of egg white-, ovomucoid-, and ovalbumin-specific IgE, IgA, and IgG subclasses by high-sensitivity allergen microarray in 26 children with egg allergy who received rush OIT. Allergen-specific IgE gradually decreased while IgG4 increased during 12-month OIT. Serum levels of IgG1, IgG3, and IgA increased significantly after the rush phase, then decreased during the maintenance phase. IgG2 levels changed in a manner similar to that of IgG4. In particular, significantly high fold increases in egg white-specific IgG1, relative to baseline, after the rush phase and high IgA levels before OIT were observed in responders, compared with low-responders to OIT. Patients who could not keep desensitization showed relatively small changes in all immunoglobulin levels during OIT. The response to OIT was associated with significant increases in serum allergen-specific IgG1 levels after rush phase and high baseline IgA levels, compared with small changes in immunoglobulin response in low-responders. The characteristic IgG1 changes and IgA levels in the responders could be potentially useful biomarkers for the prediction of positive clinical response to OIT. © 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.
Recent developments in neuroscience raise the worry that understanding how brains cause behavior will undermine our views about free will and, consequently, about moral responsibility. The potential ethical consequences of such a result are sweeping. I provide three reasons to think that these worries seemingly inspired by neuroscience are misplaced. First, problems for common-sense notions of freedom exist independently of neuroscientific advances. Second, neuroscience is not in a position to undermine our intuitive notions. Third, recent empirical studies suggest that even if people do misconstrue neuroscientific results as relevant to our notion of freedom, our judgments of moral responsibility will remain largely unaffected. These considerations suggest that neuroethical concerns about challenges to our conception of freedom are misguided.
Howell, Lydia Pleotis; Servis, Gregg; Bonham, Ann
Academic medicine is a unique work environment, one of the few where members of four different generations regularly interact and where multigenerational teams are key to fulfilling its missions, particularly education. This can lead to increased creativity, but also to intergenerational conflict, since each generation has different values and expectations. The authors describe multigenerational challenges confronted at the University of California, Davis, School of Medicine, and that school's responses to them. These challenges include issues related to work hours, workload, compensation, evaluation for advancement, recruitment and retention, and attendance at required meetings. Awareness of the different generational qualities and values allowed the school of medicine to identify the multigenerational origin of many of these ongoing issues and challenges and to plan appropriate solutions within the Office of Academic Affairs. These include policy changes related to work-life balance, utilizing multiple faculty tracks with different roles, allowing part-time faculty appointments, creating a variety of faculty development programs geared toward different generational needs (which utilize flexible modules, menus of options, and alternative technologies for presentation), defining appropriate reward and incentives through compensations plans, and creating peer-reviewed awards. The authors conclude that these efforts mitigate conflict, promote diversity, and allow multigenerational teams to function more effectively and creatively in education, research, and clinical care. Ongoing evaluation will further refine this approach.
Korošec, Peter; Šilar, Mira; Kopač, Peter; Eržen, Renato; Zidarn, Mihaela; Košnik, Mitja
We sought to determine whether basophil-allergen sensitivity could be transferred to donor basophils by passive IgE sensitisation in allergic rhinitis and anaphylactic Hymenoptera venom hypersensitivity. We studied 15 wasp venom-, 19 grass pollen- and 2 house dust mite-allergic patients, 2 healthy donors, and 8 wasp venom-allergic donors. In all subjects, we first evaluated the initial basophil response to wasp venom, grass pollen, or house dust mite allergen. Donor basophils were then stripped, sensitised with the different patients' serum IgE, and challenged with the corresponding allergen. The CD63 response of donor basophils was then compared with initial basophil responses. In wasp venom-allergic subjects, the IgE transfer did not reflect the initial basophil-allergen sensitivity, because the venom IgE of subjects with high or low basophil sensitivity induced comparable responsiveness in healthy donor basophils. Furthermore, vice versa, when we sensitised the donor basophils of wasp venom-allergic individuals with different wasp venom or house dust mite IgE, we demonstrated that their response was predictable by their initial basophil allergen sensitivity. In the rhinitis allergy model, the IgE transfer correlated with the patients' initial basophil responsiveness because the grass pollen IgE of the subjects with high basophil allergen sensitivity induced significantly higher responsiveness of donor basophils than the IgE of subjects with initially low basophil allergen sensitivity. Our results suggest that basophil allergen sensitivity evaluated by flow-cytometric CD63 analysis depends on two distinct contribution factors. In anaphylactic Hymenoptera allergy, the major factor was intrinsic cellular sensitivity, whereas in pollen allergy, the major factor was allergen-specific IgE on the cell surface. © 2016 S. Karger AG, Basel.
Navarro, Séverine; Lazzari, Anne; Kanda, Akira; Fleury, Sébastien; Dombrowicz, David; Glaichenhaus, Nicolas; Julia, Valérie
Background Allergic asthma is a chronic inflammatory disease that is characterized by airway hyper responsiveness (AHR), infiltration of Th2 cells in lungs and high levels of circulating IgE. Allergen-specific immunotherapy (SIT), in which patients are rendered tolerant by exposure to steadily increasing doses of the allergen, is the only curative treatment to date. Unfortunately, SIT is not suitable for treating multi-sensitized patients, and some allergens are too immunogenic to be used in desensitization protocols. Objective To investigate whether, and to understand how, regulatory CD4+ T cells (Treg) specific for a third-party “drug” antigen could control allergic immune responses and lung inflammation. Methods Mice were tolerized to ovalbumin (OVA), sensitized to ragweed, and eventually challenged with aerosols of ragweed alone or ragweed and OVA together. Animals were then monitored for cardinal features of allergic asthma including AHR and infiltration of Th2 cells in lungs. In additional experiments aimed at elucidating the mechanisms of OVA-induced suppression, OVA-tolerized mice were sensitized with the LACK model antigen, challenged with LACK alone or LACK and OVA together, and LACK-specific T cells were visualized by flow cytometry. Results In both the ragweed and the LACK model, allergen-induced airway inflammation and AHR were strongly reduced in mice challenged with both the allergen and OVA compared to mice challenged with the allergen alone. OVA-induced protection did not result from competition between OVA and the allergen, was mediated by OVA-specific CD25+ Treg, required both CTLA-4 and ICOS signaling, and was partially dependent on IL-10. Bystander suppression was associated with reduced proliferation of allergen-specific Th2 cells and decreased numbers of airway DC migrating to the lungs. Conclusion Our results demonstrate that Treg specific for a third-party drug antigen could control allergic immune responses and lung inflammation when
Smole, Ursula; Radauer, Christian; Lengger, Nina; Svoboda, Martin; Rigby, Neil; Bublin, Merima; Gaier, Sonja; Hoffmann-Sommergruber, Karin; Jensen-Jarolim, Erika; Mechtcheriakova, Diana; Breiteneder, Heimo
Dendritic cells play a fundamental role in shaping the immune response to allergens. The events that lead to allergic sensitization or tolerance induction during the interaction of the major birch pollen allergen Bet v 1 and dendritic cells are not very well studied. Here, we analyzed the uptake of Bet v 1 and the cross-reactive celery allergen Api g 1 by immature monocyte-derived dendritic cells (iMoDCs) of allergic and normal donors. In addition, we characterized the allergen-triggered intracellular signaling and transcriptional events. Uptake kinetics, competitive binding, and internalization pathways of labeled allergens by iMoDCs were visualized by live-cell imaging. Surface-bound IgE was detected by immunofluorescence microscopy and flow cytometry. Allergen- and IgE-induced gene expression of early growth response genes and Th1 and Th2 related cytokines and chemokines were analyzed by real-time PCR. Phosporylation of signaling kinases was analyzed by Western blot. Internalization of Bet v 1 by iMoDCs of both donor groups, likely by receptor-mediated caveolar endocytosis, followed similar kinetics. Bet v 1 outcompeted Api g 1 in cell surface binding and uptake. MoDCs of allergic and healthy donors displayed surface-bound IgE and showed a pronounced upregulation of Th2 cytokine- and NFκB-dependent genes upon non-specific Fcε receptor cross-linking. In contrast to these IgE-mediated responses, Bet v 1-stimulation increased transcript levels of the Th2 cytokines IL-4 and IL-13 but not of NFκB-related genes in MoDCs of BP allergic donors. Cells of healthy donors were either unresponsive or showed elevated mRNA levels of Th1-promoting chemokines. Moreover, Bet v 1 was able to induce Erk1/2 and p38 MAPK activation in BP allergics but only a slight p38 activation in normal donors. In conclusion, our data indicate that Bet v 1 favors the activation of a Th2 program only in DCs of BP allergic individuals. PMID:25635684
Sheehan, William J.; Phipatanakul, Wanda
Purpose of review The aim of the present review is to discuss updates on research regarding the relationship between indoor allergen exposure and childhood asthma with a focus on clinical effects, locations of exposure, and novel treatments. Recent findings Recent data continue to demonstrate that early life sensitization to indoor allergens is a predictor of asthma development later in life. Furthermore, avoidance of exposure to these allergens continues to be important especially given that the vast majority of children with asthma are sensitized to at least one indoor allergen. New research suggests that mouse allergen, more so than cockroach allergen, may be the most relevant urban allergen. Recent evidence reminds us that children are exposed to clinically important levels of indoor allergens in locations away from their home, such as schools and daycare centers. Exposure to increased levels of indoor mold in childhood has been associated with asthma development and exacerbation of current asthma; however, emerging evidence suggests that early exposure to higher fungal diversity may actually be protective for asthma development. Novel treatments have been developed that target TH2 pathways thus decreasing asthmatic responses to allergens. These therapies show promise for the treatment of severe allergic asthma refractory to avoidance strategies and standard therapies. Summary Understanding the relationship between indoor allergens and asthma outcomes is a constantly evolving study of timing, location, and amount of exposure. PMID:27653703
Application of response function methodology for the simultaneous determination of potential fragrance allergens and preservatives in personal care products using micellar electrokinetic chromatography.
Lopez-Gazpio, J; Garcia-Arrona, R; Millán, E
A micellar electrokinetic chromatography method was developed for determination of 15 suspected fragrance allergens and preservatives. The target compounds are widely used as ingredients in many personal care products, and all of them are included in the European Regulation concerning cosmetic products. The method was optimized by using a central composite experimental design and response surface methodology. A modified chromatographic response function was defined to weigh the terms in the response function adequately. After optimization of experimental conditions, a background electrolyte of 100 mM sodium dodecyl sulphate and 24 mM sodium tetraborate and pH 9.0 was selected for the separation of the analytes. The developed methodology was evaluated in terms of linearity, limits of detection and quantification, precision and accuracy, showing appropriate values (i.e., R (2) = ≥0.99 and accuracy of 89-115 %). Finally, applicability of the micellar electrokinetic chromatography method was assessed by successfully quantifying fragrance allergens and preservatives in commercial personal care products. The most commonly found analyte was linalool (48.3 % of samples) followed by benzoic acid (37.6 %). All samples contained at least one of the target compounds, thus confirming the ubiquity of fragrance allergens and preservatives in personal care products.
Wangala, B.; Vovor, A.; Gantin, R. G.; Agbeko, Y. F.; Lechner, C. J.; Huang, X.; Köhler, C.
Chemokine and antibody response profiles were investigated in children and adults with severe or uncomplicated Plasmodium falciparum malaria; the aim was to reveal which profiles are associated with severe disease, as often seen in nonimmune children, or with mild and uncomplicated disease, as seen in semi-immune adults. Blood samples were obtained from children under 5 years of age as well as adults with falciparum malaria. Classification of malaria was performed according to parasite densities and hemoglobin concentrations. Plasma levels of chemokines (IL-8, IP-10, MCP-4, TARC, PARC, MIP-1δ, eotaxins) were quantified, and antibody responses (IgE, IgG1, and IgG4) to P. falciparum, Entamoeba histolytica-specific antigen, and mite allergen extracts were determined. In children with severe malaria proinflammatory, IL-8, IP10, MIP-1δ, and LARC were at highly elevated levels, suggesting an association with severe disease. In contrast, the Th2-type chemokines TARC, PARC, and eotaxin-2 attained in children the same levels as in adults suggesting the evolution of immune regulatory components. In children with severe malaria, an elevated IgG1 and IgE reactivity to mite allergens and intestinal protozoan parasites was observed. In conclusion, exacerbated proinflammatory chemokines together with IgE responses to mite allergens or E. histolytica-specific antigen extract were observed in children with severe falciparum malaria. PMID:25883801
Background Mugwort pollen allergens represent the main cause of pollinosis in late summer. The major allergen, Art v 1, contains only one single immunodominant, solely HLA-DR-restricted T cell epitope (Art v 125-36). The frequency of HLA-DRB1*01 is highly increased in mugwort-allergic individuals and HLA-DR1 serves as restriction element for Art v 125-36. However, Art v 125-36 also binds to HLA-DR4 with high affinity and DR1-restricted Art v 125-36 -specific T cell receptors can be activated by HLA-DR4 molecules. To understand the predominance of HLA-DR1 in mugwort allergy in spite of the degeneracy in HLA/peptide-binding and TCR-recognition, we investigated the molecular background of Art v 125-36 /MHC/TCR interactions in the context of HLA-DR1 compared to -DR4. Results The majority of Art v 125-36 -specific T cell lines and clones from HLA-DR1 carrying, mugwort pollen-allergic donors reacted to synthetic and naturally processed Art v 1–peptides when presented by HLA-DR1 or HLA-DR4 expressing antigen presenting cells. However, at limiting peptide concentrations DR1 was more effective in T cell stimulation. In addition, the minimal epitope for 50% of Art v 125-36 -specific T cells was shorter for DR1 than for DR4. In vitro binding assays of Art v 125-36 mutant peptides to isolated DR1- and DR4-molecules indicated similar binding capacities and use of the same register. In silico simulation of Art v 125-36 binding to HLA-DR1 and -DR4 suggested similar binding of the central part of the peptide to either molecule, but a higher flexibility of the N- and C-terminal amino acids and detachment at the C-terminus in HLA-DR1. Conclusions The predominance of HLA-DR1 in the response to Art v 125-36 may be explained by subtle conformation changes of the peptide bound to DR1 compared to DR4. Computer simulation supported our experimental data by demonstrating differences in peptide mobility within the HLA-DR complex that may influence TCR-binding. We suggest that the minor
Wang, Tsung-Chi; Shyur, Shyh-Dar; Wen, Da-Chin; Kao, Yu-Hsuan; Huang, Li-Hsin
IgE-mediated hypersensitivity to buckwheat is common in Korea, Japan, and some other Asian countries. However, buckwheat is not a common allergen in Taiwan. We report a woman with asthma who had anaphylactic shock, generalized urticaria, and an acute exacerbation of asthma five minutes after ingesting buckwheat. The patient underwent skin prick and Pharmacia CAP testing (Uppsala, Sweden) for specific IgE to buckwheat, white sesame and soybean as well as other common allergens in Taiwan including Dermatophagoides pteronyssinus (Dp), D. farinae (Df), cat and dog dander, cockroach, egg white, cow milk and codfish. The patient had a strongly positive skin prick test response to buckwheat and positive reactions to Dp and latex. Specific IgE results were class 6 for buckwheat, class 4 for Dp and Df, and class 2 for dog dander, wheat, sesame and soybean. Results of an open food challenge with white sesame and soybean were negative. Although buckwheat is a rare allergen in Taiwan, it can cause extremely serious reactions and should be considered in patients presenting with anaphylaxis after exposure to buckwheat.
van Driel, Boaz Job; Liao, Gongxian; Engel, Pablo; Terhorst, Cox
The SLAMF family (SLAMF) of cell surface glycoproteins is comprised of nine glycoproteins and while SLAMF1, 3, 5, 6, 7, 8, and 9 are self-ligand receptors, SLAMF2 and SLAMF4 interact with each other. Their interactions induce signal transduction networks in trans, thereby shaping immune cell–cell communications. Collectively, these receptors modulate a wide range of functions, such as myeloid cell and lymphocyte development, and T and B cell responses to microbes and parasites. In addition, several SLAMF receptors serve as microbial sensors, which either positively or negatively modulate the function of macrophages, dendritic cells, neutrophils, and NK cells in response to microbial challenges. The SLAMF receptor–microbe interactions contribute both to intracellular microbicidal activity as well as to migration of phagocytes to the site of inflammation. In this review, we describe the current knowledge on how the SLAMF receptors and their specific adapters SLAM-associated protein and EAT-2 regulate innate and adaptive immune responses to microbes. PMID:26834746
Akkoc, Tunc; Akdis, Mübeccel
Allergic diseases represent a complex innate and adoptive immune response to natural environmental allergens with Th2-type T cells and allergen-specific IgE predominance. Allergen-specific immunotherapy is the most effective therapeutic approach for disregulated immune response towards allergens by enhancing immune tolerance mechanisms. The main aim of immunotherapy is the generation of allergen nonresponsive or tolerant T cells in sensitized patients and downregulation of predominant T cell- and IgE-mediated immune responses. During allergen-specific immunotherapy, T regulatory cells are generated, which secrete IL-10 and induce allergen-specific B cells for the production of IgG4 antibodies. These mechanisms induce tolerance to antigens that reduces allergic symptoms. Although current knowledge highlights the role of T regulatory cell-mediated immunetolerance, definite mechanisms that lead to a successful clinical outcomes of allergen-specific immunotherapy still remains an open area of research. PMID:21217920
Teng, Paul P. S.; Oliveros, Jurise A. P.
Food security is a complex phenomenon made up of multiple dimensions — food availability, physical access to food, economic access to food, food utilization — each of which has a stability dimension which underpins it. This review provides details on these dimensions and links them to two published indices which provide assessments of the state of food security in a country. The paper further provides analyses of the main supply and demand factors in the food security equation. Food security faces natural and anthropogenic threats such as loss of productive land and water, climate change and declining crop productivity, all of which are potentially amenable to solutions provided by science and technology. Demographic and accompanying diet changes further exacerbate the demands made on the natural resource base for food production. Finally, possible responses to the challenges confronting a secured food future are discussed from technological, policy and system level perspectives.
Zuiker, Rob G.J.A.; Tribouley, Catherine; Diamant, Zuzana; Boot, J. Diderik; Cohen, Adam F.; Van Dyck, K.; De Lepeleire, I.; Rivas, Veronica M.; Malkov, Vladislav A.; Burggraaf, Jacobus; Ruddy, Marcella K.
Background Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. Methods Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. Results Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly
Sookrung, Nitat; Chaicumpa, Wanpen
Among cockroaches (CR) that live in people's homes, two species, i.e., German CR (Blattella germanica) and American CR (Periplaneta americana) predominate in temperate and tropical areas, respectively. CR is an important source of inhalant indoor allergens that sensitize atopic subjects to (localized) type I hypersensitivity or atopy including allergic rhinitis and atopic asthma. In Thailand the predominant CR species is P. americana. CR allergens are found throughout CR infested houses; the number found in kitchens correlates with the degree of CR infestation while sensitization and reactivation of the allergic morbidity are likely to occur in the living room and bedroom. Levels of the CR allergens in homes of CR allergic Thais, measured by using locally made quantification test kits, revealed that the highest levels occur in dust samples collected from the wooden houses of urban slums and in the cool and dry season. CR allergens are proteins that may be derived from any anatomical part of the insect at any developmental stage. The allergens may be also from CR secretions, excretions, body washes or frass. The proteins may be the insect structural proteins, enzymes or hormones. They may exist as dimers/multimers and/or in different isoforms. Exposure to CR allergens in infancy leads to allergic morbidity later in life. Clinical symptoms of CR allergy are usually more severe and prolonged than those caused by other indoor allergens. The mechanisms of acute and chronic airway inflammation and airway hyper-responsiveness (AHR) have been addressed including specific IgE- and non-IgE-mediated mechanisms, i.e., role of protease-activated receptor-2 (PAR2). Participation of various allergen activated-CD4+ T cells of different sublineages, i.e., Th2, Th17, Th22, Th9, Th25, Tregs/Th3 as well as invariant NKT cells, in asthma pathogenesis have been mentioned. The diagnosis of CR allergy and the allergy intervention by CR population control are also discussed.
Reinero, Carol; Lee-Fowler, Tekla; Chang, Chee-Hoon; Cohn, Leah; Declue, Amy
The study hypothesis was that in experimentally asthmatic cats rush immunotherapy (RIT) using allergens not completely matched with sensitizing allergen(s) would at least partially attenuate the asthmatic phenotype and modulate the aberrant immune response. In phase I, cats sensitized to Bermuda grass allergen (BGA), house dust mite allergen (HDMA) or placebo received BGA RIT. In phase II, cats dually sensitized to BGA and HDMA received RIT using BGA, HDMA or placebo. Efficacy of RIT was assessed using percentage bronchoalveolar lavage fluid (BALF) eosinophils. Additionally, a variety of immunologic assays were performed. Eosinophilic airway inflammation significantly decreased over time in asthmatic cats given RIT using sensitizing allergen or unrelated allergen (P<0.001). In dually sensitized cats, single allergen RIT but not placebo reduced airway eosinophilia (P=0.038). Differences in allergen-specific lymphocyte proliferation, in the number of IL-10 producing cells and in the percentage T regulatory cells were detected between asthmatic cats getting RIT and controls. Cross-protection manifested by reduced airway eosinophilia was noted in cats treated with RIT allergens which did not completely match allergen used in asthma induction. However, the mechanism of immunologic tolerance may differ when improperly matched allergens to the sensitizing allergens are used in RIT.
Escobar, Alejandro; Aguirre, Adam; Guzmán, María Antonieta; González, Rodrigo; Catalán, Diego; Acuña-Castillo, Claudio; Larrondo, Milton; López, Mercedes; Pesce, Barbara; Rolland, Jennifer; O’Hehir, Robyn; Aguillón, Juan Carlos
Natural rubber latex (NRL; Hevea brasiliensis) allergy is an IgE-mediated reaction to latex proteins. When latex glove exposure is the main sensitizing agent, Hev b 5 is one of the major allergens. Dendritic cells (DC), the main antigen presenting cells, modulated with pharmacological agents can restore tolerance in several experimental models, including allergy. In the current study, we aimed to generate DC with tolerogenic properties from NRL-allergic patients and evaluate their ability to modulate allergen-specific T and B cell responses. Here we show that dexamethasone-treated DC (dxDC) differentiated into a subset of DC, characterized by low expression of MHC class II, CD40, CD80, CD86 and CD83 molecules. Compared with LPS-matured DC, dxDC secreted lower IL-12 and higher IL-10 after CD40L activation, and induced lower alloantigenic T cell proliferation. We also show that dxDC pulsed with the dominant Hev b 5 T-cell epitope peptide, Hev b 546–65, inhibited both proliferation of Hev b 5-specific T-cell lines and the production of Hev b 5-specific IgE. Additionally, dxDC induced a subpopulation of IL-10-producing regulatory T cells that suppressed proliferation of Hev b 5-primed T cells. In conclusion, dxDC generated from NRL-allergic patients can modulate allergen-specific T-cell responses and IgE production, supporting their potential use in allergen-specific immunotherapy. PMID:24465795
Olopatadine hydrochloride ophthalmic solution, 0.2% (olopatadine 0.2%) is approved for allergic conjunctivitis when instilled twice-daily. The objective of this study was to evaluate the efficacy and safety of olopatadine 0.2% (instilled twice-daily) versus vehicle and olopatadine 0.1% (instilled 4-times daily) in Japanese patients with allergic conjunctivitis. A multicenter, parallel-group, double-masked, randomized, conjunctival allergen challenge (CAC) study. Patients > or = 18 years of age with histories of allergic conjunctivitis were treated with either olopatadine 0.2% or olopatadine 0.1% in a single eye and the vehicle in the contralateral eye at 1 visit. Overall, 267 patients were enrolled. Olopatadine 0.2% was superior to its vehicle for ocular itching (p < 0.0001 at the time of observation) and marginally superior for total redness (p = 0.0543 at the time of observation). Olopatadine 0.2% was similar to olopatadine 0.1% for ocular itching at the time of observation. No trends were identified through a review of safety parameters. Olopatadine 0.2% (instilled twice-daily) is safe, well tolerated, superior to the vehicle, and similar to olopatadine 0.1% in preventing ocular itching. Olopatadine 0.2%, which can be instilled less often than olopatadine 0.1%, is a useful new option for allergic conjunctivitis in Japanese patients that could potentially result in better treatment compliance.
Do, D C; Zhao, Y; Gao, P
Cockroach sensitization is an important risk factor for the development of asthma. However, its underlying immune mechanisms and the genetic etiology for differences in allergic responses remain unclear. Cockroach allergens identification and their expression as biologically active recombinant proteins have provided a basis for studying the mechanisms regarding cockroach allergen-induced allergic sensitization and asthma. Glycans in allergens may play a crucial role in the immunogenicity of allergic diseases. Protease-activated receptor (PAR)-2, Toll-like receptor (TLR), and C-type lectin receptors have been suggested to be important for the penetration of cockroach allergens through epithelial cells to mediate allergen uptake, dendritic cell maturation, antigen-presenting cell (APC) function in T-cell polarization, and cytokine production. Environmental pollutants, which often coexist with the allergen, could synergistically elicit allergic inflammation, and aryl hydrocarbon receptor (AhR) activation and signaling may serve as a link between these two elements. Genetic factors may also play an important role in conferring the susceptibility to cockroach sensitization. Several genes have been associated with cockroach sensitization and asthma-related phenotypes. In this review, we will discuss the epidemiological evidence for cockroach allergen-induced asthma, cockroach allergens, the mechanisms regarding cockroach allergen-induced innate immune responses, and the genetic basis for cockroach sensitization.
Do, Danh C.; Zhao, Yilin; Gao, Peisong
Cockroach sensitization is an important risk factor for the development of asthma. However, its underlying immune mechanisms and the genetic etiology for differences in allergic responses remain unclear. Cockroach allergens identification and their expression as biologically active recombinant proteins has provided a basis for studying the mechanisms regarding cockroach allergens induced allergic sensitization and asthma. Glycans in allergens may play a crucial role in the immunogenicity of allergic diseases. Protease-activated receptor (PAR)-2, Toll-like receptor (TLR), and C-type lectin receptors have been suggested to be important for the penetration of cockroach allergens through epithelial cells to mediate allergen uptake, dendritic cell maturation, antigen presenting cell (APC) function in T cell polarization, and cytokine production. Environmental pollutants, which often co-exist with the allergen, could synergistically elicit allergic inflammation, and aryl hydrocarbon receptor (AhR) activation and signaling may serve as a link between these two elements. Genetic factors may also play an important role in conferring the susceptibility to cockroach sensitization. Several genes have been associated with cockroach sensitization and asthma-related phenotypes. In this review, we will discuss the epidemiological evidence for cockroach allergen-induced asthma, cockroach allergens, the mechanisms regarding cockroach allergens induced innate immune responses, and the genetic basis for cockroach sensitization. PMID:26706467
Shah, Rachna; Grammer, Leslie C
Most allergens are proteins or glycoproteins that range in molecular weight from 5000 to 100,000 Da, although polysaccharides and low molecular weight substances also may be allergenic. Common allergens include pollens, fungal spores, house-dust mites, and animal epithelial materials but can also include drugs, biological products, and insect venoms. The allergic response is dependent on the route of exposure. If exposure is to an inhaled aeroallergen, the allergic response will be a respiratory reaction in nature. Ingested or injected exposure gives rise to gastrointestinal, cutaneous, or anaphylactic reactions. Size of pollen determines clinical manifestation of allergy. For example, particles between 20 and 60 μm in diameter can be carried in the wind and cause nasal and ocular symptoms (allergic rhinoconjunctivitis). Particles <7 μm can deposit in the airways and cause symptoms of asthma. Animals produce allergens in forms unique to each species. Cat allergen, most importantly Fel d 1, is found mainly in cat saliva, sebaceous glands in the skin, and in urine of male cats. It is buoyant and "sticky," which means it easily remains airborne and may last in a home for up to 6-9 months after the source is removed. Cat allergen adheres to clothes and can be found in public places such as schools. Dog allergen, particularly Can f 1, is present in dander, saliva, urine, and serum. There are allergens specific to dog breeds, but all breeds produce allergenic proteins (even poodles and "hairless" dogs).
Zhou, E M; Kisil, F T
An internal image anti-idiotypic antibody, designated B1/1, was generated against an idiotope (Id91) of the monoclonal antibody (mAb91) specific for Lol pIV. The administration of B1/1 in PBS, at doses ranging from 100 ng to 100 micrograms/mouse, to syngeneic Balb/c mice resulted in the suppression of the formation of anti-Lol pIV antibodies that possessed the Id91. Spleen cells obtained from the mice 2 weeks after the treatment with B1/1 (25 micrograms/mouse) were adoptively transferred intravenously into the syngeneic recipients which were challenged intraperitoneally with Lol pIV in alum 2 hr after the transfer. The recipients were boosted with Lol pIV 14 days later. It was demonstrated that the transfer of splenic B cells (but not of T cells) from B1/1-treated donors induced a significant suppression of not only the level of IgE and IgG antibodies to Lol pIV, but also the level of antibodies possessing the Id91. Treatment of the B cells with mAb91 plus complement abrogated their ability to transfer the suppression. This study indicates that the treatment with the anti-Id B1/1 generated B cells that were characterized, serologically, as possessing the anti-Id-like antibodies on their surface and were responsible for transferring the suppression of the formation of antibodies to allergen Lol pIV and the expression of Id91.
Pinot de Moira, Angela; Jones, Frances M; Wilson, Shona; Tukahebwa, Edridah; Fitzsimmons, Colin M; Mwatha, Joseph K; Bethony, Jeffrey M; Kabatereine, Narcis B; Dunne, David W
Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent treatment of schoolchildren coinfected with Schistosoma mansoni and hookworm. Antibody responses to schistosome egg (soluble egg antigen and SmTAL2) or somatic adult hookworm (AHW) antigens either decreased after treatment or were unchanged, whereas those to schistosome worm antigens (soluble worm antigen and SmTAL1) increased. The observed different effects of treatment likely reflect the different modes of drug action and sites of infection for these two helminths. Importantly, there was no evidence that the simultaneous treatment of coinfected children with praziquantel and albendazole affected schistosome- and hookworm-specific humoral responses differently from those characteristic of populations in which only one organism is endemic; schistosome- and hookworm-specific responses were not associated, and there was no evidence for cross-regulation. Posttreatment increases in the levels of IgE to schistosome worm antigens were associated with lower Schistosoma mansoni reinfection intensity, while no associations between humoral responses to AHW antigen and protection from hookworm reinfection were observed in this sample of school-aged children.
Endotoxin exposure has been associated with both protection against development of TH2-immune responses during childhood and exacerbation of asthma in persons who already have allergic airway inflammation.1 Occupational and experimental inhalation exposures to endotoxin have been...
Endotoxin exposure has been associated with both protection against development of TH2-immune responses during childhood and exacerbation of asthma in persons who already have allergic airway inflammation.1 Occupational and experimental inhalation exposures to endotoxin have been...
Chen, Ruchong; Smith, Steven G; Salter, Brittany; El-Gammal, Amani; Oliveria, John Paul; Obminski, Caitlin; Watson, Rick; O'Byrne, Paul M; Gauvreau, Gail M; Sehmi, Roma
Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. To investigate the role of ILC2 in allergen-induced airway eosinophilic responses in subjects with atopy and asthma. Using a diluent-controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen-induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge. ILC2 (lin(-)FcεRI(-)CD45(+)CD127(+)ST2(+)) and CD4(+)T lymphocytes were enumerated by flow cytometry, as well as intracellular IL-5 and IL-13 expression. Steroid sensitivity of ILC2 and CD4(+) T cells was investigated in vitro. A significant increase in total, IL-5(+), IL-13(+), and CRTH2(+) ILC2 was found in sputum, 24 hours after allergen, coincident with a significant decrease in blood ILC2. Total, IL-5(+), and IL-13(+), but not CRTH2(+), CD4(+) T cells significantly increased at 24 and 48 hours after allergen in sputum. In blood and bone marrow, only CD4(+) cells demonstrated increased activation after allergen. Airway eosinophilia correlated with IL-5(+) ILC2 at all time points and allergen-induced changes in IL-5(+) CD4(+) cells at 48 hours after allergen. Dexamethasone significantly attenuated IL-2- and IL-33-stimulated IL-5 and IL-13 production by both cell types. Innate and adaptive immune cells are increased in the airways associated with allergic asthmatic responses. Total and type 2 cytokine-positive ILC2 are increased only within the airways, whereas CD4(+) T lymphocytes demonstrated local and systemic increases. Steroid sensitivity of both cells may explain effectiveness of this therapy in those with mild asthma.
Yi, Lingling; Cheng, Dan; Zhang, Kan; Huo, Xiaorong; Mo, Yuqing; Shi, Huimin; Di, Honghong; Zou, Yun; Zhang, Huilan; Zhao, Jianping; Xu, Yongjian; Erle, David J.; Zhen, Guohua
The epithelial and epidermal innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) play pivotal roles in the initiation of allergic inflammation in asthma and atopic dermatitis. However, the mechanism by which the expression of these innate cytokines is regulated remains unclear. Intelectin (ITLN) is expressed in airway epithelial cells and promotes allergic airway inflammation. We hypothesized that ITLN is required for allergen-induced IL-25, IL-33 and TSLP expression. In two asthma models, Itln knockdown reduced allergen-induced increases in Il-25, Il-33, and Tslp and development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness. Itln knockdown also inhibited house dust mite (HDM)-induced early upregulation of Il-25, Il-33, and Tslp in a model solely inducing airway sensitization. Using human airway epithelial cells, we demonstrated that HDM-induced increases in ITLN led to phosphorylation of EGFR and ERK which were required for induction of IL-25, IL-33, and TSLP expression. In two atopic dermatitis models, Itln knockdown suppressed expression of Il-33, Tslp and Th2 cytokines and eosinophilic inflammation. In humans, ITLN1 expression was significantly increased in asthmatic airways and in lesional skin of atopic dermatitis. We conclude that intelectin contributes to allergen-induced Il-25, Il-33 and Tslp expression in asthma and atopic dermatitis. PMID:28224996
Yi, L; Cheng, D; Zhang, K; Huo, X; Mo, Y; Shi, H; Di, H; Zou, Y; Zhang, H; Zhao, J; Xu, Y; Erle, D J; Zhen, G
The epithelial and epidermal innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) have pivotal roles in the initiation of allergic inflammation in asthma and atopic dermatitis (AD). However, the mechanism by which the expression of these innate cytokines is regulated remains unclear. Intelectin (ITLN) is expressed in airway epithelial cells and promotes allergic airway inflammation. We hypothesized that ITLN is required for allergen-induced IL-25, IL-33, and TSLP expression. In two asthma models, Itln knockdown reduced allergen-induced increases in Il-25, Il-33, and Tslp and development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness. Itln knockdown also inhibited house dust mite (HDM)-induced early upregulation of Il-25, Il-33, and Tslp in a model solely inducing airway sensitization. Using human airway epithelial cells, we demonstrated that HDM-induced increases in ITLN led to phosphorylation of epidermal growth factor receptor and extracellular-signal regulated kinase, which were required for induction of IL-25, IL-33, and TSLP expression. In two AD models, Itln knockdown suppressed expression of Il-33, Tslp, and Th2 cytokines and eosinophilic inflammation. In humans, ITLN1 expression was significantly increased in asthmatic airways and in lesional skin of AD. We conclude that ITLN contributes to allergen-induced Il-25, Il-33, and Tslp expression in asthma and AD.Mucosal Immunology advance online publication 22 February 2017. doi:10.1038/mi.2017.10.
Khurana, Taruna; Bridgewater, Jennifer L; Rabin, Ronald L
To review allergenic extracts used to diagnose or treat insect allergies, including how the extracts are manufactured and their measurements of potency or concentration. Peer-reviewed articles derived from searching PubMed (National Center for Biotechnology Information) about insect allergies and extract preparation. Encyclopedia of Life (http://www.eol.org/) and http://allergome.org/ were also referenced for background information on insects and associated allergens. Search terms used for the PubMed searches included insect allergens and allergies, Apidae, Vespidae, fire ants, cockroach allergies, insect allergen extract preparation, and standardization. Humans may be sensitized to insect allergens by inhalation or through stings. Cockroaches and moths are predominantly responsible for inhalation insect allergy and are a major indoor allergen in urban settings. Bees, fire ants, and wasps are responsible for sting allergy. In the United States, there are multiple insect allergen products commercially available that are regulated by the US Food and Drug Administration. Of those extracts, honeybee venom and insect venom proteins are standardized with measurements of potency. The remaining insect allergen extracts are nonstandardized products that do not have potency measurements. Sensitization to inhalational and stinging insect allergens is reported worldwide. Crude insect allergen extracts are used for diagnosis and specific immunotherapy. A variety of source materials are used by different manufacturers to prepare these extracts, which may result in qualitative differences that are not reflected in measurements of potency or protein concentration. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
A small number of protein families are responsible for food allergies suffered by the majority of allergy patients. What properties of these proteins make them allergens is not clear at present. Reliable methods for allergen prediction and mitigation are lacking. Most the immediate type of food alle...
Spiric, Jelena; Engin, Anna M.; Karas, Michael; Reuter, Andreas
Allergy against birch pollen is among the most common causes of spring pollinosis in Europe and is diagnosed and treated using extracts from natural sources. Quality control is crucial for safe and effective diagnosis and treatment. However, current methods are very difficult to standardize and do not address individual allergen or isoallergen composition. MS provides information regarding selected proteins or the entire proteome and could overcome the aforementioned limitations. We studied the proteome of birch pollen, focusing on allergens and isoallergens, to clarify which of the 93 published sequence variants of the major allergen, Bet v 1, are expressed as proteins within one source material in parallel. The unexpectedly complex Bet v 1 isoallergen composition required manual data interpretation and a specific design of databases, as current database search engines fail to unambiguously assign spectra to highly homologous, partially identical proteins. We identified 47 non-allergenic proteins and all 5 known birch pollen allergens, and unambiguously proved the existence of 18 Bet v 1 isoallergens and variants by manual data analysis. This highly complex isoallergen composition raises questions whether isoallergens can be ignored or must be included for the quality control of allergen products, and which data analysis strategies are to be applied. PMID:26561299
Monoclonal antibodies against Olea europaea major allergen: allergenic activity of affinity-purified allergen and depleted extract and development of a radioimmunoassay for the quantitation of the allergen.
Lombardero, M; Quirce, S; Duffort, O; Barber, D; Carpizo, J; Chamorro, M J; Lezaun, A; Carreira, J
Several monoclonal antibodies (MAbs) were raised against Olea europaea pollen-extract components. Two of these antibodies, named OL 2 and OL 7, recognize two nonoverlapping, nonrepeating epitopes on the olive-allergen Ole e I, as demonstrated by different techniques. The allergen was purified in a single step by MAb-based affinity chromatography, and the allergen revealed a band at molecular weight 20 kd as well as a minor band at 18 kd on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The contribution of allergen Ole e I to the allergenic activity of O. europaea pollen extracts was determined from the effect of allergen depletion by affinity chromatography on skin reactivity and a histamine-release test. The removal of allergen caused a large reduction in the activity of the preparation in 25 monospecific olive-allergic patients. In agreement, the affinity-purified allergen demonstrated a similar response when it was compared with the whole extract in these assays. The results indicated that Ole e I is by far the most important olive-pollen allergen. A two-site solid-phase radioimmunoassay was developed for the quantitation of the allergen Ole e I in mass units. The assay was based on the MAbs, OL 2 and OL 7, and had a detection limit in the nanogram range. A good correlation was found between allergenic activity, as determined by RAST inhibition, and allergen content in 18 olive-pollen extracts. This result indicates that the assay can be a good alternative to RAST inhibition for the standardization of O. europaea extracts.
Lehrer, S B; Karr, R M; Salvaggio, J E
Workers in the coffee industry can develop occupational allergic disease upon exposure to dust associated with coffee manufacturing. Since controversy exists as to the source or chemical nature of these allergens, the mouse model of reaginic antibody production was used to assess the potential sources of allergens in samples obtained from a local coffee manufacturing plant. Mice were immunized with extracts of coffee dust and beans and the resulting reaginic antibody response determined by the passive cutaneous anaphylaxis reaction. Cross-reacting allergens were detected in samples of coffee dust, cleaner can debris and green coffee beans, but not in chaff or roasted coffee beans. None of the allergens detected in coffee samples cross-reacted with extract of castor beans, although these extracts contained the potent castor bean allergen. Green coffee bean allergens partially purified by gel filtration were heterogeneous with respect to molecular size, although quite similar in their reactivity with reaginic antiserum. These results suggest that the green coffee bean is the major source of allergen in coffee manufacturing plants. This allergen is heterogeneous with respect to size and heat lability, and is immunochemically different from the castor bean allergen.
López, Marta Sánchez-Paniagua; Cabanillas, Gloria Frutos; Castañón, M Jesús Lobo; López-Ruiz, Beatriz
A new selective electrochemical genosensor has been developed for the detection of an 86-mer DNA peanut sequence encoding part of the allergen Ara h 2 (conglutin-homolog protein). The method is based on a sandwich format, which presents two advantages: it permits shortening the capture probe and avoids labeling of the target. Screen-printed gold electrodes have been used as platform for the immobilization of oligonucleotides by the well-known S-Au bond. Mixed self-assembled monolayers (SAM), including thiol-modified capture probe and mercaptohexanol, were prepared to achieve an organized, homogeneous and not too compact SAM in which unspecific adsorption of the capture probe would be prevented. The optimization of the sensing phase was carried out using the Design of Experiments (DoE) approach. Traditionally, response optimization is achieved by changing the value of one factor at a time until there is no further improvement. However, DoE involves regulating the important factors so that the result becomes optimal. Optimized conditions were found to be 1.34 µM for capture probe concentration and 3.15 mM for mercaptohexanol (spacer) concentration. When the optimal conditions were employed the analytical performance of the proposed genosensor improved significantly, showing a sensitivity as high as 3 µA/nM, with a linear range from 5×10(-11) to 5×10(-8) M and a detection limit of 10 pM. Copyright © 2014 Elsevier B.V. All rights reserved.
Asero, R; Marzban, G; Martinelli, A; Zaccarini, M; Machado, M Laimer da Camara
Due to the cross-reactivity between Bet v 1 and proteins present in vegetable foods, birch pollen allergic patients frequently develop allergy to fruits and vegetables, mostly apples. Since many apple cultivars exist some of them might contain sufficiently low amounts of Mal d 1 to be tolerated by most allergic patients. To assess whether apple cultivars containing low amounts of Mal d 1 are better tolerated by apple-allergic patients. Mal d 1 content was determined in many apple cultivars by ELISA. Selected cultivars containing high (Golden Delicious) or low (Orim, G 198 and Vienna) amounts of Mal d 1 were compared in apple allergic patients both by SPT and oral challenges. The 3 different apple cultivars induced wheals of similar size in most patients. Upon oral challenges no patient reported the total absence of oral symptoms following the ingestion of either high or low allergenic apples. Golden Delicious and G-198 elicited OAS of similar severity 3/7 cases. The 2 cultivars induced significantly more severe symptoms in 2 cases each. Allergy to Mal d 1 is characterized by significant inter-patient variability. Moreover, marked inter-apple and intra-apple variability exists. As a consequence, the amount of Mal d 1 in apples classified as containing low concentrations of allergen may be sufficient to induce both clinical symptoms and skin reactivity in birch pollen-allergic patients. The search for low allergenic apples therefore should be continued and extended to other germplasm accessions, be it cultivars, breeding lines or wild species.
Sinkford, Jeanne C; Valachovic, Richard W; Weaver, Richard G; West, Joseph F
Over at least the last twenty years, the American Dental Education Association (ADEA) has given attention and priority to increasing the number of underrepresented minority (URM) dental school applicants, enrollees, and faculty members and to meeting the challenges of achieving diversity in the oral health workforce of the future as racial and ethnic minorities continue to grow and are expected to comprise more than 50 percent of the U.S. population by the middle of the twenty-first century. Dental schools have the responsibility of preparing dentists to provide oral health care for the nation's population. This includes creating a workforce of adequate size and racial/ethnic composition. As part of ADEA's priorities to improve the recruitment, retention, and development of URMs in the dental profession, with funding from the W.K. Kellogg Foundation, ADEA launched the Minority Dental Faculty Development Program in 2004. The intent of the program is to foster academic partnerships, mentoring, and institutional commitment and leadership designed to increase the number of URM individuals interested in and prepared for careers in academic dentistry.
Jin, Yafang; Deng, Yun; Qian, Bingjun; Zhang, Yifeng; Liu, Zhenmin; Zhao, Yanyun
The structural and allergenic modifications of tropomyosin Tod p1 (TMTp1) in fresh squids induced by high hydrostatic pressure (HHP) were investigated. The α-helix in TMTp1 decreased along with increasing pressure from 200 to 600 MPa, where almost 53% α-helix was converted into β-sheet and random coils at 600 MPa. The free sulfhydryl group dropped significantly as pressure went up, but the surface hydrophobicity increased at 200 and 400 MPa, while it slightly decreased at 600 MPa. Based on in vitro gastrointestinal digestion test, digestibility of TMTp1 was promoted by HHP treatment, in which 400 and 600 MPa were more effective in reducing the allergenicity than 200 MPa based on indirect ELISA. This study suggested that HHP can decrease allergenicity of TMTp1 by protein unfolding and secondary structure modification, thus providing potential for alleviating allergenicity of squid. Copyright © 2014 Elsevier Ltd. All rights reserved.
Hadebe, Sabelo; Kirstein, Frank; Fierens, Kaat; Redelinghuys, Pierre; Murray, Graeme I; Williams, David L; Lambrecht, Bart N; Brombacher, Frank; Brown, Gordon D
β-(1,3)-Glucan is present in mould cell walls and frequently detected in house dust mite (HDM) faeces. β-Glucan exposure is thought to be associated with pulmonary allergic inflammation in mouse and man, although the published data are inconsistent. Here, we show that highly purified β-glucan exacerbates HDM-induced eosinophilic, T helper 2 type airway responses by acting as an adjuvant, promoting activation, proliferation and polarisation of HDM-specific T cells (1-Derβ T cells). We therefore provide definitive evidence that β-glucan can influence allergic pulmonary inflammation.
Dutkiewicz, J; Skórska, C; Milanowski, J; Mackiewicz, B; Krysińska-Traczyk, E; Dutkiewicz, E; Matuszyk, A; Sitkowska, J; Golec, M
A group of 51 herb processing workers employed in a big herb processing facility located in eastern Poland were examined by the skin and precipitin tests with, respectively, 4 and 17 extracts of microorganisms associated with organic dusts. Out of this number, 32 workers were examined by the skin test with 7 extracts of selected herbs processed in the facility. All the subjects were asked about the occurrence of work-related symptoms. 32 healthy office workers were examined with microbial extracts as a reference group. The herb processing workers showed a high proportion of early skin reactions (after 20 min) to the extract of Gram-negative bacterium Alcaligenes faecalis (41.2%), significantly higher compared to the reference group (p<0.01). At all time intervals (20 min, 8 hrs, 24 hrs), the workers responded with a high frequency to the extract of Bacillus subtilis (respectively 72.5%, 64.7%, and 15.7%), significantly greater compared to the reference group (respectively p<0.001, p<0.001, and p<0.05). No significant differences were found between the groups of herb processing workers and referents in skin response to the extracts of Streptomyces albus and Alternaria alternata and, except for the extract of Pantoea agglomerans, in the frequency of positive precipitin reactions to microbial antigens. In the skin test with herb extracts, the highest response among workers were caused by the extracts of chamomile flowers and nettle leaves which evoked 40-65% of positive skin reactions at all time intervals. 39 out of 51 interviewed herb processing workers (76.5%) reported the occurrence of work-related general, respiratory and skin symptoms. The positive skin reactions occurred more frequently among symptomatic workers which suggests that the specific immunologic response might be implicated in etiopathogenesis of work-related symptoms in examined workers. However, in most cases the differences did not attain a significance level which indicates that there is no
Ansari, A A; Freidhoff, L R; Meyers, D A; Bias, W B; Marsh, D G
A well-characterized allergen of Lolium perenne (perennial rye grass) pollen, Lol p III, has been used as a model antigen to study the genetic control of the human immune response. Associations between HLA type and IgE or IgG antibody (Ab) responsiveness to Lol p III were studied in two groups of skin-test-positive Caucasoid adults (N = 135 and 67). We found by nonparametric and parametric analyses that immune responsiveness to Lol p III was significantly associated with HLA-DR3 and DR5. No association was found between any DQ type and immune responsiveness to Lol p III. Geometric mean IgE or IgG Ab levels to Lol p III were not different between B8+, DR3+ subjects and B8-, DR3+ subjects, showing that HLA-B8 had no influence on the association. Lol p III IgG Ab data obtained on subjects after grass antigen immunotherapy showed that 100% of DR3 subjects and 100% of DR5 subjects were Ab+. A comparison of all the available protein sequences of DRB gene products showed that the first hypervariable region of DR3 and DR5 (and DRw6), and no other region, contains the sequence Glu9-Tyr-Ser-Thr-Ser13. Our observations are consistent with the possibility that immune responsiveness to the allergen Lol p III is associated with this amino acid sequence in the first hypervariable region of the DR beta 1 polypeptide chain.
Kouzaki, Hideaki; Iijima, Koji; Kobayashi, Takao; O'Grady, Scott M; Kita, Hirohito
The molecular mechanisms underlying the initiation of innate and adaptive proallergic Th2-type responses in the airways are not well understood. IL-33 is a new member of the IL-1 family of molecules that is implicated in Th2-type responses. Airway exposure of naive mice to a common environmental aeroallergen, the fungus Alternaria alternata, induces rapid release of IL-33 into the airway lumen, followed by innate Th2-type responses. Biologically active IL-33 is constitutively stored in the nuclei of human airway epithelial cells. Exposing these epithelial cells to A. alternata releases IL-33 extracellularly in vitro. Allergen exposure also induces acute extracellular accumulation of a danger signal, ATP; autocrine ATP sustains increases in intracellular Ca(2+) concentration and releases IL-33 through activation of P2 purinergic receptors. Pharmacological inhibitors of purinergic receptors or deficiency in the P2Y2 gene abrogate IL-33 release and Th2-type responses in the Alternaria-induced airway inflammation model in naive mice, emphasizing the essential roles for ATP and the P2Y(2) receptor. Thus, ATP and purinergic signaling in the respiratory epithelium are critical sensors for airway exposure to airborne allergens, and they may provide novel opportunities to dampen the hypersensitivity response in Th2-type airway diseases such as asthma.
Leyva-Castillo, Juan Manuel; Hener, Pierre; Jiang, Hua; Li, Mei
Atopic dermatitis often precedes the development of asthma, a phenomenon known as "atopic march". An important role of allergen sensitization developed through barrier-defective skin has been recognized in the onset of atopic march; however, the underlying mechanism remains poorly understood. In this study, we use an experimental atopic march mouse model, in which the sensitization to allergen is achieved through barrier-impaired skin, followed by allergen challenge in the airway. By using thymic stromal lymphopoietin (TSLP)(iep-/-) mice in which the cytokine TSLP is selectively and inducibly ablated in epidermal keratinocytes, we demonstrate that keratinocytic TSLP, the expression of which is induced by skin barrier impairment, is essential for generating skin allergic inflammation and allergen-induced T helper type 2 response, for developing sensitization to allergen, and for triggering a subsequent allergic asthma. Furthermore, using TSLP(over) mice in which overexpression of keratinocytic TSLP is induced by skin topical application of MC903 (a vitamin D3 analog) in a dose-dependent manner, we show that keratinocytic TSLP levels are correlated with skin sensitization strength and asthma severity. Taken together, our study uncovers a crucial role of keratinocytic TSLP in the "atopic march" by promoting allergen sensitization occurring in barrier-impaired skin, which ultimately leads to allergic asthma.
Recer, G M
Sensitization and exposure to dust-mite antigens are causative factors in the development and exacerbation of asthma. Impermeable bedding encasements are considered a first-line treatment to reduce dust-mite antigen exposure in clinical asthma-management guidelines. Public-health recommendations for environmental asthma treatments should be based on the weight of evidence supporting the reliability of environmental interventions so that uncertainties regarding their effectiveness can be accurately communicated to patients, and so that limited public-health resources can be most effectively utilized. To evaluate the strength of a clinical-trial evidence supporting the efficacy of bedding encasements as an asthma treatment. A narrative review was conducted of all clinical trials involving bedding encasement for the treatment of asthma. Collective statistical analyses were also performed to characterize the quantitative effect of bedding encasement on dust-mite allergen exposure and bronchial hyper-responsiveness (BHR) when used by asthma patients. Over 30 clinical trials were reviewed. Of those studies reporting adequate exposure and BHR results, four reported significant reduction in dust-mite allergen exposure and concomitant BHR reduction in active-treatment groups using bedding encasements. In 10 studies, mite-allergen exposure was reportedly decreased during the study, but BHR was not changed in the active-treatment group or was reduced to a similar degree in the active-treatment and control groups. Five other studies reported a lack of significant effect of the intervention on exposure and BHR. Collective paired analyses found that the effect of bedding encasement on allergen exposure and BHR tended toward only a modest, non-significant improvement. Collectively, effects of bedding encasement on BHR and dust-mite allergen exposure were modestly correlated only when the baseline exposure was above 2 microg Type 1 antigen per gram settled dust. Although bedding
Frati, F; Incorvaia, C; Cadario, G; Fiocchi, A; Senna, G E; Rossi, O; Romano, A; Scala, E; Romano, C; Ingrassia, A; Zambito, M; Dell'albani, I; Scurati, S; Passalacqua, G; Canonica, G W
The evidence of efficacy of allergen immunotherapy (AIT) for respiratory allergy has been demonstrated by a number of meta-analyses. However, the daily practice of AIT is quite different from controlled trials, facing challenges in terms of selection of patients, practical performance, and, of particular importance, use of allergen extracts of inadequate quality. We here performed a survey, named the Allergen Immunotherapy Decision Analysis (AIDA), to evaluate which criteria are used by specialists to choose a product for sublingual immunotherapy (SLIT) in patients with respiratory allergy. A questionnaire composed of 14 items to be ranked by each participant according to the importance attributed when choosing SLIT products was submitted to 444 Italian specialists. The responses of the 169 (38.1%) physicians, who answered all questions, were analysed. Most of the respondents were allergists (79%), followed by pulmonologists (10.8%), both allergists and pulmonologists (4.8%), and otorhinolaryngologists (3%); 59.8% of the respondents were males and 40.2% were females. The age distribution showed that 89.9% of the respondents were aged between 35 and 64 years. All respondents usually prescribed AIT products in their clinical practice: 31.4% used only SLIT, whereas 69.2% used both subcutaneous and sublingual administration. The rankings, expressed as means, attributed by physicians for each of the 14 items were as follows: level of evidence-based medicine (EBM ) validation of efficacy (3.44), level of EBM validation of safety (4.30), standardization of the product (5.37), efficacy based on personal experience (5.82), defined content(s) of the major allergen(s) in micrograms (5.96), scientific evidence for each single allergen (6.17), safety based on personal experience (6.32), ease of administration protocol (8.08), cost and terms of payment (e.g. instalments) (9.17), dose personalization (9.24), patient preference (9.25), ease of product storage (9.93), reimbursement
Zimmer, Julia; Vieths, Stefan; Kaul, Susanne
Product-specific standardization is of prime importance to ensure persistent quality, safety, and efficacy of allergen products. The regulatory framework in the EU has induced great advancements in the field in the last years although national implementation still remains heterogeneous. Scores of methods for quantification of individual allergen molecules are developed each year and also the challenging characterization of chemically modified allergen products is progressing. However, despite the unquestionable increase in knowledge and the subsequent improvements in control of quality parameters of allergen products, an important aim has not been reached yet, namely cross-product comparability. Still, comparison of allergen product potency, either based on total allergenic activity or individual allergen molecule content, is not possible due to a lack of standard reference preparations in conjunction with validated standard methods. This review aims at presenting the most recent developments in product-specific standardization as well as activities to facilitate cross-product comparability in the EU.
Schymeinsky, Jürgen; Mayer, Hannah; Tomsic, Christopher; Tilp, Cornelia; Schuetz, John D; Cui, Yunhai; Wollin, Lutz; Gantner, Florian; Erb, Klaus J
The multidrug resistance protein 4 (Mrp4) is an ATP-binding cassette transporter that is capable of exporting the second messenger cAMP from cells, a process that might regulate cAMP-mediated anti-inflammatory processes. However, using LPS- or cigarette smoke (CS)-inflammation models, we found that neutrophil numbers in the bronchoalveolar lavage fluid (BALF) were similar in Mrp4(-/-) and Mrp4(+/+) mice treated with LPS or CS. Similarly, neutrophil numbers were not reduced in the BALF of LPS-challenged wt mice after treatment with 10 or 30 mg/kg of the Mrp1/4 inhibitor MK571. The absence of Mrp4 also had no impact on the influx of eosinophils or IL-4 and IL-5 levels in the BALF after OVA airway challenge in mice sensitized with OVA/alum. LPS-induced cytokine release in whole blood ex vivo was also not affected by the absence of Mrp4. These data clearly suggest that Mrp4 deficiency alone is not sufficient to reduce inflammatory processes in vivo. We hypothesized that in combination with PDE4 inhibitors, used at suboptimal concentrations, the anti-inflammatory effect would be more pronounced. However, LPS-induced neutrophil recruitment into the lung was no different between Mrp4(-/-) and Mrp4(+/+) mice treated with 3 mg/kg Roflumilast. Finally, the single and combined administration of 10 and 30 mg/kg MK571 and the specific breast cancer resistance protein (BCRP) inhibitor KO143 showed no reduction of LPS-induced TNFα release into the BALF compared to vehicle treated control animals. Similarly, LPS-induced TNFα release in murine whole blood of Mrp4(+/+) or Mrp4(-/-) mice was not reduced by KO143 (1, 10 µM). Thus, BCRP seems not to be able to compensate for the absence or inhibition of Mrp4 in the used models. Taken together, our data suggest that Mrp4 is not essential for the recruitment of neutrophils into the lung after LPS or CS exposure or of eosinophils after allergen exposure.
Resnik, David B.; Elliott, Kevin C.
Social responsibility is an essential part of the responsible conduct of research that presents difficult ethical questions for scientists. Recognizing one’s social responsibilities as a scientist is an important first step toward exercising social responsibility, but it is only the beginning, since scientists may confront difficult value questions when deciding how to act responsibly. Ethical dilemmas related to socially responsible science fall into at least three basic categories: 1) dilemmas related to problem selection, 2) dilemmas related to publication and data sharing, and 3) dilemmas related to engaging society. In responding to these dilemmas, scientists must decide how to balance their social responsibilities against other professional commitments and how to avoid compromising their objectivity. In this article, we will examine the philosophical and ethical basis of social responsibility in science, discuss some of the ethical dilemmas related to exercising social responsibility, and make five recommendations to help scientists deal with these issues. PMID:26193168
Resnik, David B; Elliott, Kevin C
Social responsibility is an essential part of the responsible conduct of research that presents difficult ethical questions for scientists. Recognizing one's social responsibilities as a scientist is an important first step toward exercising social responsibility, but it is only the beginning, since scientists may confront difficult value questions when deciding how to act responsibly. Ethical dilemmas related to socially responsible science fall into at least three basic categories: 1) dilemmas related to problem selection, 2) dilemmas related to publication and data sharing, and 3) dilemmas related to engaging society. In responding to these dilemmas, scientists must decide how to balance their social responsibilities against other professional commitments and how to avoid compromising their objectivity. In this article, we will examine the philosophical and ethical basis of social responsibility in science, discuss some of the ethical dilemmas related to exercising social responsibility, and make five recommendations to help scientists deal with these issues.
Janković, V.; Popov Raljić, J.; Đorđević, V.
Consumers with potentially fatal food allergies are dependent on correct product labelling to protect their health. The food industry is responsible for providing every detail consumers need to make informed decisions. Considering public health, food suppliers have to monitor the presence of allergens, prevent cross-contamination and label products accurately. Allergen labelling of food products, drinks and non pre-packed food and drink products is clearly defined with legal regulations. To achieve this, a complete understanding of each product’s allergenic ingredients is needed and cross-contamination of food with allergens must be avoided. Raw materials need to be checked, every ingredient must be verified and every single allergen has to be stipulated. A mislabeled product could be recalled at potential cost, financially damaging business and at the same time, negatively impacting brand and reputation.
Chen, Miaolin; Xu, Jie; Devis, Deborah; Shi, Jianxin; Ren, Kang; Searle, Iain; Zhang, Dabing
Pollen allergies have long been a major pandemic health problem for human. However, the evolutionary events and biological function of pollen allergens in plants remain largely unknown. Here, we report the genome-wide prediction of pollen allergens and their biological function in the dicotyledonous model plant Arabidopsis (Arabidopsis thaliana) and the monocotyledonous model plant rice (Oryza sativa). In total, 145 and 107 pollen allergens were predicted from rice and Arabidopsis, respectively. These pollen allergens are putatively involved in stress responses and metabolic processes such as cell wall metabolism during pollen development. Interestingly, these putative pollen allergen genes were derived from large gene families and became diversified during evolution. Sequence analysis across 25 plant species from green alga to angiosperms suggest that about 40% of putative pollen allergenic proteins existed in both lower and higher plants, while other allergens emerged during evolution. Although a high proportion of gene duplication has been observed among allergen-coding genes, our data show that these genes might have undergone purifying selection during evolution. We also observed that epitopes of an allergen might have a biological function, as revealed by comprehensive analysis of two known allergens, expansin and profilin. This implies a crucial role of conserved amino acid residues in both in planta biological function and allergenicity. Finally, a model explaining how pollen allergens were generated and maintained in plants is proposed. Prediction and systematic analysis of pollen allergens in model plants suggest that pollen allergens were evolved by gene duplication and then functional specification. This study provides insight into the phylogenetic and evolutionary scenario of pollen allergens that will be helpful to future characterization and epitope screening of pollen allergens. © 2016 American Society of Plant Biologists. All rights reserved.
Chong, K T; Wong, S F; Mak, J W; Loh, L C; Ho, T M
Allergens of Dermatophagoides and Blomia species are well-characterized but not for other species. This study was conducted to determine the prevalence of allergic sensitization to house dust (HDM) and storage mites (SM). One hundred adult subjects (aged ≥ 18) were recruited. The mite specific IgE of all allergic subjects were higher compared with healthy subjetcs despite being not statistically significant except for D. farinae and G. malaysiensis. The mean serum IgE levels against HDM and SM for allergic subjects were significantly higher compared with those in healthy subjects. They were mainly sensitized to Dermatophagoides farinae (35%) and Glycycometus malaysiensis (37%). Immunoblots revealed not all allergic subjects showed positive immuno-reactivity against the mites tested. Single or multiple bands were observed for different species. The subjects were commonly sensitized to Group 2 (9-12 kDa), 10 (38 kDa) and 18 (40-48 kDa) allergens. Twenty-one out of 60 allergic subjects were sensitized to either one or more species. The majority of them (71%) were sensitized to single species. The allergic subjects were mainly sensitized to D. pteronyssinus, followed by Tyrophagus putrecentiae and Aleuroglyphus ovatus. Seven were solely sensitized to HDM while 10 were solely sensitized to SM. Four subjects were sensitized to both. Pre-adsorption study revealed no cross-reactivity. There was difference between the prevalence and reactivity to allergens of HDM and SM in these subjects. Both ELISA and immunoblot did not correlate well but can complement each other in improving the detection of mite allergens to the species level.
Campbell, E M; Kunkel, S L; Strieter, R M; Lukacs, N W
The increase in inner-city asthma among children appears to be due to allergic responses to several allergens. Recent studies have demonstrated that Ags derived from cockroaches are especially prominent in these settings and a significant health concern for the induction of asthma in children. In the present study, we have outlined the development of a murine model of cockroach allergen-induced airway disease and assessed specific mechanisms of the response, which resembles atopic human asthma. The allergic responses in this model include allergen-specific airway eosinophilia and significantly altered airway physiology, which directly correlates with inflammation. We have further utilized this allergen to establish primary and secondary rechallenge stages of late phase hyperreactivity exacerbation. This latter stage is characterized by greater changes in airway physiology than the primary stage, and it is likely due to the preexisting peribronchial inflammation present at the time of the second allergen rechallenge. We have identified specific roles for CC chemokines during these stages, with MIP-1alpha being an important eosinophil attractant during the primary stage and eotaxin during the secondary rechallenge stage. The development of these models allows the evaluation of mediators involved in both stages of cockroach allergen challenge, as well as the testing of specific therapeutic modalities.
The 7S vicilin and 11S legumin seed storage globulins belong to the cupin protein superfamily and are major food allergens in many of the “big eight” food allergen groups. Korean pine vicilin and pecan vicilin are thus predicted to be food allergens. Recombinant vicilins were expressed in E. coli an...
A concept of responsive computer systems will be introduced. The emerging responsive systems demand fault-tolerant and real-time performance in parallel and distributed computing environments. The design methodologies for fault-tolerant, real time and responsive systems will be presented. Novel techniques of introducing redundancy for improved performance and dependability will be illustrated. The methods of system responsiveness evaluation will be proposed. The issues of determinism, closed and open systems will also be discussed from the perspective of responsive systems design.
Saravanan, Vijayakumar; Lakshmi, P T V
The path to personalized medicine demands the use of new and customized biopharmaceutical products containing modified proteins. Hence, assessment of these products for allergenicity becomes mandatory before they are introduced as therapeutics. Despite the availability of different tools to predict the allergenicity of proteins, it remains challenging to predict the allergens and nonallergens, when they share significant sequence similarity with known nonallergens and allergens, respectively. Hence, we propose "FuzzyApp," a novel fuzzy rule based system to evaluate the quality of the query protein to be an allergen. It measures the allergenicity of the protein based on the fuzzy IF-THEN rules derived from five different modules. On various datasets, FuzzyApp outperformed other existing methods and retained balance between sensitivity and specificity, with positive Mathew's correlation coefficient. The high specificity of allergen-like putative nonallergens (APN) revealed the FuzzyApp's capability in distinguishing the APN from allergens. In addition, the error analysis and whole proteome dataset analysis suggest the efficiency and consistency of the proposed method. Further, FuzzyApp predicted the Tropomyosin from various allergenic and nonallergenic sources accurately. The web service created allows batch sequence submission, and outputs the result as readable sentences rather than values alone, which assists the user in understanding why and what features are responsible for the prediction. FuzzyApp is implemented using PERL CGI and is freely accessible at http://fuzzyapp.bicpu.edu.in/predict.php . We suggest the use of Fuzzy logic has much potential in biomarker and personalized medicine research to enhance predictive capabilities of post-genomics diagnostics.
Evaluation of comfort using olopatadine hydrochloride 0.1% ophthalmic solution in the treatment of allergic conjunctivitis in contact lens wearers compared to placebo using the conjunctival allergen-challenge model.
Brodsky, Miguel; Berger, William E; Butrus, Salim; Epstein, Arthur B; Irkec, Murat
Olopatadine hydrochloride 0.1% ophthalmic solution is a topical antiallergy agent indicated for treatment of the signs and symptoms of allergic conjunctivitis. The purpose of this study was to evaluate the comfort of olopatadine used for contact lens wearers in the conjunctival allergen-challenge (CAC) model. This was a single-center, randomized, double-masked, parallel-controlled CAC study. Contact lens-wearing subjects with a history of allergic conjunctivitis were randomized to receive olopatadine or placebo bilaterally. Fifteen minutes after study medication instillation, subjects inserted contact lenses. Allergen challenge was performed 10 minutes after contact lens insertion. Subjective evaluations of ocular comfort were obtained immediately and every minute after CAC, up to and including 10 minutes. Thereafter, comfort evaluations were made every 5 minutes up to and including 60 minutes. Subjects evaluated itching at 3, 7, and 10 minutes and redness was graded at 5, 10, and 20 minutes. All evaluations were graded on standardized scales. Subjects were given diaries in which to rate comfort at 2, 4, 6, 9, 12, and 13 hours and the time of contact lens removal. At post-study medication instillation, post-lens insertion, and at time points from 1 to 10 minutes post-allergen challenge, ocular comfort evaluations were statistically superior in subjects receiving olopatadine as compared with those receiving placebo (P < 0.05). The difference in time until contact lens removal was clinically significant, with subjects who were treated with olopatadine wearing lenses for an average of 2.1 hours longer than placebo group. As evidenced by significantly greater comfort and longer duration of lens wear, olopatadine provides superior comfort to contact lens wearers suffering from the signs and symptoms of seasonal allergic conjunctivitis, as induced by the CAC model.
Freidhoff, L R; Ehrlich-Kautzky, E; Meyers, D A; Ansari, A A; Bias, W B; Marsh, D G
Associations between HLA type and IgE or IgG antibody (Ab) responses to two well-characterized, antigenetically non-crossreactive components of Lolium perenne (rye grass) pollen extract, Lol p I (Rye I) and Lol p II (Rye II) were studied in two groups of skin-test positive (ST+) Caucasoid adults. By both nonparametric and parametric statistical methods, significant associations were found between Ab responses to both Lol I and Lol II and the possession of HLA-DR3. In view of the well-known associations of both DR3 and B8 (which are in linkage disequilibrium) with many autoimmune diseases, differences in anti-Lol I and anti-Lol II mean log[Ab] levels between B8+, DR3- vs B8-, DR3- subjects and B8+, DR3+ vs B8-, DR3+ subjects were investigated. No differences were found. Our data, along with recent RFLP and DNA sequence studies, suggest that an Ia molecule involved in immune recognition of a similar major Ia recognition site of both the Lol molecules may consist of a DR3 alpha-beta I pair. Abbreviations used: Ab: Antibody. HLA: Human leukocyte antigen. Lol p I, Lol I: Group I allergen from Lolium perenne pollen (Rye I). Lol p II, Lol II: Group II allergen from Lolium perenne pollen (Rye II). Mr: Relative molecular mass. Rx: Immunotherapy with grass pollen extracts. ST: Skin test.
Geng, Xiao-Rui; Qiu, Shu-Qi; Yang, Li-Tao; Liu, Zhi-Qiang; Yang, Gui; Liu, Jiang-Qi; Zeng, Lu; Li, Xiao-Xi; Mo, Li-Hua; Liu, Zhi-Gang; Yang, Ping-Chang
Interleukin (IL)-10-expressing B cells play a critical role in the immune homeostasis in the body; its regulation has not been fully understood. Micro-RNA (miR)-17-92 cluster has strong regulation in the immunity. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells. In this study, peripheral B cells were collected from patients with allergic rhinitis (AR). The B cells were treated with specific allergens, dust mite extracts, in the culture. The expressions of miR-17-92 cluster and IL-10 in the culture were assessed by real-time quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that the levels of miR-19a, but not the rest of the 5 members (miR-17, miR-18a, miR-19b, miR-20a, and miR-92a), were significantly higher in peripheral B cells from AR patients as than in B cells from healthy participants. Exposure of B cells from AR patients to specific allergen, dust mite extracts, significantly increased the levels if miR-19a and suppressed the expression of IL-10 in B cells. The levels of histone deacetylase 11 and acetylated H3K9 were higher, and the RNA polymerase II and c-Maf (the IL-10 transcription factor) were lower, at the IL-10 promoter locus. In conclusion, miR-19a mediates the allergen-specific immune response-decreased IL-10 expression in B cells.
A comparison of the clinical efficacy of pheniramine maleate/naphazoline hydrochloride ophthalmic solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model.
Greiner, Jack V; Udell, Ira J
The signs and symptoms of allergic conjunctivitis include ocular redness and itching. Two treatment options currently indicated for acute ocular allergic reaction are pheniramine maleate 0.3%/naphazoline hydrochloride 0.025% ophthalmic solution, an over-the-counter antihistamine/vasoconstrictor combination; and olopatadine hydrochloride 0.1% ophthalmic solution, a prescription antihistamine/mast cell stabilizer. This study was designed to compare, at onset of action, the relative effectiveness of pheniramine/naphazoline and olopatadine, when administered before conjunctival allergen challenge (CAC), using the ocular allergy index (OAI) as the primary end point. This was a prospective, randomized, double-masked, contralateral, active- and placebo-controlled, single-center study of the CAC model. The first 2 study visits established and confirmed the subjects' ocular allergic reaction (no medication administered). At visit 3, the subjects were randomly assigned to 1 of 3 contralateral (right eye vs left eye) treatment combinations: pheniramine/naphazoline + olopatadine, pheniramine/naphazoline + placebo, or olopatadine + placebo. Medication was given 10 minutes before CAC. The subjects' erythema in the ciliary, conjunctival, and episcleral vessel beds; eyelid swelling; chemosis; and itching were evaluated at 7, 12, and 20 minutes after CAC. The OAI was calculated as a composite score of 6 signs and symptoms of allergic conjunctivitis to assess global severity. Between-treatment differences in OAI scores were used to evaluate efficacy. Subjects were asked their eye drop preference at the conclusion of visit 3. Subjects (n = 83) ranged in age from 20 to 70 years (mean, 42.5 years), 61.4% (n = 51) were female, and 94.0% (n = 78) were white. Both pheniramine/naphazoline and olopatadine were associated with significantly lower OAI scores than placebo at all 3 time points (all, P < 0.001). OAI scores were significantly lower with pheniramine/naphazoline than with
Mueller, R S; Janda, J; Jensen-Jarolim, E; Rhyner, C; Marti, E
Allergic diseases in animals are increasingly gaining importance in veterinary practice and as research models. For intradermal testing and allergen immunotherapy, a good knowledge of relevant allergens for the individual species is of great importance. Currently, the knowledge about relevant veterinary allergens is based on sensitization rates identified by intradermal testing or serum testing for allergen-specific IgE; crude extracts are the basis for most evaluations. Only a few studies provide evidence about the molecular structure of (particularly) dust mite, insect and mould allergens in dogs and horses, respectively. In those species, some major allergens differ from those in humans. This position paper summarizes the current knowledge about relevant allergens in dogs, cats and horses.
Rego, Francisca X M; Giavina-Bianchi, Pedro; Kalil, Jorge; Arruda, L. Karla; Toledo-Barros, Myrthes
INTRODUCTION: Asthma affects approximately 10% of the world's population. Sensitization to allergens is an important risk factor, and exposure to allergens is associated with disease severity. METHODS: We performed skin tests to evaluate allergen sensitization to mites, cockroaches, cats, dogs, and molds in 73 asthmatic patients. Enzyme Linked Immunosorbent Assay was used to assay the mite and cockroach allergens found in dust from the bedding, hammocks, bedroom floors, living rooms, and kitchens of 29 patients and 14 controls. RESULTS: Fifty patients (68.5%) had positive skin test responses. There were positive responses to D. pteronyssinus (52.0%), B. tropicalis (53.4%), T. putrescentiae (15.0%), E. maynei (12.3%), L. destructor (8.2%), B. germanica (20.5%), P. americana (21.9%), Felis catus (10.9%), C. herbarium (2.7%), A. alternata (4.1%), and P. notatun (1.3%). The exposure to mite and cockroach allergens was similar in the patients and the controls. The Dermatophagoides pteronyssinus Group 1 levels were highest in the beds and hammocks. The Blattella germanica Group 1 levels were highest in the kitchens, living rooms and hammocks. DISCUSSION: The positive skin tests to mites, cockroaches and cats were consistent with previous studies. D pteronyssinus was the most prevalent home dust mite, and hammocks were a source of allergens. To improve asthma prophylaxis, it is important to determine its association with mite allergen exposure in hammocks. PMID:21876974
Hochwallner, H.; Schulmeister, U.; Swoboda, I.; Focke-Tejkl, M.; Reininger, R.; Civaj, V.; Campana, R.; Thalhamer, J.; Scheiblhofer, S.; Balic, N.; Horak, F.; Ollert, M.; Papadopoulos, N. G.; Quirce, S.; Szepfalusi, Z.; Herz, U.; van Tol, E. A. F.; Spitzauer, S.; Valenta, R.
Background Several hydrolyzed cow’s milk (CM) formulas are available for avoidance of allergic reactions in CM-allergic children and for prevention of allergy development in high-risk infants. Our aim was to compare CM formulas regarding the presence of immunoreactive CM components, IgE reactivity, allergenic activity, ability to induce T-cell proliferation, and cytokine secretion. Methods A blinded analysis of eight CM formulas, one nonhydrolyzed, two partially hydrolyzed (PH), four extensively hydrolyzed (EH), and one amino acid formula, using biochemical techniques and specific antibody probes was conducted. IgE reactivity and allergenic activity of the formulas were tested with sera from CM-allergic patients (n = 26) in RAST-based assays and with rat basophils transfected with the human FcεRI, respectively. The induction of T-cell proliferation and the secretion of cytokines in Peripheral blood mononuclear cell (PBMC) culture from CM allergic patients and nonallergic individuals were assessed. Results Immune-reactive α-lactalbumin and β-lactoglobulin were found in the two PH formulas and casein components in one of the EH formulas. One PH formula and the EH formula containing casein components showed remaining IgE reactivity, whereas the other hydrolyzed formulas lacked IgE reactivity. Only two EH formulas and the amino acid formula did not induce T-cell proliferation and proinflammatory cytokine release. The remaining formulas varied regarding the induction of Th2, Th1, and proinflammatory cytokines. Conclusion Our results show that certain CM formulas without allergenic and low proinflammatory properties can be identified and they may also explain different outcomes obtained in clinical studies using CM formulas. PMID:27455132
Salari, Farhad; Varasteh, Abdol-Reza; Vahedi, Fatemeh; Hashemi, Maryam; Sankian, Mojtaba
The goal of this study was to investigate whether poly (lactic-co-glycolic) acid (PLGA) nanoparticles could enhance sublingual immunotherapy (SLIT) efficacy. BALB/c mice sensitized to rChe a 3 were treated sublingually either with soluble rChe a 3 (100μg/dose) or PLGA-encapsulated rChe a 3 (5, 25, or 50μg/dose). SLIT with PLGA-encapsulated rChe a 3 (equivalent to 25 and 50μg rChe a 3 per dose) led to significantly increased antigen-specific IgG2a, along with no effect on allergen-specific IgE and IgG1 antibody levels. In addition, interleukin 4 (IL-4) levels in restimulated splenocytes were significantly less, while interferon-γ (IFN-γ), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) levels, as well as Foxp3 expression, were significantly greater than in the control groups. Our findings suggest that PLGA nanoparticle-based vaccination may help rational development of sublingual immunotherapy through reduction of the needed allergen doses and also significantly enhanced systemic T regulatory (Treg) and T helper 1 (Th1) immune responses.
Molnar, Alex, Ed.
Social responsibility is a difficult but essential aspect of being a professional educator. The contributors to this volume hope that the social policy debate within the education profession will be encouraged. The book provides practical assistance for educators in developing curriculum and instruction programs that foster creativity and critical…
Foskett, Nicholas H.
Develops an analytical methodology for service organizations by examining four key cultural and managerial developments: understandings of markets and marketing held within the school; organizational responses to the market; use of analytical tools; and development of appropriate marketing strategies. Shows variations in schools' development of a…
Seeing the present situation, I think that, at the very least, it behooves us as scientists and as human beings to work responsibly both for the future of our science and for the future of our languages, not so much for reward according to the fashion of the day, but for the sake of posterity. What we need to do now stares us in the face. If we do…
Seeing the present situation, I think that, at the very least, it behooves us as scientists and as human beings to work responsibly both for the future of our science and for the future of our languages, not so much for reward according to the fashion of the day, but for the sake of posterity. What we need to do now stares us in the face. If we do…
Weido, A J; Reece, L M; Alam, R; Cook, C K; Sim, T C
Allergen-induced nasal responses are associated with the recovery of proinflammatory mediators and cytokines. In recent years, a distinct group of chemotactic cytokines, chemokines, has been the focus of intense investigation as to their possible role in the pathogenesis of allergic diseases. Although corticosteroids have been known to be effective in the treatment of allergic diseases, their mechanism(s) of action has not been fully elucidated. To study the effect of topical fluticasone on the recovery of chemokines (IL-8, MIP-1 alpha, and RANTES) and other cytokines (IL-1 beta, IL-6, and GM-CSF) from nasal mucosa following allergen challenge. To correlate the improvement of rhinitis symptoms with cytokine levels during early-phase and late-phase allergic responses. A randomized, double-blind, placebo-controlled crossover study of fluticasone propionate, 200 micrograms q d, was performed in ten subjects with allergic rhinitis. Allergen challenge was administered after 1 week of treatment. Nasal secretions were collected immediately after challenge and during the late-phase reactions; symptom scores were recorded simultaneously. Nasal cytokines were assayed by specific ELISA. The allergen challenge caused early-phase and late-phase allergic reactions and increased recovery of IL-1 beta, IL-6, IL-8, RANTES, MIP-1 alpha, and GM-CSF from the nasal mucosa. Intranasal fluticasone inhibited the allergen-induced increase in nasal symptoms. This was associated with decreases in cytokine recovery. A significant correlation was observed between decreases in cytokine levels and in symptom scores after treatment. Our results suggest that treatment with topical fluticasone propionate inhibits allergen-induced nasal responses and the associated increase in the production/secretion of chemokines and other proinflammatory cytokines.
Jolly, Ana; Morsella, Claudia; Bass, Laura; Fiorentino, María Andrea; Paolicchi, Fernando Alberto; Mundo, Silvia Leonor
This study aimed to evaluate the immune response in bovines following immunization with a mycobaterial Lipoarabinomannan extract (LAMe) and the effect of Map challenge. LAMe vaccine induced specific antibody levels that diminished after the challenge and affected Map excretion at least for 100 days thereafter. PMID:24294248
Jolly, Ana; Morsella, Claudia; Bass, Laura; Fiorentino, María Andrea; Paolicchi, Fernando Alberto; Mundo, Silvia Leonor
This study aimed to evaluate the immune response in bovines following immunization with a mycobaterial Lipoarabinomannan extract (LAMe) and the effect of Map challenge. LAMe vaccine induced specific antibody levels that diminished after the challenge and affected Map excretion at least for 100 days thereafter.
Background Over the last 100 years, several persistent misconceptions or ‘false beliefs’ have built up around allergen immunotherapy and its use in allergic rhinitis. This is perhaps because enthusiastic physicians administered complex allergen extracts to a diverse population of patients suffering from heterogeneous atopic conditions. Here, we review evidence that counters seven of these ‘false beliefs.’ Discussion 1. The symptoms of allergic rhinitis can be more heterogeneous, more severe and more troublesome in everyday life than many physicians believe. Large-scale epidemiological surveys show that the majority of allergic rhinitis patients have at least one symptom severe enough to interfere with sleep quality, productivity and/or well-being. 2. Allergen immunotherapy is not necessarily suitable for all allergic rhinitis patients (notably those with mild symptoms). Recent evidence from double-blind, placebo-controlled, randomized clinical trials suggests that the more severe the disease, the greater the treatment effect. 3. Allergen immunotherapy is often accused of lack of efficacy (relative to pharmacotherapy, for example). However, there are now many meta-analyses, systematic reviews and high-quality clinical trials that find overwhelmingly in favor of the efficacy of allergen immunotherapy (including sublingual formulations) in allergic rhinitis induced by pollen and, increasingly, other allergens. 4. Natural-exposure and challenge-chamber trials have shown that symptom relief may become apparent within months or even weeks of the initiation of allergen immunotherapy. 5. In pollen-induced allergic rhinitis, several years of subcutaneous or sublingual allergen immunotherapy are associated with sustained clinical efficacy after subsequent treatment cessation – confirming the disease-modifying nature of this therapy. 6. Most patients seeking treatment for allergic rhinitis are polysensitized, and allergen immunotherapy has proven efficacy in large
Esteve, C; Montealegre, C; Marina, M L; García, M C
Olive pollen is one of the most important causes of seasonal respiratory allergy in Mediterranean countries, where this tree is intensely cultivated. Besides this, some cases of contact dermatitis and food allergy to the olive fruit and olive oil have been also described. Several scientific studies dealing with olive allergens has been reported, being the information available about them constantly increasing. Up to date, twelve allergens have been identified in olive pollen while just one allergen has been identified in olive fruit. This review article describes considerations about allergen extraction and production, also describing the different methodologies employed in the physicochemical and immunological characterization of olive allergens. Finally, a revision of the most relevant studies in the analysis of both olive pollen and olive fruit allergens is carried out.
Pandey, Ravi Shankar; Sahu, Satish; Sudheesh, M S; Madan, Jitender; Kumar, Manoj; Dixit, Vinod Kumar
The uses of drug-delivery systems in allergen specific immunotherapy appear to be a promising approach due to their ability to act as adjuvants, transport the allergens to immune-competent cells and tissues and reduce the number of administrations. The aim of this work was to evaluate the carbohydrate modified ultrafine ceramic core based nanoparticles (aquasomes) as adjuvant/delivery vehicle in specific immunotherapy using ovalbumin (OVA) as an allergen model. Prepared nanoparticles were characterized for size, shape, zeta potential, antigen integrity, surface adsorption efficiency and in vitro release. The humoral and cellular-induced immune responses generated by OVA adsorbed aquasomes were studied by two intradermal immunizations in BALB/c mice. OVA sensitized mice were treated with OVA adsorbed aquasomes and OVA adsorbed aluminum hydroxide following established protocol. Fifteen days after therapy, animals were challenged with OVA and different signs of anaphylactic shock were evaluated. Developed aquasomes possessed a negative zeta potential (-11.3 mV) and an average size of 47 nm with OVA adsorption efficiency of ~60.2 μg mg(-1) of hydroxyapatite core. In vivo immune response after two intradermal injections with OVA adsorbed aquasomes resulted in a mixed Th1/Th2-type immune response. OVA-sensitized mice model, treatment with OVA adsorbed aquasomes elicited lower levels of IgE (p<0.05), serum histamine and higher survival rate in comparison with alum adsorbed OVA. Symptoms of anaphylactic shock in OVA aquasome-treated mice were weaker than the one induced in the alum adsorbed OVA group. Results from this study demonstrate the valuable use of aquasomes in allergen immunotherapy. Copyright © 2011 Elsevier B.V. All rights reserved.
Chapman, Martin D; Briza, Peter
Molecular approaches to allergen standardization include the development of purified natural or recombinant allergen standards whose structural and allergenic properties have been validated, in tandem with certified immunoassays for allergen measurement. Purified allergens can be used individually or incorporated into multiple allergen standards. Multicenter international collaborative studies are required to validate candidate allergen standards and immunoassays, as a prelude to being approved by regulatory agencies. Mass spectrometry is a sophisticated and powerful proteomics tool that is being developed for allergen analysis. Recent results using pollen allergens show that mass spectrometry can identify and measure specific allergens in a complex mixture and can provide precise information of the variability of natural allergen extracts. In future, the combined use of immunoassays and mass spectrometry will provide complete standardization of allergenic products. Molecular standardization will form the basis of new allergy diagnostics and therapeutics, as well as assessment of environmental exposure, and will improve the quality of treatment options for allergic patients.
Knaysi, George; Smith, Anna R; Wilson, Jeffrey M; Wisniewski, Julia A
This second part of the article aims to highlight recent contributions in the literature that enhance our understanding of the cutaneous immune response to allergen. Several properties of allergens facilitate barrier disruption and cutaneous sensitization. There is a strong epidemiologic relationship between the microbiome, both the gut and skin, and atopic dermatitis (AD). The mechanisms connecting these two entities remain enigmatic; however, recent murine models show that commensal skin bacteria play an active role in supporting skin barrier homeostasis and defense against microbial penetration. Likewise, the association between the lack of colonization with Staph species and AD development suggests a potentially functional role for these organisms in regulating the skin barrier and response to environmental allergens. In undisrupted skin, evidence suggests that the cutaneous route may promote allergen tolerance. Properties of environmental allergens and commensal bacteria add to the complex landscape of skin immunity. Further investigation is needed to elucidate how these properties regulate the cutaneous immune response to allergen.
Alves, Rita C; Barroso, M Fátima; González-García, María Begoña; Oliveira, M Beatriz P P; Delerue-Matos, Cristina
Food allergens are a real threat to sensitized individuals. Although food labeling is crucial to provide information to consumers with food allergies, accidental exposure to allergenic proteins may result from undeclared allergenic substances by means of food adulteration, fraud or uncontrolled cross-contamination. Allergens detection in foodstuffs can be a very hard task, due to their presence usually in trace amounts, together with the natural interference of the matrix. Methods for allergens analysis can be mainly divided in two large groups: the immunological assays and the DNA-based ones. Mass spectrometry has also been used as a confirmatory tool. Recently, biosensors appeared as innovative, sensitive, selective, environmentally friendly, cheaper and fast techniques (especially when automated and/or miniaturized), able to effectively replace the classical methodologies. In this review, we present the advances in the field of food allergens detection toward the biosensing strategies and discuss the challenges and future perspectives of this technology.
Shrivastava, Pratima; Sarkar, Indranil; Atanley, Ethel; Gomis, Susantha; van Drunen Littel-van den Hurk, Sylvia
Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in infants and pneumonia virus of mice (PVM) causes similar disease. BALB/c mice are highly susceptible, while C57BL/6 mice are more resistant to PVM. IL-12 was significantly more up-regulated in response to PVM infection in BALB/c than in C57BL/6 mice. IL-12p40-deficient neonatal and adult BALB/c mice showed significantly less weight loss than wild-type mice after PVM challenge. The percentage of regulatory T cells, as well as IFN-β and IL-18 expression, was higher in the lungs of both neonatal and adult IL-12p40-/- mice. Adult IL-12p40-/- mice also showed enhanced TGF-β and IL-10 expression and reduced inflammatory responses. Furthermore, IL-12p40-/- mice showed decreased sensitization to inhaled cockroach antigen after PVM infection when compared to wild-type mice. In conclusion, these data suggest that a depressed regulatory capacity in BALB/c mice to PVM infection results in enhanced immunopathology and sensitization to allergen. Copyright © 2016 Elsevier Inc. All rights reserved.
Verhoeckx, Kitty C M; Vissers, Yvonne M; Baumert, Joseph L; Faludi, Roland; Feys, Marcel; Flanagan, Simon; Herouet-Guicheney, Corinne; Holzhauser, Thomas; Shimojo, Ryo; van der Bolt, Nieke; Wichers, Harry; Kimber, Ian
Food processing can have many beneficial effects. However, processing may also alter the allergenic properties of food proteins. A wide variety of processing methods is available and their use depends largely on the food to be processed. In this review the impact of processing (heat and non-heat treatment) on the allergenic potential of proteins, and on the antigenic (IgG-binding) and allergenic (IgE-binding) properties of proteins has been considered. A variety of allergenic foods (peanuts, tree nuts, cows' milk, hens' eggs, soy, wheat and mustard) have been reviewed. The overall conclusion drawn is that processing does not completely abolish the allergenic potential of allergens. Currently, only fermentation and hydrolysis may have potential to reduce allergenicity to such an extent that symptoms will not be elicited, while other methods might be promising but need more data. Literature on the effect of processing on allergenic potential and the ability to induce sensitisation is scarce. This is an important issue since processing may impact on the ability of proteins to cause the acquisition of allergic sensitisation, and the subject should be a focus of future research. Also, there remains a need to develop robust and integrated methods for the risk assessment of food allergenicity. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
In this presentation I intend to narrate a story that has its particular origins in three strategic decisions collectively taken, almost 20 years ago now, by a small group of educators within a small agricultural polytechnic located on the urban/rural fringe of Australia's largest city. It is a story which arises out of the integrated thoughts and actions of an academic community, which, tired of its marginal status, decided in the late 1970s, to profoundly and concurrently transform itself as a School of Agriculture in three fundamental ways: (a) to change its own focus from production agriculture to responsible rural development, (b) to change its own emphasis from a teaching approach based on courses to one of learning based on projects, and (c) to change its own prevailing reductionist paradigm to embrace an holistic one. The mission became one of helping people in rural communities across the state, to learn their way forward to better futures, in the face of the immensely complex, dynamic, and slowly degrading environments - socio-economic, politico-cultural and bio-physical - in which they increasingly recognised they were deeply embedded. The intent would thus become that of helping people to see their worlds differently as a prelude for doing things differently - essentially more systemically. The context for this grand enterprise is captured in the aphorism 'if we always see how we've always seen, we'll always be who we've always been'! Changing the way we collectively construe ourselves means collectively changing the way we think about ourselves, to lead in turn, to changing the way we collectively act.
Many philosophers ignore developments in the behavioral, cognitive, and neurosciences that purport to challenge our ideas of free will and responsibility. The reason for this is that the challenge is often framed as a denial of the idea that we are able to act differently than we do. However, most philosophers think that the ability to do otherwise is irrelevant to responsibility and free will. Rather it is our ability to act for reasons that is crucial. We argue that the scientific findings indicate that it is not so obvious that our views of free will and responsibility can be grounded in the ability to act for reasons without introducing metaphysical obscurities. This poses a challenge to philosophers. We draw the conclusion that philosophers are wrong not to address the recent scientific developments and that scientists are mistaken in formulating their challenge in terms of the freedom to do otherwise. PMID:21124755
Lechner, Christian J; Komander, Karl; Hegewald, Jana; Huang, Xiangsheng; Gantin, Richard G; Soboslay, Peter T; Agossou, Abram; Banla, Meba; Köhler, Carsten
In rural sub-Saharan Africa, endemic populations are often infected concurrently with several intestinal and intravascular helminth and protozoan parasites. A specific, balanced and, to an extent, protective immunity will develop over time in response to repeated parasite encounters, with immune responses initially being poorly adapted and non-protective. The cellular production of pro-inflammatory and regulatory cytokines and chemokines in response to helminth, protozoan antigens and ubiquitous allergens were studied in neonates, children, adults and the elderly. In children schistosomiasis prevailed (33%) while hookworm and Entamoeba histolytica/E. dispar was found in up to half of adults and the elderly. Mansonella perstans filariasis was only present in adults (24%) and the elderly (25%). Two or more parasite infections were diagnosed in 41% of children, while such polyparasitism was present in 34% and 38% of adults and the elderly. Cytokine and chemokine production was distinctively inducible by parasite antigens; pro-inflammatory Th2-type cytokine IL-19 was activated by Entamoeba and Ascaris antigens, being low in neonates and children while IL-19 production enhanced "stepwise" in adults and elderly. In contrast, highest production of MIP-1delta/CCL15 was present in neonates and children and inducible by Entamoeba-specific antigens only. Adults and the elderly had enhanced regulatory IL-27 cytokine responses, with Th2-type chemokines (MCP-4/CCL13, Eotaxin-2/CCL24) and cytokines (IL-33) being notably inducible by helminth- and Entamoeba-specific antigens and fungus-derived allergens. The lower cellular responsiveness in neonates and children highlighted the development of a parasite-specific cellular response profile in response to repeated episodes of exposure and re-infection. Following repeated exposure to parasites, and as a consequence of host inability to prevent or eliminate intestinal helminth or protozoa infections, a repertoire of immune responses
Comparison of the clinical efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension in the conjunctival allergen challenge model.
Berdy, Gregg J; Stoppel, Juan O; Epstein, Arthur B
Olopatadine hydrochloride 0.1% ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension are topical antiallergic agents indicated for treatment of the signs and symptoms of allergic conjunctivitis and seasonal allergic conjunctivitis (SAC), respectively. The purpose of this study was to compare the efficacy and tolerability of olopatadine, loteprednol, and placebo in inhibiting the early-phase allergic reaction (within 30 minutes) after conjunctival allergen challenge (CAC). This was a single-center, randomized, double-masked, parallel-controlled CAC study. It consisted of 3 visits, with CAC performed at visit 1, confirmation and randomization at visit 2, and evaluation of the treatments at visit 3. Subjects with a history of allergic conjunctivitis were randomized to receive olopatadine, loteprednol, or placebo in a 2:2:1 ratio. Because loteprednol requires a loading period to achieve maximum efficacy, subjects assigned to this treatment received loteprednol QID bilaterally for a 14-day period; the olopatadine and placebo groups received placebo QID bilaterally during this period. At the evaluation visit, subjects received 1 drop of the assigned treatment in each eye. Fifteen minutes later, they were challenged with allergen. Subjects evaluated itching at 3, 5, and 10 minutes after challenge using a standardized 5-point scale; the investigator evaluated redness at 10, 15, and 20 minutes after challenge. Intraocular pressure (IOP) was measured at baseline and after the 14-day loading period. Nonparametric analyses were performed on the change from visit 2 to visit 3 in mean itching and redness scores for each time point, and on the change in mean IOP from visit 1 to visit 3. Fifty subjects (86% white; 42% male, 58% female; age range, 21-71 years) were enrolled and completed the study (20 olopatadine, 20 loteprednol, 10 placebo). The allergens to which subjects reacted were ragweed pollen (40%), cat hair or dander (30%), grass pollen (24%), and tree
Yeung, J M; Applebaum, R S; Hildwine, R
The emergent health issue of food allergens presents an important challenge to the food industry. More than 170 foods have been reported in the scientific literature as causing allergic reactions. Clearly, it would be impossible to deal with the presence of trace amounts of all these in the context of food labeling. If the decision to classify major allergens is based solely on the knowledge and experience of allergists and food scientists in the field, without scientifically defined criteria, it is likely to lead to a proliferation of lists. Such practices may lead to an unnecessary elimination of foods containing important nutrients. This paper defines food allergy, food intolerance, and food anaphylaxis and identifies criteria for classifying food allergens associated with frequent allergic reactions. A practical list of food allergens that may result in potentially life-threatening allergic reactions is provided. A mechanism-based (i.e., immunoglobulin E mediated), acute life-threatening anaphylaxis that is standardized and measurable and reflects the severity of health risk is proposed as the principal inclusion criterion for food allergen labeling. Where available, prevalence in the population and threshold levels of allergens should be used as an additional guide to identify possible future labeling needs.
Delbourg, M F; Moneret-Vautrin, D A; Guilloux, L; Ville, G
Association between allergy to Ficus benjamina and Hevea brasiliensis, two botanically unrelated plants, was suspected in consequence of two clinical observations. Symptoms were rhinitis and asthma. This study was undertaken to assess the in vivo and in vitro cross-reactivity between Ficus benjamina and Hevea brasiliensis allergens. The two patients were asked about use and contact with latex devices and relationship between symptoms and Ficus benjamina exposure. Skin prick tests were performed with Ficus benjamina, Hevea brasiliensis extracts and common allergens. Double-blind nasal and bronchial challenge tests were done using the rinse fluid from a brand of latex gloves. Total and specific IgE antibodies to Ficus benjamina and Hevea brasiliensis were determined. In vitro cross-reactivity was investigated by means of CAP RAST and immunodot inhibition experiments. We observed that for the first patient the primary phenomenon is probably allergy to latex followed by allergy to Ficus benjamina. For the second patient, allergy to Ficus benjamina was diagnosed (improvement related to the avoidance of exposure to Ficus benjamina allergens) and positivity to latex skin prick tests may be due to the cross-reacting allergens. In vitro assays showed specific IgE antibodies to both allergens and cross-reactivity was confirmed in the two cases by reciprocal inhibition of the two extracts. The increasing risk of sensitization to widely used latex devices and extensive exposure to Ficus species in households and offices indicates increased allergenic risk from this newly recognized cross-reactivity.
Nelson, Harold S
Evidence for one airway continues to accumulate. Nasal allergen challenges increase lower airway inflammation, and nasal corticosteroid treatment reduces lower airway inflammation. Allergic respiratory inflammation might even spread systemically to involve nonrespiratory organs. Eosinophilic enteritis and eosinophilic esophagitis are reported during pollen seasons in patients with seasonal allergic rhinitis. Chronic hypertrophic sinusitis (CHS) is found in the majority of patients with asthma. Like asthma, the histology of CHS is characterized by epithelial damage, basement membrane thickening, and eosinophilic inflammation. The damaged epithelium might explain the acute bacterial exacerbations seen in patients with CHS. Studies have extended evidence of the safety and efficacy of the second- and third-generation antihistamines to younger children and to patients with perennial rhinitis but continue to show improvement of symptom scores over that seen with placebo of less than 20%. Studies on antihistamine use in the first trimester in nearly 500 women (65% taking loratadine) revealed no increase in the complications of pregnancy or congenital anomalies. Positive skin prick test responses to birch in asymptomatic young adults predicted later development of clinical allergic rhinitis. A dose response was demonstrated for immunotherapy with cat dander extract. The best results were in subjects receiving a dose containing 15 microg of the major cat allergen Fel d 1 (equivalent to approximately 2500 bioequivalent allergen units). Both topical intranasal immunotherapy and high-dose sublingual immunotherapy have been repeatedly proved to be safe and effective in double-blind, placebo-controlled studies. CD4+CD25+ regulatory T cells secreting IL-10, TGF-beta, or both appear important in normal individuals and in patients treated with allergen immunotherapy in maintaining or restoring normal T(H)1/T(H)2 balance and overall suppression of both phenotypes.
Rodríguez, Rosalía; Villalba, Mayte; Batanero, Eva; Palomares, Oscar; Salamanca, Guillermo
Numerous pollen allergens have been reported over the last few years. Most of them belong to well-known families of proteins but some others constitute the first member of new allergenic families. Some of the factors that can contribute to the detection and identification of new pollen allergens are: a) advances in the technology tools for molecular analysis; and b) the deep knowledge of many allergenic sources. The combination of these factors has provided vast information on the olive pollen allergogram and the identification of minor allergens that become major ones for a significant population. The close taxonomical relationship between olive tree and ash -both Oleaceae- has permitted to identify Fra e 1 (the Ole e 1-like allergen) in ash pollen and to detect the presence of protein homologues of Ole e 3 and Ole e 6. In the other hand, extensive areas of south Europe are suffering an increasing desertification. As a consequence of this, new botanical species are spontaneously growing in these areas or being used in greening ground programs: Chenopodium album and Salsola kali are some examples recently recognized as allergenic woods. The identification of the complete panel of allergens from the hypersensitizing sources might help to develop more accurate diagnosis, and efficient and safer therapy tools for Type-I allergic diseases.
De Blay, F; Bessot, J C; Pauli, G
As the number of proteins recognized as causing allergic respiratory diseases increases, new aero allergens have appeared in the animal and vegetable realms, both in home and professional environments. Lepidoglyphus destructor and Blomia tropicalis, two mites found in storage areas, are particularly important in agricultural areas and in homes. Over the last ten years, the frequency of reactions to cockroaches has also increased in several countries. The allergenicity of non-biting insects is a frequent cause of allergy in certain countries including Japan. Chironomides cause respiratory diseases in professional and outdoor environments. The important role of Alternaria, a mold, in producing severe asthma has also been demonstrated. The pathophysiology of pollen-induced asthma has been shown to result from pollen allergens carried by particles less than 5 microns in diameter. Cyprus and ash tree pollen also cause an increasing number of pollinoses and flowers can cause rhinitis and asthma. Respiratory allergy to Ficus benjamina inaugurated a new type of allergies caused airborne allergens from non-pollinating plants. Allergy to latex raises a particular problem for health care workers. The immunochemical structures of the major and minor airborne allergens are now better known and the homologous structures of different allergens largely explains certain cross-reactions. In the future, recombinant allergens will probably be used to better understand the role of allergens in inducing and maintaining the allergic reaction and should help in our approach to diagnosis and therapy.
Tater, Kathy C; Jackson, Hilary A; Paps, Judy; Hammerberg, Bruce
To determine the acute corn-specific serum IgE and IgG, total serum IgE, and clinical responses to s.c. administration of prophylactic vaccines and aluminum adjuvant in corn-allergic dogs. 20 allergic and 8 nonallergic dogs. 17 corn-allergic dogs were vaccinated. Eight clinically normal dogs also were vaccinated as a control group. Serum corn-specific IgE, corn-specific IgG, and total IgE concentrations were measured in each dog before vaccination and 1 and 3 weeks after vaccination by use of an ELISA. The corn-allergic dogs also had serum immunoglobulin concentrations measured at 8 and 9 weeks after vaccination. Twenty allergic dogs received a s.c. injection of aluminum adjuvant, and serum immunoglobulin concentrations were measured in each dog 1, 2, 3, 4, and 8 weeks after injection. The allergic dogs were examined during the 8 weeks after aluminum administration for clinical signs of allergic disease. The allergic dogs had significant increases in serum corn-specific IgE and IgG concentrations 1 and 3 weeks after vaccination but not 8 or 9 weeks after vaccination. Control dogs did not have a significant change in serum immunoglobulin concentrations after vaccination. After injection of aluminum adjuvant, the allergic dogs did not have a significant change in serum immunoglobulin concentrations or clinical signs. Allergen-specific IgE and IgG concentrations increase after prophylactic vaccination in allergic dogs but not in clinically normal dogs. Prophylactic vaccination of dogs with food allergies may affect results of serologic allergen-specific immunoglobulin testing performed within 8 weeks after vaccination.
Lin, Ching-Huei; Shen, Mei-Lin; Zhou, Ning; Lee, Chen-Chen; Kao, Shung-Te; Wu, Dong Chuan
Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.
Phase 3 Randomized Double-Masked Study of Efficacy and Safety of Once-Daily 0.77% Olopatadine Hydrochloride Ophthalmic Solution in Subjects With Allergic Conjunctivitis Using the Conjunctival Allergen Challenge Model.
McLaurin, Eugene; Narvekar, Abhijit; Gomes, Paul; Adewale, Adeniyi; Torkildsen, Gail
To assess the efficacy and safety of a novel once-daily 0.77% olopatadine hydrochloride ophthalmic solution in subjects with allergic conjunctivitis (AC) using the conjunctival allergen challenge (CAC) model. In this 5-week, multicenter, double-masked, phase 3, randomized trial, subjects aged ≥18 years with a history of AC and a confirmed positive bilateral CAC response were randomized 2:2:2:1 to receive olopatadine 0.77%, olopatadine 0.2%, olopatadine 0.1%, or vehicle, respectively, following a single topical dose in each eye. The primary objective was superiority of olopatadine 0.77% over all comparators on ocular itching according to a 0 to 4 scale (0 = none and 4 = incapacitating itch) at 24-hour duration of action and over vehicle only at the onset of action (3, 5, and 7 minutes after CAC for both). In total, 345 subjects were randomized. Olopatadine 0.77% was superior to the vehicle at alleviating ocular itching at all post-CAC time points at the onset of action and at 24 hours (difference in means: -0.9 to -1.5; P < 0.0001). Superiority in relieving ocular itching was also demonstrated for olopatadine 0.77% versus olopatadine 0.2% and 0.1% at 24 hours (difference in means: -0.3 to -0.5; P < 0.05). Additionally, olopatadine 0.77% significantly improved conjunctival redness and total redness compared with all comparators at the onset of action (differences in means: -0.3 to -0.6 and -0.8 to -2.0, respectively; both P < 0.05). No safety concerns for olopatadine 0.77% were identified. Olopatadine 0.77% demonstrated a rapid onset and prolonged duration of action. It was superior to all comparators in alleviating AC-associated ocular itching with a favorable safety profile.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01743027.
Linhart, Birgit; Valenta, Rudolf
Hundred years ago therapeutic vaccination with allergen-containing extracts has been introduced as a clinically effective, disease-modifying, allergen-specific and long-lasting form of therapy for allergy, a hypersensitivity disease affecting more than 25% of the population. Today, the structures of most of the disease-causing allergens have been elucidated and recombinant hypoallergenic allergen derivatives with reduced allergenic activity have been engineered to reduce side effects during allergen-specific immunotherapy (SIT). These recombinant hypoallergens have been characterized in vitro, in experimental animal models and in clinical trials in allergic patients. This review provides a summary of the molecular, immunological and preclinical evaluation criteria applied for this new generation of allergy vaccines. Furthermore, we summarize the mechanisms underlying SIT with recombinant hypoallergens which are thought to be responsible for their therapeutic effect. PMID:22100888
Matsuo, Hiroaki; Yokooji, Tomoharu; Taogoshi, Takanori
Food allergy is an adverse immune response to certain kinds of food. Although any food can cause allergic reactions, chicken egg, cow's milk, wheat, shellfish, fruit, and buckwheat account for 75% of food allergies in Japan. Allergen-specific immunoglobulin E (IgE) antibodies play a pivotal role in the development of food allergy. Recent advances in molecular biological techniques have enabled the efficient analysis of food allergens. As a result, many food allergens have been identified, and their molecular structure and IgE-binding epitopes have also been identified. Studies of allergens have demonstrated that IgE antibodies specific to allergen components and/or the peptide epitopes are good indicators for the identification of patients with food allergy, prediction of clinical severity and development of tolerance. In this review, we summarize our current knowledge regarding the allergens and IgE epitopes in the well-researched allergies to chicken egg, cow's milk, wheat, shrimp, and peanut.
Marogna, M; Massolo, A; Berra, D; Zanon, P; Chiodini, E; Canonica, G W; Passalacqua, G
Numerous factors affect the evolution of respiratory allergy, in children, but little is known in adults. We assessed in a prospective study the influence of the type of allergen on the progression of disease. Outpatients, with respiratory allergy underwent skin tests and pulmonary function/methacholine challenge at baseline and after 3 years. Patients were subdivided in pure rhinitis or rhinitis + bronchial hyperreactivity (BHR). In polysensitized subjects a single relevant allergen (mites, grasses, birch, Parietaria) was identified based on symptom distribution and when needed on nasal challenge. 6750 patients (age range 12-46) were studied. Of them, 17.8% were monosensitized but this percentage decreased to 10.4% after 3 years (P < 0.05). Subjects with pure rhinitis were 81% at the beginning and 48% at the end. After 3 years, the patients with bronchial responsiveness increased from 18% to 58% for mites, 22% to 49% for birch, 18% to 44% for grasses, 17% to 32% for Parietaria, with a significant difference among allergens (P < 0.05). Almost the same was seen in monosensitized subjects, being mites most likely to cause a worsening. All patients with BHR at baseline received immunotherapy. In these patients the onset of new sensitizations was significantly lower than in the group (pure rhinitis) receiving drugs only and lower airways symptoms disappeared more frequently. The different type of allergen influences the course of the disease, as well as the use of immunotherapy.
Berlin, Aaron A; Hogaboam, Cory M; Lukacs, Nicholas W
The progression and severity of chronic asthma likely depends upon the intensity of the damage and remodeling of the tissue. We have developed a chronic model of allergic asthma using multiple cockroach allergen challenges. Using this clinically relevant allergen we have established significant peribronchial fibrosis and mucus overproduction. These remodeling events are accompanied by intense peribronchial inflammation, including lymphocytes and eosinophils. A cytokine that has been identified as having a prominent role in short-term allergic events, stem cell factor (SCF), appears to have a significant role in this late-stage process. Using our polyclonal antibody specific for SCF administered into the airways of mice during the final allergen challenges, we find a significant effect on the chronic peribronchial allergen-induced fibrotic remodeling. This was characterized by reduced inflammation, especially eosinophils, as well as reduced hydroxyproline levels in anti-SCF compared to control antibody-treated animals. In addition, when we examined chemokines associated with the chronic disease and neutralized SCF in vivo we observed a corresponding decrease in CCL6 and CCL17. Using an inhibitor, imatinib mesylate, that blocks SCF/c-kit-associated RTK, we find similar results as with anti-SCF for attenuating AHR and fibrotic changes, suggesting that a potential clinical treatment for chronic asthma already exists related to this pathway. These results further support the potential use of SCF/c-kit inhibition for targeting chronic severe asthmatic responses.
Arruda, L Karla; Barbosa, Michelle C R; Santos, Ana Beatriz R; Moreno, Adriana S; Chapman, Martin D; Pomés, Anna
Molecular cloning of cockroach allergens and their expression as recombinant proteins have allowed a better understanding of the mechanisms of cockroach allergic disease. Recombinant cockroach allergens have been used for skin testing or in vitro methods to measure IgE antibody levels in serum. Early studies evaluating selected U.S. patients revealed that a cocktail of four cockroach allergens, Bla g 1, Bla g 2, Bla g 4, and Bla g 5, would identify 95 % of cockroach allergic patients. More recent studies pointed to an important role of sensitization to tropomyosin among certain populations, and suggested that a cocktail of five allergens Bla g 1 and/or Per a 1, Bla g 2, Bla g 4, Bla g 5, and Bla g 7, and/or Per a 7, would be expected to diagnose 50- 64 % of cockroach-allergic patients worldwide. Variation in IgE reactivity profiles could be in part due to IgE responses to cross-reactive homologous allergens from different origins. The availability of purified natural or recombinant cockroach allergens provides the capacity to improve diagnosis of cockroach allergy and to develop novel forms of immunotherapy for cockroach-allergic patients.
Lindgren, S; Belin, L; Dreborg, S; Einarsson, R; Påhlman, I
Fifty-one patients with clinical history of dog allergy were skin prick tested with eight individual standardized dog breed-allergen preparations, one mixed breed-allergen preparation (Poodle/Alsatian), dog-serum albumin, and histamine hydrochloride, 1 mg/ml. All extracts were characterized by crossed immunoelectrophoresis and crossed radioimmunoelectrophoresis with a pool of sera from patients clinically sensitive to dog. The dog-breed extracts contained common antigens/allergens, as well as components represented only in one or two dog-breed extracts. The concentration corresponding 1000 BU/ml varied from 16 to 100 micrograms of protein per milliliter. The sensitivity of skin prick test was 67% to 88% for the various dog breed-allergen preparations, but only 18% for dog-serum albumin. Significant difference between the skin test response to different dog breed-allergen preparations indicating dog breed-specific allergens was obtained in 15% of the patients. There was no significant correlation between skin prick test results and symptoms related to a specific dog breed.
Barbosa, Michelle C. R.; Santos, Ana Beatriz R.; Moreno, Adriana S.; Chapman, Martin D.; Pomés, Anna
Molecular cloning of cockroach allergens and their expression as recombinant proteins have allowed a better understanding of the mechanisms of cockroach allergic disease. Recombinant cockroach allergens have been used for skin testing or in vitro methods to measure IgE antibody levels in serum. Early studies evaluating selected U.S. patients revealed that a cocktail of four cockroach allergens, Bla g 1, Bla g 2, Bla g 4, and Bla g 5, would identify 95 % of cockroach allergic patients. More recent studies pointed to an important role of sensitization to tropomyosin among certain populations, and suggested that a cocktail of five allergens Bla g 1 and/or Per a 1, Bla g 2, Bla g 4, Bla g 5, and Bla g 7, and/or Per a 7, would be expected to diagnose 50–64 % of cockroach-allergic patients worldwide. Variation in IgE reactivity profiles could be in part due to IgE responses to cross-reactive homologous allergens from different origins. The availability of purified natural or recombinant cockroach allergens provides the capacity to improve diagnosis of cockroach allergy and to develop novel forms of immunotherapy for cockroach-allergic patients. PMID:24563284
Falagiani, P; Mistrello, G; Rapisarda, G; Festa, A; Cislaghi, C; Zanoni, D
The potency of allergenic extracts can be determined in vitro by RAST inhibition, and this has become the preferred method for the standardization of allergens. A disadvantage of this technique is the impossibility of obtaining data about allergens bound to the solid phase, i.e., the counterpart of the inhibiting extract. The REAST (reverse enzyme allergosorbent test) is based on the capture of IgE by a specific antibody bound to microtiter wells, the reaction of captured IgE with biotinylated allergen and the development of a colour reaction by subsequent addition of streptavidin-peroxidase and chromogenic substrate. The addition of an allergen extract in a dose-response fashion competes with the biotinylated allergen and inhibits the test. In the present study REAST inhibition has been evaluated with Dermatophagoides pteronyssinus, Parietaria judaica and mixed grass pollen extracts. The correlation of REAST inhibition with RAST inhibition and both intra-assay and inter-assay reproducibility have been evaluated. REAST inhibition is a potentially valuable new tool for the standardization of allergenic extracts.
Li, Pu; Cai, Qinhong; Lin, Weiyun; Chen, Bing; Zhang, Baiyu
Offshore oil spills are of tremendous concern due to their potential impact on economic and ecological systems. A number of major oil spills triggered worldwide consciousness of oil spill preparedness and response. Challenges remain in diverse aspects such as oil spill monitoring, analysis, assessment, contingency planning, response, cleanup, and decision support. This article provides a comprehensive review of the current situations and impacts of offshore oil spills, as well as the policies and technologies in offshore oil spill response and countermeasures. Correspondingly, new strategies and a decision support framework are recommended for improving the capacities and effectiveness of oil spill response and countermeasures. In addition, the emerging challenges in cold and harsh environments are reviewed with recommendations due to increasing risk of oil spills in the northern regions from the expansion of the Arctic Passage.
van de Veen, Willem; Wirz, Oliver F; Globinska, Anna; Akdis, Mübeccel
Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a clinical tolerance-inducing and immune tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms including early desensitization of basophils and mast cells, regulating T-cell and B-cell responses, changing antibody isotypes, and decreasing activation, mediator release and affected tissue migration of eosinophils, basophils, and mast cells. Similar molecular and cellular mechanisms have been observed in subcutaneous AIT, sublingual AIT and peptide immunotherapy as well as natural tolerance to high doses of allergen exposure in beekeepers and cat owners. Copyright © 2017 Elsevier Ltd. All rights reserved.
Pomés, A; Wünschmann, S; Hindley, J; Vailes, L D; Chapman, M D
Cockroach allergy is a widespread health problem in the world, associated with the development of asthma. The German and American cockroach species are important producers of a wide variety of allergens. Knowledge of their structure and function contributes to understand their role in allergy and to design tools for diagnosis and immunotherapy.
Mueller, Geoffrey A
Allergy is defined as an inappropriate immune response to something normally considered harmless. The symptomatic immune response is driven by IgE antibodies directed against allergens. The study of allergens has contributed significantly to our understanding of allergic disease in 3 main areas. First, identifying allergens as the cause of symptoms and developing allergen standards has led to many advances in exposure assessment and patient diagnostics. Second, a biochemical understanding of allergens has suggested a number of hypotheses related to the mechanisms of allergic sensitization. And finally, studies of allergen-antibody interactions have contributed to understanding the cross-reactivity of allergens, mapping patient epitopes, and the development of hypoallergens. In this review, a few select cases are highlighted where structural biology, in particular, has contributed significantly to allergen research and provided new avenues for investigation. © 2017 S. Karger AG, Basel.
This paper maps out the challenges and responses to inclusive education in Sweden from a cultural/historical point of view. Core concepts that have bearing on inclusive education practices are discussed. The analysis incorporates varied materials. As the current Swedish political and educational discourses reflect contradictions and dilemmas among…
Purpose. The purpose of this research was to further an understanding of how the federal government is addressing the challenges of interoperability for emergency response or crisis management (FEMA, 2009) by informing the development of standards through the review of current congressional law, commissions, studies, executive orders, and…
Rosenfeld, Melodie; Rosenfeld, Sherman
The research literature is just beginning to uncover factors involved in sustaining constructivist learning environments, such as Project-Based Learning (PBL). Our case study investigates teacher responses to the challenges of constructivist environments, since teachers can play strong roles in supporting or undermining even the best…
Purpose. The purpose of this research was to further an understanding of how the federal government is addressing the challenges of interoperability for emergency response or crisis management (FEMA, 2009) by informing the development of standards through the review of current congressional law, commissions, studies, executive orders, and…
Basketter, David; Poole, Alan; Kimber, Ian
Asthma resulting from sensitisation of the respiratory tract to chemicals is an important occupational health issue, presenting many toxicological challenges. Most importantly there are no recognised predictive methods for respiratory allergens. Nevertheless, it has been found that all known chemical respiratory allergens elicit positive responses in assays for skin sensitising chemicals. Thus, chemicals failing to induce a positive response in skin sensitisation assays such as the local lymph node assay (LLNA) lack not only skin sensitising activity, but also the potential to cause respiratory sensitisation. However, it is unclear whether it will be possible to regard chemicals that are negative in in vitro skin sensitisation tests also as lacking respiratory sensitising activity. To address this, the behaviour of chemical respiratory allergens in the LLNA and in recently validated non-animal tests for skin sensitisation have been examined. Most chemical respiratory allergens are positive in one or more newly validated non-animal test methods, although the situation varies between individual assays. The use of an integrated testing strategy could provide a basis for recognition of most respiratory sensitising chemicals. However, a more complete picture of the performance characteristics of such tests is required before specific recommendations can be made.
Curin, Mirela; Garib, Viktoriya; Valenta, Rudolf
To review the current knowledge regarding recombinant and purified allergens and allergen-derived peptides. PubMed, homepages relevant to the topic, and the National Institutes of Health clinical trial database were searched. The literature was screened for studies describing purified and recombinant allergens and allergen-derived peptides. Studies relevant to the topic were included in this review. Advantages and drawbacks of pure and defined recombinant allergens and peptides over allergen extracts in the context of allergy research, diagnosis, and allergen immunotherapy are discussed. We describe how these molecules are manufactured, which products are currently available on the market, and what the regulative issues are. We furthermore provide an overview of clinical studies with vaccines based on recombinant allergens and synthetic peptides. The possibility of prophylactic vaccination based on recombinant fusion proteins consisting of viral carrier proteins and allergen-derived peptides without allergenic activity are also discussed. During the last 25 years more than several hundred allergen sequences were determined, which led to a production of recombinant allergens that mimic biochemically and immunologically their natural counterparts. Especially in Europe, recombinant allergens are increasingly replacing allergen extracts in diagnosis of allergy. Despite many challenges, such as high cost of clinical trials and regulative issues, allergy vaccines based on recombinant allergens and peptides are being developed and will likely soon be available on the market. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens fol...
Rationale: An in vitro assay to identify respiratory sensitizers will provide a rapid screen and reduce animal use. The study goal was to identify biomarkers that differentiate allergen versus non-allergen responses following an acute exposure. Methods: Female BALB/c mice rec...
Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens fol...
Rationale: An in vitro assay to identify respiratory sensitizers will provide a rapid screen and reduce animal use. The study goal was to identify biomarkers that differentiate allergen versus non-allergen responses following an acute exposure. Methods: Female BALB/c mice rec...
Twaroch, Teresa E; Curin, Mirela; Swoboda, Ines
Allergic reactions to fungi were described 300 years ago, but the importance of allergy to fungi has been underestimated for a long time. Allergens from fungi mainly cause respiratory and skin symptoms in sensitized patients. In this review, we will focus on fungi and fungal allergens involved in respiratory forms of allergy, such as allergic rhinitis and asthma. Fungi can act as indoor and outdoor respiratory allergen sources, and depending on climate conditions, the rates of sensitization in individuals attending allergy clinics range from 5% to 20%. Due to the poor quality of natural fungal allergen extracts, diagnosis of fungal allergy is hampered, and allergen-specific immunotherapy is rarely given. Several factors are responsible for the poor quality of natural fungal extracts, among which the influence of culture conditions on allergen contents. However, molecular cloning techniques have allowed us to isolate DNAs coding for fungal allergens and to produce a continuously growing panel of recombinant allergens for the diagnosis of fungal allergy. Moreover, technologies are now available for the preparation of recombinant and synthetic fungal allergen derivatives which can be used to develop safe vaccines for the treatment of fungal allergy. PMID:25840710
Fisher, Thomas M.
Points out the health and legal implications related to laboratory substances that could cause allergic reactions. Presents a list of potential cosmetic allergens and irritants. Includes precautionary measures dealing with allergy situations. (ML)
Fisher, Thomas M.
Points out the health and legal implications related to laboratory substances that could cause allergic reactions. Presents a list of potential cosmetic allergens and irritants. Includes precautionary measures dealing with allergy situations. (ML)
Nasser, Shuaib M; Pulimood, Thomas B
Thunderstorm-related asthma is increasingly recognized in many parts of the world. This review focuses on important advances in the understanding of the mechanism of the role of allergens, in particular fungal spores such as Alternaria, in asthma epidemics associated with thunderstorms. From our observations, we have proposed that the prerequisites for this phenomenon are as follows: 1) a sensitized, atopic, asthmatic individual; 2) prior airway hyperresponsiveness before a sudden, large allergen exposure; 3) a large-scale thunderstorm with cold outflow occurring at a time and location during an allergen season in which large numbers of asthmatics are outdoors; and 4) sudden release of large amounts of respirable allergenic fragments, particularly fungal spores such as Alternaria.
It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a "mirror" inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer's disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders.
Lupinek, Christian; Wollmann, Eva; Baar, Alexandra; Banerjee, Srinita; Breiteneder, Heimo; Broecker, Barbara M; Bublin, Merima; Curin, Mirela; Flicker, Sabine; Garmatiuk, Tetiana; Hochwallner, Heidrun; Mittermann, Irene; Pahr, Sandra; Resch, Yvonne; Roux, Kenneth H; Srinivasan, Bharani; Stentzel, Sebastian; Vrtala, Susanne; Willison, Leanna N; Wickman, Magnus; Lødrup-Carlsen, Karin C; Antó, Josep Maria; Bousquet, Jean; Bachert, Claus; Ebner, Daniel; Schlederer, Thomas; Harwanegg, Christian; Valenta, Rudolf
Allergy diagnosis based on purified allergen molecules provides detailed information regarding the individual sensitization profile of allergic patients, allows monitoring of the development of allergic disease and of the effect of therapies on the immune response to individual allergen molecules. Allergen microarrays contain a large variety of allergen molecules and thus allow the simultaneous detection of allergic patients' antibody reactivity profiles towards each of the allergen molecules with only minute amounts of serum. In this article we summarize recent progress in the field of allergen microarray technology and introduce the MeDALL allergen-chip which has been developed for the specific and sensitive monitoring of IgE and IgG reactivity profiles towards more than 170 allergen molecules in sera collected in European birth cohorts. MeDALL is a European research program in which allergen microarray technology is used for the monitoring of the development of allergic disease in childhood, to draw a geographic map of the recognition of clinically relevant allergens in different populations and to establish reactivity profiles which are associated with and predict certain disease manifestations. We describe technical advances of the MeDALL allergen-chip regarding specificity, sensitivity and its ability to deliver test results which are close to in vivo reactivity. In addition, the usefulness and numerous advantages of allergen microarrays for allergy research, refined allergy diagnosis, monitoring of disease, of the effects of therapies, for improving the prescription of specific immunotherapy and for prevention are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.
Vickery, Brian P.; Lin, Jing; Kulis, Michael; Fu, Zhiyan; Steele, Pamela H.; Jones, Stacie M.; Scurlock, Amy M.; Gimenez, Gustavo; Bardina, Ludmilla; Sampson, Hugh A.; Burks, A. Wesley
Background Peanut-allergic subjects have highly stable pathologic antibody repertoires to the immunodominant B cell epitopes of the major peanut allergens Ara h 1-3. Objective We used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires. Methods Measurements of total peanut-specific IgE (psIgE) and psIgG4 were made with CAP-FEIA. We analyzed sera from 22 OIT subjects and 6 controls and measured serum specific IgE and IgG4 binding to epitopes of Ara h 1-3 using a high-throughput peptide microarray technique. Antibody affinity was measured using a competitive peptide microarray as previously described. Results At baseline, psIgE and psIgG4 diversity were similar between subjects and controls, and there was broad variation in epitope recognition. After a median 41 months of OIT, polyclonal psIgG4 increased from a median 0.3 mcg/mL (IQR 0.1-0.43) at baseline to 10.5 mcg/mL (3.95-45.48) (p<0.0001) and included de novo specificities. PsIgE was reduced from a median baseline of 85.45 kUA/L (23.05-101.0) to 7.75 kUA/L (2.58-30.55) (p<0.0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated subjects, several subjects generated new IgE specificities even as the total psIgE decreased. Global epitope-specific shifts from IgE to IgG4 binding occurred, including at an informative epitope of Ara h 2. Conclusion OIT differentially alters Ara h 1-3 binding patterns. These changes are variable between subjects, not observed in controls, and include a progressive polyclonal increase in IgG4, with concurrent reduction in IgE amount and diversity. PMID:23199605
Burge, H.A. )
Monitoring for allergens can provide some information on the kinds and levels of exposure experienced by local patient populations, providing volumetric methods are used for sample collection and analysis is accurate and consistent. Such data can also be used to develop standards for the specific environment and to begin to develop predictive models. Comparing outdoor allergen aerosols between different monitoring sites requires identical collection and analysis methods and some kind of rational standard, whether arbitrary, or based on recognized health effects.32 references.
Kornerup, Kristin N; Page, Clive P; Moffatt, James D
The effect of adenosine on transepithelial ion transport was investigated in isolated preparations of murine trachea mounted in Ussing chambers. The possible regulation of adenosine receptors in an established model of allergic airway inflammation was also investigated. Mucosally applied adenosine caused increases in short-circuit current (ISC) that corresponded to approximately 50% of the response to the most efficacious secretogogue, ATP (ΔISC 69.5±6.7 μA cm2). In contrast, submucosally applied adenosine caused only small (<20%) increases in ISC, which were not investigated further. The A1-selective (N6-cyclopentyladenosine, CPA, 1 nM–10 μM), A2A-selective (2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxoamido adenosine; CGS 21680; 0.1–100 μM) and A3-selective (1-deoxy-1-[6-[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide; IB-MECA; 30 nM–100 μM) adenosine receptor agonists were either equipotent or less potent than adenosine, suggesting that these receptors do not mediate the response to adenosine. The A1 receptor selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 10 nM–1 μM) caused a rightward shift of the adenosine concentration–effect curve only at 1 μM. The mixed A2A/A2B receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) also caused rightward shift of the adenosine concentration–effect curve, again only at micromolar concentrations, suggestive of the involvement of A2B receptors. In preparations from animals sensitised to ovalbumin and challenged over 3 days with aerosol ovalbumin, a decrease in baseline ISC was observed and responses to ATP were diminished. Similarly, the amplitude of responses to adenosine were attenuated although there was no change in potency. These results suggest that the A2B receptor mediates the ISC response to adenosine in the mouse trachea. This receptor does not appear to be
Kornerup, Kristin N; Page, Clive P; Moffatt, James D
The effect of adenosine on transepithelial ion transport was investigated in isolated preparations of murine trachea mounted in Ussing chambers. The possible regulation of adenosine receptors in an established model of allergic airway inflammation was also investigated. Mucosally applied adenosine caused increases in short-circuit current (I(SC)) that corresponded to approximately 50% of the response to the most efficacious secretogogue, ATP (delta I(SC) 69.5 +/- 6.7 microA cm2). In contrast, submucosally applied adenosine caused only small (<20%) increases in I(SC), which were not investigated further. The A1-selective (N6-cyclopentyladenosine, CPA, 1 nM-10 microM), A2A-selective (2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxoamido adenosine; CGS 21680; 0.1-100 microM) and A3-selective (1-deoxy-1-[6-[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-N-methyl-beta-D-ribofuranuronamide; IB-MECA; 30 nM-100 microM) adenosine receptor agonists were either equipotent or less potent than adenosine, suggesting that these receptors do not mediate the response to adenosine. The A1 receptor selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 10 nM-1 microM) caused a rightward shift of the adenosine concentration-effect curve only at 1 microM. The mixed A2A/A2B receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) also caused rightward shift of the adenosine concentration-effect curve, again only at micromolar concentrations, suggestive of the involvement of A2B receptors. In preparations from animals sensitised to ovalbumin and challenged over 3 days with aerosol ovalbumin, a decrease in baseline I(SC) was observed and responses to ATP were diminished. Similarly, the amplitude of responses to adenosine were attenuated although there was no change in potency. These results suggest that the A2B receptor mediates the I(SC) response to adenosine in the mouse trachea. This receptor does not appear to be
Harris, J M; Williams, H C; White, C; Moffat, S; Mills, P; Newman Taylor, A J; Cullinan, P
The relationship between exposure to indoor aeroallergens in early life and subsequent eczema is unclear. We have previously failed to show any significant associations between early life exposure to house dust mite and cat fur allergens and either sensitization to these allergens or wheeze. We have also previously reported a lower prevalence of parent-reported, doctor-diagnosed eczema by age 2 years for children exposed to higher concentrations of house dust mite, but no other associations with other definitions of eczema or for exposure to cat allergen. To extend the exposure-response analysis of allergen exposure and eczema outcomes measured up to age 8 years, and to investigate the role of other genetic and environmental determinants. A total of 593 children (92 x 4% of those eligible) born to all newly pregnant women attending one of three general practitioner surgeries in Ashford, Kent, were followed from birth to age 8 years. Concentrations of house dust mite and cat allergen were measured in dust samples collected from the home at 8 weeks after birth. The risk of subsequent eczema as defined by the U.K. diagnostic criteria was determined according to different levels (quintiles) of allergen exposure at birth. By age 8 years, 150 (25 x 3%) children had met the diagnostic criteria for eczema at least once. Visible flexural dermatitis was recorded at least once for 129 (28 x 0%). As in other studies, parental allergic history was positively associated with most eczema outcomes, as were higher maternal education and less crowded homes. No clear linear associations between early exposure to house dust mite or cat allergen were found, regardless of the definition of eczema used. The risk of eczema appeared to increase for the three lowest quintiles of house dust mite allergen exposure (odds ratio, OR 1 x 37 for third quintile compared with first), and then to fall for the two highest quintiles (OR 0 x 66 and 0 x 71) even after controlling for confounding factors
Coloe, Jacquelyn; Zirwas, Matthew J
Whereas allergy to vehicle ingredients (ie, excipients and preservatives) in topical steroid vehicles is well recognized, there are no data regarding which vehicle ingredients are in common use or on which vehicles and active molecules are associated with which ingredients. To produce descriptive data on the use of allergenic vehicle ingredients in prescription topical corticosteroids. The package insert for every steroid in widespread use in the United States was obtained from the manufacturer and used to generate an ingredient list for the product. There are seven vehicle ingredients that are commonly used in topical corticosteroid vehicles that are well-known allergens: propylene glycol, sorbitan sesquioleate, formaldehyde-releasing preservatives, parabens, methylchloroisothiazolinone/methylisothiazolinone, lanolin, and fragrance. Of 166 topical corticosteroids, 128 (including all creams) had at least one of these vehicle ingredients. More generic products were free of allergens than were branded products. Solutions and ointments were the least allergenic vehicles. The most commonly present potential allergens were propylene glycol and sorbitan sesquioleate. Most prescription topical corticosteroids have the potential to cause allergic contact dermatitis owing to vehicle ingredients. Dermatologists should be aware of this possibility and should consider prescribing agents that do not contain potentially allergenic vehicle ingredients.
Allergen-specific immunotherapy (allergen-SIT) is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg) cells and inducible IL-10- and TGF-β-producing type 1 Treg (Tr1) cells may prevent the development of allergic diseases and play a role in successful allergen-SIT and healthy immune response via several mechanisms. The mechanisms of suppression of different pro-inflammatory cells, such as eosinophils, mast cells and basophils and the development of allergen tolerance also directly or indirectly involves Treg cells. Furthermore, the formation of non-inflammatory antibodies particularly IgG4 is induced by IL-10. Knowledge of these molecular basis is crucial in the understanding the regulation of immune responses and their possible therapeutic targets in allergic diseases. PMID:22409879
Martín-Muñoz, M F; Diaz-Perales, A; Cannabal, J; Quirce, S
More than 170 foods have been identified as being potentially allergenic. However, a minority of these foods cause the majority of reactions. Sweets are frequently implicated in allergic reactions in children with cow's milk, egg, nuts or fruits allergy, and they are the most relevant foods investigated as responsible allergens. We report an anaphylactic reaction to candies in an egg and peach allergic boy. We performed a study to identify responsible allergens for the reaction. We investigated hidden egg and peach allergens in the candies, but they were not found. Finally, the causative allergen resulted to be a vegetable protein from potato peel. We diagnosed a new allergy in our patient and Sol t 4 was identified as the responsible allergen of the anaphylactic reaction. We conclude that responsible allergens should always be studied and identified in whatever allergic reaction in order to prevent new reactions.
Pham, John; Oseroff, Carla; Hinz, Denise; Sidney, John; Paul, Sinu; Greenbaum, Jason; Vita, Randi; Phillips, Elizabeth; Mallal, Simon; Peters, Bjoern; Sette, Alessandro
Background Ragweed is a major cause of seasonal allergy, affecting millions of people worldwide. Several allergens have been defined based on IgE reactivity, but their relative immunogenicity in terms of T cell responses has not been studied. Objective We comprehensively characterized T cell responses from atopic, ragweed-allergic subjects to Amb a 1, Amb a 3, Amb a 4, Amb a 5, Amb a 6, Amb a 8, Amb a 9, Amb a 10, Amb a 11, and Amb p 5, and examined their correlation with serological reactivity and sequence conservation in other allergens. Methods Peripheral blood mononuclear cells (PBMCs) from donors positive for IgE toward ragweed extracts after in vitro expansion for secretion of IL-5 (a representative Th2 cytokine) and IFNγ (Th1) in response to a panel of overlapping peptides spanning the above listed allergens. Results Three previously identified dominant T cell epitopes (Amb a 1 176–191, 200–215, and 344–359) were confirmed and three novel dominant epitopes (Amb a 1 280–295, 304–319, and 320–335) were identified. Amb a 1, the dominant IgE allergen, was also the dominant T cell allergen, but dominance patterns for T cell and IgE responses for the other ragweed allergens did not correlate. Dominance for T cell responses correlated with conservation of ragweed epitopes with sequences of other well-known allergens. Conclusion and clinical relevance These results provide the first assessment of the hierarchy of T cell reactivity in ragweed allergens, which is distinct from that observed for IgE reactivity and influenced by T cell epitope sequence conservation. The results suggest that ragweed allergens associated with lesser IgE reactivity and significant T cell reactivity may be targeted for T cell immunotherapy, and further support the development of immunotherapies against epitopes conserved across species to generate broad reactivity against many common allergens. PMID:27359111
Thomas, Wayne R
The allergenic load of house dust mite allergy is largely constituted by a few proteins with a hierarchical pattern of allergenicity. The serodominant specificities are the group 1&2 and the group 23 faecal allergens. The collective IgE binding to the group 1&2 allergens can measure unequivocal HDM sensitisation better than HDM extracts although discrepancies have been found in regions with complex acarofauna suggesting a need to investigate the specificity with allergen components. The group 4, 5, 7&21 allergens that each induce responses in about 40% of subjects are mid-tier allergens accounting for most of the remaining IgE binding. Their titres are proportional to the concomitant responses to Der p1&2. Group 2 allergen variants have different antibody binding. Body proteins only occasionally induce sensitisation although a higher prevalence of binding by atopic dermatitis patients provides a new avenue of research. A broad spectrum of IgE binding has been associated with diverse symptoms but not with the severity of asthma which is associated with low IgG antibody. Some allergens such as the group 14 large lipid binding proteins and the recently described proteins Der f 24-33, need further investigation but with the cognoscence that other denominated allergens have been found to be minor sensitisers by comparative quantitative analyses. Scabies is a confounder for diagnosis with extracts, inducing cross-reactive antibodies with Der p 4&20 as is seafood allergy with cross reactivity to Der p 10 a minor HDM allergen. The HDM genome sequence can now be used to verify allelic and paralogous variations.
Martín-Muñoz, M F; Pineda, F; García Parrado, G; Guillén, D; Rivero, D; Belver, T; Quirce, S
Food allergy is a rare disorder among breastfeeding babies. Our aim was to identify responsible allergens in human milk. We studied babies developing allergic symptoms at the time they were breastfeeding. Skin prick tests (SPT) were performed with breast milk and food allergens. Specific IgE was assessed and IgE Immunoblotting experiments with breast milk were carried out to identify food allergens. Clinical evolution was evaluated after a maternal free diet. Five babies had confirmed breast milk allergy. Peanut, white egg and/or cow's milk were demonstrated as the hidden responsible allergens. No baby returned to develop symptoms once mother started a free diet. Three of these babies showed tolerance to other food allergens identified in human milk. A maternal free diet should be recommended only if food allergy is confirmed in breastfed babies.
Charpin, D; Vervloet, D
There is a qualitative as well as a quantitative change in allergen exposure. From a qualitative viewpoint, the relevance of some allergens (domestic allergens i.e. cockroaches, outdoor allergens i.e. plane tree, chestnut and ash tree pollens) has been established. The role of some other allergens has been, strictly speaking, discovered: latex from Hevea and ficus, trichophyton mold, some occupational allergens and very recently transgenic allergens. From a quantitative viewpoint, the concentration and/or distribution of some allergens has increased. Plantation of numerous trees or fortuitous introduction of weeds has led to an increased specific sensitization. In like manner, introduction of new foods or food processing procedures has created new food allergens and allergy. Besides, the distribution of some well-known aero-allergens is better known since discovery of ELISA--technology allowing measurements of minute amounts of these allergens. A burning issue today is to know whether irritant factors could modify allergens. Few data, sometimes contradictory, are available in the field of interaction between air pollutants and allergens.
Datta, Ankur; Moitra, Saibal; Hazra, Iman; Mondal, Somnath; Das, Prasanta Kumar; Singh, Manoj Kumar; Chaudhuri, Suhnrita; Bhattacharya, Debanjan; Tripathi, Santanu Kumar; Chaudhuri, Swapna
Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of FcɛRI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, FcɛRI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities. Copyright © 2015 Elsevier B.V. All rights reserved.
Karp, Christopher L
Why specific, ubiquitous, otherwise innocuous environmental proteins tend to provoke maladaptive, T(H)2-polarized immune responses in susceptible hosts is a fundamental mechanistic question for those interested in the pathogenesis, therapy, and prevention of allergic disease. The current renaissance in the study of innate immunity has provided important insights into this question. The theme emerging from recent studies is that direct (dys)functional interactions with pathways of innate immune activation that evolved to signal the presence of microbial infection are central to the molecular basis for allergenicity. This article reviews these data. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Rhee, Chae-Seo; Libet, Lev; Chisholm, Dugald; Takabayashi, Kenji; Baird, Stephen; Bigby, Timothy D; Lee, Chul Hee; Horner, Anthony A; Raz, Eyal
While effective for the prevention and treatment of allergic rhinitis (AR) symptoms, currently available medications do not reverse allergen specific hypersensitivities. Therefore, pharmacotherapeutics are not curative and their daily use is often required for years. These investigations were conducted to determine whether immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) delivery protects previously sensitized mice from AR hypersensitivity responses and modulates their allergen specific immune profiles. Mice were first sensitized with ovalbumin (OVA) and alum, twenty-four hr before beginning a series of seven daily intranasal (i.n.) allergen challenges, subsets of mice received a single i.n. or intradermal (i.d.) dose of ISS-ODN or control oligodeoxynucleotide (C-ODN), a single intraperitoneal (i.p.) injection of dexamethasone (DXM), or no intervention. Mice receiving i.d. or i.n. ISS-ODN were found to have attenuated immediate and late phase effector cell responses to i.n. OVA challenge. Specifically, ISS-ODN treated mice had less histamine and cysteinyl leukotriene release and eosinophilic inflammation in their nasal passages than mice treated with C-ODN. In addition, splenocytes from ISS-ODN but not C-ODN treated mice displayed attenuated OVA-specific interleukin (IL)-4, IL-5, and IL-13 but increased interferon-gamma responses. Finally, ISS-ODN was generally a more effective treatment than DXM, both in blunting AR hypersensitivity responses and in shifting T helper 2 Th2-biased immune parameters towards Th1 dominance. As ISS-ODN delivery rapidly attenuated effector cell responses in this AR model in an allergen independent manner, the present results suggest that therapy with ISS-ODN alone may be an effective alternative to corticosteroid medications for the clinical management of AR.
Kelada, Samir N. P.; Wilson, Mark S.; Tavarez, Urraca; Kubalanza, Kari; Borate, Bhavesh; Whitehead, Greg S.; Maruoka, Shuichiro; Roy, Michelle G.; Olive, Michelle; Carpenter, Danielle E.; Brass, David M.; Wynn, Thomas A.; Cook, Donald N.; Evans, Christopher M.; Schwartz, David A.
Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the strain-dependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1–challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein–coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain–dependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the down-modulation of expression of G-protein–coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation. PMID:21378263
Sinha, Mau; Singh, Rashmi Prabha; Kushwaha, Gajraj Singh; Iqbal, Naseer; Singh, Avinash; Kaushik, Sanket; Kaur, Punit; Sharma, Sujata; Singh, Tej P
Pathogenesis related (PR) proteins are one of the major sources of plant derived allergens. These proteins are induced by the plants as a defense response system in stress conditions like microbial and insect infections, wounding, exposure to harsh chemicals, and atmospheric conditions. However, some plant tissues that are more exposed to environmental conditions like UV irradiation and insect or fungal attacks express these proteins constitutively. These proteins are mostly resistant to proteases and most of them show considerable stability at low pH. Many of these plant pathogenesis related proteins are found to act as food allergens, latex allergens, and pollen allergens. Proteins having similar amino acid sequences among the members of PR proteins may be responsible for cross-reactivity among allergens from diverse plants. This review analyzes the different pathogenesis related protein families that have been reported as allergens. Proteins of these families have been characterized in regard to their biological functions, amino acid sequence, and cross-reactivity. The three-dimensional structures of some of these allergens have also been evaluated to elucidate the antigenic determinants of these molecules and to explain the cross-reactivity among the various allergens.
Sinha, Mau; Singh, Rashmi Prabha; Kushwaha, Gajraj Singh; Iqbal, Naseer; Singh, Avinash; Kaushik, Sanket; Sharma, Sujata; Singh, Tej P.
Pathogenesis related (PR) proteins are one of the major sources of plant derived allergens. These proteins are induced by the plants as a defense response system in stress conditions like microbial and insect infections, wounding, exposure to harsh chemicals, and atmospheric conditions. However, some plant tissues that are more exposed to environmental conditions like UV irradiation and insect or fungal attacks express these proteins constitutively. These proteins are mostly resistant to proteases and most of them show considerable stability at low pH. Many of these plant pathogenesis related proteins are found to act as food allergens, latex allergens, and pollen allergens. Proteins having similar amino acid sequences among the members of PR proteins may be responsible for cross-reactivity among allergens from diverse plants. This review analyzes the different pathogenesis related protein families that have been reported as allergens. Proteins of these families have been characterized in regard to their biological functions, amino acid sequence, and cross-reactivity. The three-dimensional structures of some of these allergens have also been evaluated to elucidate the antigenic determinants of these molecules and to explain the cross-reactivity among the various allergens. PMID:24696647
Cao, Sishuo; He, Xiaoyun; Xu, Wentao; Luo, Yunbo; Ran, Wenjun; Liang, Lixing; Dai, Yunqing; Huang, Kunlun
With the development of genetically modified crops, there has been a growing interest in available approaches to assess the potential allergenicity of novel gene products. We were not sure whether Cry1C could induce allergy. We examined the protein with three other proteins to determine the potential allergenicity of Cry1C protein from genetically modified rice. Female Brown Norway (BN) rats received 0.1 mg peanut agglutinin (PNA), 1mg potato acid phosphatase (PAP), 1mg ovalbumin (OVA) or 5 mg purified Cry1C protein dissolved in 1 mL water by daily gavage for 42 days to test potential allergenicity. Ten days after the last gavage, rats were orally challenged with antigens, and physiologic and immunologic responses were studied. In contrast to sensitization with PNA, PAP and OVA Cry1C protein did not induce antigen-specific IgG2a in BN rats. Cytokine expression, serum IgE and histamine levels and the number of eosinophils and mast cells in the blood of Cry1C group rats were comparable to the control group rats, which were treated with water alone. As Cry1C did not show any allergenicity, we make the following conclusion that the protein could be safety used in rice or other plants.
Flicker, Sabine; Linhart, Birgit; Wild, Carmen; Wiedermann, Ursula; Valenta, Rudolf
IgE antibody-mediated allergies affect more than 25% of the population worldwide. To investigate therapeutic and preventive effects of passive immunization with allergen-specific IgG antibodies on allergy in mouse models we used clinically relevant pollen allergens. In a treatment model, mice were sensitized to the major birch pollen allergen Bet v 1 and to the major grass pollen allergens, Phl p 1 and Phl p 5 and then received passive immunization with rabbit IgG antibodies specific for the sensitizing or an unrelated allergen. In a prevention model, mice obtained passive immunization with allergen-specific rabbit IgG before sensitization. Kinetics of the levels of administered IgG antibodies, effects of administered allergen-specific IgG on allergen-specific IgE reactivity, the development of IgE and IgG responses and on immediate allergic reactions were studied by ELISA, rat basophil leukaemia degranulation assays and skin testing, respectively. Treated mice showed an approximately 80% reduction of allergen-specific IgE binding and basophil degranulation which was associated with the levels of administered allergen-specific IgG antibodies. Preventive administration of allergen-specific IgG antibodies suppressed the development of allergen-specific IgE and IgG1 antibody responses as well as allergen-induced basophil degranulation and skin reactivity. Our results show that passive immunization with allergen-specific IgG antibodies is effective for treatment and prevention of allergy to clinically important pollen allergens in a mouse model and thus may pave the road for the clinical application of allergen-specific antibodies in humans. PMID:23182706
Cho, Min Kyoung; Park, Mi Kyung; Kang, Shin Ae; Caballero, Maria Luisa; Perez-Pinar, Teresa; Rodriguez-Perez, Rosa; Ock, Mee Sun; Cha, Hee Jae; Hong, Yeon Chul; Yu, Hak Sun
Anisakis (Anisakidae) is one of the most important causes of helminth-induced allergic reactions and elicits clinical responses that include urticaria, rhinitis, bronco-constriction, cough, and/or gastrointestinal symptoms. More than 13 reactive allergens have been identified in the serum of Anisakis allergy patients, but the allergenicity of only a few of these have been evaluated in vivo using a mouse model. To evaluate the allergenicity of two important allergens, Ani s 1 and Ani s 9, we induced experimental allergic airway inflammation in a mouse model by repeated intranasal administration of the allergens. Both recombinant proteins (rAni s 1 and rAni s 9) elicited increased airway hyperresponsivity, airway infiltration by inflammatory cells (especially eosinophils), bronchial epithelial cell hyperplasia, all of which are characteristic of allergic airway inflammation. These allergens significantly increased the levels of Th2-related cytokines (IL-4, IL-5, IL-13, and IL-25) and Th17 related cytokines (IL-6 and IL-17) in both splenocytes and airway (except IL-17 in airway by rAni s 9). OVA-specific IgE and total IgE were increased in rAni s 1 and rAni s 9 treated mice as compared with controls treated with OVA alone. In addition, these two allergens induced gene expression of thymic stromal lymphopoietin (TSLP) and IL-25 (initiators of the Th2 response), as well as CXCL1 (initiator of the Th17 response) in mouse lung epithelial cells. In conclusion, repeated intranasal treatments with rAni s 1 and rAni s 9 induced airway inflammation in mice by elevating of Th2 and Th17 responses in the lung.
Macchiaverni, Patricia; Ynoue, Leandro H.; Arslanian, Christina; Verhasselt, Valérie; Condino-Neto, Antonio
The relationship between allergen exposure and the onset of or protection from allergic diseases remains unclear. Many factors could be related to immunological responses, such as the age when the exposure occurs, type of allergen, timing, dose, and allergen route. In this study, we investigated whether exposure to respiratory allergens could occur in pregnancy or early life. In particular, we assessed whether Der p 1 and Blo t 5, as well as specific antibodies against these allergens, could be detected in 90 paired cord blood and colostrum samples. Der p 1 was detected in 58.6% of colostrum and 29% of cord blood samples, whereas Blot 5 was positive in 41.3% and 9.6% of the samples, respectively. Similar to specific IgA, which could be detected in all samples for both mites, specific IgG was found in a high number of colostrum samples, 93.5% and 94.8% for Dp and Bt, respectively. Although allergens were not detected in all cord blood samples, a high percentage of them (≥95%) were positive for specific IgM to both mites in cord blood samples, suggesting that neonates can be exposed and sensitized to airborne allergens during pregnancy. Many studies have attempted to correlate allergen exposure or its prevention in early infancy with the onset of or protection from allergic diseases. However, conflicting and inconsistent data do not show a clear correlation with or suggest a way to prevent allergen sensitization. Nevertheless, these unconvincing results could be better understood if the relationship with many aspects of allergen exposure after pregnancy could be clarified. Thus, it is necessary to address basic issues related to allergen exposure, including the development of reproducible, standardized and reliable methods, and to determine how and where the exposure occurs. PMID:26398234
Ryan, D; Gerth van Wijk, R; Angier, E; Kristiansen, M; Zaman, H; Sheikh, A; Cardona, V; Vidal, C; Warner, A; Agache, I; Arasi, S; Fernandez-Rivas, M; Halken, S; Jutel, M; Lau, S; Pajno, G; Pfaar, O; Roberts, G; Sturm, G; Varga, E M; Van Ree, R; Muraro, A
The European Academy of Allergy and Clinical Immunology (EAACI) has produced Guidelines on Allergen Immunotherapy (AIT). We sought to gauge the preparedness of primary care to participate in the delivery of AIT in Europe. We undertook a mixed-methods, situational analysis. This involved a purposeful literature search, and two surveys: one to primary care clinicians and the other to a wider group of stakeholders across Europe. The 10 papers identified all pointed out gaps or deficiencies in allergy care provision in primary care. The surveys also highlighted similar concerns, particularly in relation to concerns about lack of knowledge, skills, infrastructural weaknesses, reimbursement policies and communication with specialists as barriers to evidence-based care. Almost all countries (92%) reported the availability of AIT. In spite of that, only 28% and 44% of the countries reported the availability of guidelines for primary care physicians and specialists, respectively. Agreed pathways between specialists and primary care physicians were reported as existing in 32-48% of countries. Reimbursement appeared to be an important barrier as AIT was only fully reimbursed in 32% of countries. Additionally, 44% of respondents considered accessibility to AIT and 36% stating patient costs were barriers. Successful working with primary care providers is essential to scaling-up AIT provision in Europe, but to achieve this the identified barriers must be overcome. Development of primary care interpretation of guidelines to aid patient selection, establishment of disease management pathways and collaboration with specialist groups are required as a matter of urgency. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Allergic reaction is a sensitivity to a specific substance, called an allergen, that is contacted through the skin, inhaled into the lungs, swallowed or injected. The body's reaction to an allergen can be mild, such as ...
Mares-Mejía, Israel; Martínez-Caballero, Siseth; Garay-Canales, Claudia; Cano-Sánchez, Patricia; Torres-Larios, Alfredo; Lara-González, Samuel; Ortega, Enrique; Rodríguez-Romero, Adela
Oligomerization of allergens plays an important role in IgE-mediated reactions, as effective crosslinking of IgE- FcεRI complexes on the cell membrane is dependent on the number of exposed B-cell epitopes in a single allergen molecule or on the occurrence of identical epitopes in a symmetrical arrangement. Few studies have attempted to experimentally demonstrate the connection between allergen dimerization and the ability to trigger allergic reactions. Here we studied plant allergenic profilins rHev b 8 (rubber tree) and rZea m 12 (maize) because they represent an important example of cross-reactivity in the latex-pollen-food syndrome. Both allergens in their monomeric and dimeric states were isolated and characterized by exclusion chromatography and mass spectrometry and were used in immunological in vitro experiments. Their crystal structures were solved, and for Hev b 8 a disulfide-linked homodimer was found. Comparing the structures we established that the longest loop is relevant for recognition by IgE antibodies, whereas the conserved regions are important for cross-reactivity. We produced a novel monoclonal murine IgE (mAb 2F5), specific for rHev b 8, which was useful to provide evidence that profilin dimerization considerably increases the IgE-mediated degranulation in rat basophilic leukemia cells. PMID:27586352
It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response (APR) via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a “mirror” inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer's disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders. PMID:26526143
Vigh-Conrad, Katinka A.; Conrad, Donald F.; Preuss, Daphne
Background Current diagnostics for allergies, such as skin prick and radioallergosorbent tests, do not allow for inexpensive, high-throughput screening of patients. Additionally, extracts used in these methods are made from washed pollen that lacks pollen surface materials that may contain allergens. Methodology/Principal Findings We sought to develop a high-throughput assay to rapidly measure allergen-specific IgE in sera and to explore the relative allergenicity of different pollen fractions (i.e. surface, cytoplasmic, commercial extracts). To do this, we generated a protein microarray containing surface, cytoplasmic, and commercial extracts from 22 pollen species, commercial extracts from nine non-pollen allergens, and five recombinant allergenic proteins. Pollen surface and cytoplasmic fractions were prepared by extraction into organic solvents and aqueous buffers, respectively. Arrays were incubated with <25 uL of serum from 176 individuals and bound IgE was detected by indirect immunofluorescence, providing a high-throughput measurement of IgE. We demonstrated that the allergen microarray is a reproducible method to measure allergen-specific IgE in small amounts of sera. Using this tool, we demonstrated that specific IgE clusters according to the phylogeny of the allergen source. We also showed that the pollen surface, which has been largely overlooked in the past, contained potent allergens. Although, as a class, cytoplasmic fractions obtained by our pulverization/precipitation method were comparable to commercial extracts, many individual allergens showed significant differences. Conclusions/Significance These results support the hypothesis that protein microarray technology is a useful tool for both research and in the clinic. It could provide a more efficient and less painful alternative to traditionally used skin prick tests, making it economically feasible to compare allergen sensitivity of different populations, monitor individual responses over time
Chen, Miaolin; Xu, Jie; Ren, Kang; Searle, Iain
Pollen allergies have long been a major pandemic health problem for human. However, the evolutionary events and biological function of pollen allergens in plants remain largely unknown. Here, we report the genome-wide prediction of pollen allergens and their biological function in the dicotyledonous model plant Arabidopsis (Arabidopsis thaliana) and the monocotyledonous model plant rice (Oryza sativa). In total, 145 and 107 pollen allergens were predicted from rice and Arabidopsis, respectively. These pollen allergens are putatively involved in stress responses and metabolic processes such as cell wall metabolism during pollen development. Interestingly, these putative pollen allergen genes were derived from large gene families and became diversified during evolution. Sequence analysis across 25 plant species from green alga to angiosperms suggest that about 40% of putative pollen allergenic proteins existed in both lower and higher plants, while other allergens emerged during evolution. Although a high proportion of gene duplication has been observed among allergen-coding genes, our data show that these genes might have undergone purifying selection during evolution. We also observed that epitopes of an allergen might have a biological function, as revealed by comprehensive analysis of two known allergens, expansin and profilin. This implies a crucial role of conserved amino acid residues in both in planta biological function and allergenicity. Finally, a model explaining how pollen allergens were generated and maintained in plants is proposed. Prediction and systematic analysis of pollen allergens in model plants suggest that pollen allergens were evolved by gene duplication and then functional specification. This study provides insight into the phylogenetic and evolutionary scenario of pollen allergens that will be helpful to future characterization and epitope screening of pollen allergens. PMID:27436829
Wright, Rex A; Lockard, Stephanie
Male and female participants were led to believe they could secure a low or high chance of winning a prize by meeting a modest standard on a purportedly masculine task, that is, a task on which men ostensibly had higher ability. As expected, systolic blood pressure responses measured during performance were greater for women than men when the chance of winning was high, but low for both groups when the chance of winning was low. Similar effects were observed for diastolic and mean arterial pressure responses, although analysis of the mean arterial pressure data produced only a main effect for the chance factor. These results conceptually replicate cardiovascular findings obtained in a previous sex difference study. They also confirm the implication of previous ability perception studies that effort-related cardiovascular responses should be low for both sexes when the importance of meeting a gender-relevant challenge is low.
Hassan, A K G; Venkatesh, Y P
Plant allergens, being one of the most widespread allergenic substances, are hard to avoid. Hence, their identification and characterization are of prime importance for the diagnosis and treatment of food allergy. The reported allergies to fruits mainly evoke oral allergy syndrome caused by the presence of cross-reactive IgE to certain pollens and thus, allergy to fruits has also been linked to particular pollens. Many fruit allergies are being studied for their causative allergens, and are being characterized. Some tropical or exotic fruits are responsible for region-specific allergies for which only limited information is available, and generally lack allergen characterization. From a survey of the literature on fruit allergy, it is clear that some common fruits (apple, peach, musk melon, kiwi fruit, cherry, grape, strawberry, banana, custard apple, mango and pomegranate) and their allergens appear to be at the center of current research on food allergy. The present review focuses on common fruits reported as allergenic and their identified allergens; a brief description of allergens from six rare/tropical fruits is also covered.
Carlsten, Chris; Blomberg, Anders; Pui, Mandy; Sandstrom, Thomas; Wong, Sze Wing; Alexis, Neil; Hirota, Jeremy
Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. To test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. 18 blinded atopic volunteers were exposed to filtered air or 300 µg PM(2.5)/m(3) of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. NCT01792232. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Ge, Xiao Na; Greenberg, Yana; Hosseinkhani, M Reza; Long, Eric K; Bahaie, Nooshin S; Rao, Amrita; Ha, Sung Gil; Rao, Savita P; Bernlohr, David A; Sriramarao, P
Obesity is an important risk factor for asthma but the mechanistic basis for this association is not well understood. In the current study, the impact of obesity on lung inflammatory responses after allergen exposure was investigated. C57BL/6 mice maintained on a high-fat diet (HFD) or a normal diet (ND) after weaning were sensitized and challenged with cockroach allergen (CRA). Airway inflammation was assessed based on inflammatory cell recruitment, measurement of lung Th1-Th2 cytokines, chemokines, eicosanoids, and other proinflammatory mediators as well as airway hyperresponsiveness (AHR). CRA-challenged mice fed a HFD exhibited significantly decreased allergen-induced airway eosinophilia along with reduced lung IL-5, IL-13, LTC4, CCL11, and CCL2 levels as well as reduced mucus secretion and smooth muscle mass compared to ND fed mice. However, allergen-challenged HFD fed mice demonstrated significantly increased PAI-1 and reduced PGE2 levels in the lung relative to corresponding ND fed mice. Interestingly, saline-exposed HFD fed mice demonstrated elevated baseline levels of TGF-β1, arginase-1, hypoxia-inducible factor-1α, and lung collagen expression associated with decreased lung function compared to corresponding ND fed mice. These studies indicate that a HFD inhibits airway eosinophilia while altering levels of PAI-1 and PGE2 in response to CRA in mice. Further, a HFD can lead to the development of lung fibrosis even in the absence of allergen exposure which could be due to innate elevated levels of specific profibrotic factors, potentially affecting lung function during asthma.
Joad, Jesse P. . E-mail: email@example.com; Kott, Kayleen S.; Bric, John M.; Peake, Janice L.; Plopper, Charles G.; Schelegle, Edward S.; Gershwin, Laurel J.; Pinkerton, Kent E.
Both allergen and ozone exposure increase asthma symptoms and airway responsiveness in children. Little is known about how these inhalants may differentially modify airway responsiveness in large proximal as compared to small distal airways. We evaluated whether bronchi and respiratory bronchioles from infant monkeys exposed episodically to allergen and/or ozone differentially develop intrinsic hyperresponsiveness to methacholine and whether eosinophils and/or pulmonary neuroendocrine cells play a role. Infant monkeys were exposed episodically for 5 months to: (1) filtered air, (2) aerosolized house dust mite allergen, (3) ozone 0.5 ppm, or (4) house dust mite allergen + ozone. Studying the function/structure relationship of the same lung slices, we evaluated methacholine airway responsiveness and histology of bronchi and respiratory bronchioles. In bronchi, intrinsic responsiveness was increased by allergen exposure, an effect reduced by bombesin antagonist. In respiratory bronchioles, intrinsic airway responsiveness was increased by allergen + ozone exposure. Eosinophils were increased by allergen and allergen + ozone exposure in bronchi and by allergen exposure in respiratory bronchioles. In both airways, exposure to allergen + ozone resulted in fewer tissue eosinophils than did allergen exposure alone. In bronchi, but not in respiratory bronchioles, the number of eosinophils and neuroendocrine cells correlated with airway responsiveness. We conclude that episodically exposing infant monkeys to house dust mite allergen with or without ozone increased intrinsic airway responsiveness to methacholine in bronchi differently than in respiratory bronchioles. In bronchi, eosinophils and neuroendocrine cells may play a role in the development of airway hyperresponsiveness.
Ventura, M T; Rodriguez-Perez, R; Caballero, M L; Garcia-Alonso, M; Antonicelli, L; Asero, R
Background. Anisakis simplex hypersensitive subjects may be sensitized without clinical allergy, or experience acute symptoms or chronic urticaria induced by raw fish. We studied whether the 3 subgroups differ in IgE, IgG1 or IgG4 reactivity to specific Anisakis simplex allergens. Methods. 28 Anisakis simplex-hypersensitive adults, 11 with acute symptoms, 9 with chronic urticaria, and 8 sensitized were studied. IgE, IgG1 and IgG4 to rAni s 1, 5, 9 and 10 were sought by ELISA. IgE and IgG4 to nAni s 4 were determined by WB. Results. IgE to Ani s 1, 4, 5, 9, and 10 were found in 8, 3, 2, 5, and 9 sera, respectively. Nine sera did not react to any allergen. IgG1 to Ani s 1, 5, 9, and 10 were detected in 5, 16, 14, and 4 sera, respectively. Four sera did not react to any of the 4 allergens. IgG4 to Ani s 1, 4, 5, 9, and 10 were detected in 10, 0, 2, 6 and 1 sera, respectively. Fifteen subjects did not react to any of the 5 allergens. On ELISA sensitized subjects showed lower IgE and IgG1 levels than patients. IgG4 levels were highest in the sensitized group. The prevalence of IgE, IgG1 or IgG4 reactivity to any of the studied allergens did not differ between the 3 subgroups. Conclusion. The clinical expression of Anisakis simplex sensitization does not seem to depend on IgE reactivity to a specific allergen of the parasite, nor on the presence of IgG antibodies possibly related with blocking activity.
Glocova, Ivana; Brück, Jürgen; Geisel, Julia; Müller-Hermelink, Eva; Widmaier, Katja; Yazdi, Amir S; Röcken, Martin; Ghoreschi, Kamran
Atopic dermatitis (AD) is a common inflammatory skin disease with dysfunction of the skin barrier, an abnormal immune response and frequent allergies to environmental antigens like food antigens. Clinical observations suggest that certain diets can influence the course of AD. Here we compared the phenotype of food allergen-specific T cells activated through skin or gut allergen exposure to transfer skin inflammation into naïve recipients upon epicutaenous allergen challenge. Ovalbumin (OVA) TCR-transgenic mice were treated epicutaneously with OVA or were fed OVA. CD4(+) T cells from skin lymph nodes or mesenteric lymph nodes were transferred into naïve BALB/c mice, which were challenged with OVA epicutaneously. Skin inflammation was determined by histological parameters. In addition, we analyzed the phenotype of the immune response in lymphoid tissues and in skin tissue. TCR-transgenic T cells activated through epicutaneous or oral OVA exposure both migrate to skin lymph nodes after adoptive transfer and epicutaenous OVA exposure. AD-like skin inflammation could only be induced by the transfer of epicutaneously primed OVA T cells. Analysis of the immune phenotype demonstrated an IL-22/IL-17A-dominated immune phenotype of skin-pathogenic T cells. IL-22 seems to be the critical cytokine for the development of AD and is induced in this model by epicutaneous sensitization with OVA. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
Yokoyama, A; Kohno, N; Sakai, K; Kondo, K; Hamada, H; Hiwada, K
Allergen inhalation in atopic patients results in cytokines production or release of preformed cytokines, some of which are known to induce adrenocorticotropic hormone (ACTH) secretion in experimental conditions. We examined whether allergen inhalation can induce ACTH secretion in vivo. A significant elevation of ACTH levels was observed in 2 and 24 hr after allergen inhalation challenge. However, methacholine challenge with the same degree of airflow limitation did not induce ACTH elevation, indicating that this may not be due to bronchoconstriction per se. Our results indicate that allergen inhalation can trigger ACTH secretion in patients with atopic asthma.
Fulton, J E
Selection for immune function in the commercial breeding environment is a challenging proposition for commercial breeding companies. Immune response is only one of many traits that are under intensive selection, thus selection pressure needs to be carefully balanced across multiple traits. The selection environment (single bird cages, biosecure facilities, controlled environment) is a very different environment than the commercial production facilities (multiple bird cages, potential disease exposure, variable environment) in which birds are to produce. The testing of individual birds is difficult, time consuming, and expensive. It is essential that the results of any tests be relevant to actual disease or environmental challenge in the commercial environment. The use of genetic markers as indicators of immune function is being explored by breeding companies. Use of genetic markers would eliminate many of the limitations in enhancing immune function currently encountered by commercial breeding companies. Information on genetic markers would allow selection to proceed without subjecting breeding stock to disease conditions and could be done before production traits are measured. These markers could be candidate genes with known interaction or involvement with disease pathology or DNA markers that are closely linked to genetic regions that influence the immune response. The current major limitation to this approach is the paucity of mapped chicken immune response genes and the limited number of DNA markers mapped on the chicken genome. These limitations should be eliminated once the chicken genome is sequenced.
Intraspecific variation in response to rising atmospheric carbon dioxide concentration, [CO2], could, potentially, be used as a means to begin selection for improved quantitative or qualitative characteristics for a given crop. Peanut (Arachis hypogaea L.) is a leguminous crop of global importance;...
Negi, Surendra S; Braun, Werner
The phenomenon of cross-reactivity between allergenic proteins plays an important role to understand how the immune system recognizes different antigen proteins. Allergen proteins are known to cross-react if their sequence comparison shows a high sequence identity which also implies that the proteins have a similar 3D fold. In such cases, linear sequence alignment methods are frequently used to predict cross-reactivity between allergenic proteins. However, the prediction of cross-reactivity between distantly related allergens continues to be a challenging task. To overcome this problem, we developed a new structure-based computational method, Cross-React, to predict cross-reactivity between allergenic proteins available in the Structural Database of Allergens (SDAP). Our method is based on the hypothesis that we can find surface patches on 3D structures of potential allergens with amino acid compositions similar to an epitope in a known allergen. We applied the Cross-React method to a diverse set of seven allergens, and successfully identified several cross-reactive allergens with high to moderate sequence identity which have also been experimentally shown to cross-react. Based on these findings, we suggest that Cross-React can be used as a predictive tool to assess protein allergenicity and cross-reactivity. : Cross-React is available at: http://curie.utmb.edu/Cross-React.html. firstname.lastname@example.org.
Niedoszytko, Marek; Ratajska, Magdalena; Chełmińska, Marta; Makowiecki, Michał; Malek, Ewelina; Siemińska, Alicja; Limon, Janusz; Jassem, Ewa
Insect venom allergy (IVA) is present in 1-3% of the population. A group of patients with high specific IgE do not react to stings. In contrast, a proportion of patients with IVA have low specific IgE levels. These findings indicate that factors other than specific IgE may also be involved in IVA. Dysfunction of the renin-angiotensin system (RAS) has been described as a potential factor in IVA. The objective of this study was to determine the prevalence of angiotensin AGT p.M235T and angiotensin-converting enzyme ACE I/D, I/I, D/D gene polymorphisms in patients with IVA and to relate the presence of these gene variants to the course of IVA and the safety of treatment. A total of 107 patients with IVA and 113 controls were studied. AGT p.M235T and ACE (ID, I/I, D/D) gene polymorphisms were examined, and angiotensin I levels were measured by immunoassay. The frequency of the AGT MM M235T variant was significantly higher in IVA patients (29.9%) than in controls (17%, p = 0.02). The presence of the MM M235T genotype increased the risk of grade IV reactions (odds ratio = 2.5 and 95% confidence interval 1.04-6.08). There were no differences in the prevalence of the ACE I/D polymorphism and angiotensin I levels between control groups and patients with different grades of anaphylactic reactions or patients with side effects of venom immunotherapy. The AGT M235T MM variant may be responsible for severe anaphylactic reactions to insect venom allergens in some patients. Copyright © 2010 S. Karger AG, Basel.
Liu, Ko-Jiunn; Leu, Sy-Jye; Su, Ching-Hua; Chiang, Bor-Luen; Chen, Yi-Lien; Lee, Yueh-Lun
Asthma is a chronic disease characterized by airway inflammation caused by the dysregulated production of cytokines secreted by allergen-specific type 2 T helper (Th2) cells. Antrodia camphorata is a commonly used fungus in Asian folk medicine, and A. camphorata polysaccharides are reported to possess anti-cancer activities. In this study, the immunomodulatory effects of purified fractionated polysaccharides (GF2) from A. camphorata on dendritic cells (DCs) and their potential preventive effects against ovalbumin (OVA) -induced asthma were investigated. In the presence of GF2, lipopolysaccharide (LPS) -activated DCs exhibited up-regulated expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules, as well as enhanced interleukin-10 (IL-10) and IL-12 production. GF2 treatment on LPS-activated DCs suppressed naïve CD4(+) T-cell proliferation and Th2 cell polarization with IL-10 production in an allogeneic mixed lymphocyte reaction. In animal experiments, a high dose of GF2 efficiently reduced expression levels of OVA-specific immunoglobulin G1 (IgG1) and IgE. However, lower doses of GF2 significantly enhanced OVA-specific IgG2a production. Our data also showed that administration of GF2 dose-dependently inhibited the development of airway hyperresponsiveness, airway eosinophilia and Th2 responses. OVA-specific CD4(+) T cells from higher doses of GF2-treated mice had significantly lower proliferative capacities compared with control mice. Moreover, treatment with GF2 significantly increased the high levels of IL-10 and low levels of interferon-gamma produced by T cells. Taken together, these data indicate that administration of A. camphorata polysaccharides (GF2) may have therapeutic potential when used as an adjuvant for the immunomodulatory treatment of allergic asthma.
Barr, Jonathan L.; Peddicord, Annie M Boe; Burtner, Edwin R.; Mahy, Heidi A.
This paper describes the development of a framework targeted to technology providers in order to better understand the grand domain challenges of the emergency response and management community (EM). In developing this framework, Pacific Northwest National Laboratory researchers interviewed subject matter experts (SMEs) across the EM domain and corroborated these findings with current literature. We are currently examining relationships and dependencies within the framework. A thorough understanding of these gaps and dependencies will allow for a more informed approach prioritizing research, developing tools, and applying technology to enhance performance in the EM community.
all of a nation’s forces -- land, sea, and air . Each rating is an average; in most nations’ audlts and for most periods, major deviations can be cited...and French in May-June 1940. 8 10.* From the essays of the Military Project, we can conclude that for the highest quolity of response to challenge...Royal Air Force (RAF) Fighter Command. From 1936 when Britain first formed Fighter Command to the Battle of Britain which began in July 1940, the RAF
Background Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air. Methods This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18) or purified natural Alt a1 (n = 22) subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine, exhaled nitric oxide (ENO), exhaled breath condensate (EBC) pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered. Results The mean (95% CI) allergen-specific IgG4 value for the active treatment group increased from 0.07 μg/mL (0.03-0.11) at baseline to 1.21 μg/mL (0.69-1.73, P < 0.001) at 6 months and to 1.62 μg/mL (1.02-2.22, P < 0.001) at 12 months of treatment. In the placebo group, IgG4 value increased nonsignificantly from 0.09 μg/mL (0.06-0.12) at baseline to 0.13 μg/mL (0.07-0.18) at 6 months and to 0.11 μg/mL (0.07-0.15) at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P < 0.001) and at 12 months of treatment (P < 0.0001). However, changes in AMP and methacholine responsiveness, ENO and EBC pH levels were not significantly different between treatment groups. The overall incidence of adverse events was comparable between the treatment groups. Conclusion Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with
Cho, Chung Y; Nowatzke, William; Oliver, Kerry; Garber, Eric A E
To help safeguard the food supply and detect the presence of undeclared food allergens and gluten, most producers and regulatory agencies rely on commercial test kits. Most of these are ELISAs with a few being PCR-based. These methods are very sensitive and analyte specific, requiring different assays to detect each of the different food allergens. Mass spectrometry offers an alternative approach whereby multiple allergens may be detected simultaneously. However, mass spectrometry requires expensive equipment, highly trained analysts, and several years before a quantitative approach can be achieved. Using multianalyte profiling (xMAP®) technology, a commercial multiplex test kit based on the use of established antibodies was developed for the simultaneous detection of up to 14 different food allergens plus gluten. The assay simultaneously detects crustacean seafood, egg, gluten, milk, peanut, soy, and nine tree nuts (almond, Brazil nut, cashew, coconut, hazelnut, macadamia, pine nut, pistachio, and walnut). By simultaneously performing multiple tests (typically two) for each analyte, this magnetic bead-based assay offers built-in confirmatory analyses without the need for additional resources. Twenty-five of the assays were performed on buffer extracted samples, while five were conducted on samples extracted using reduced-denatured conditions. Thus, complete analysis for all 14 allergens and gluten requires only two wells of a 96-well microtiter plate. This makes it possible to include in a single analytical run up to 48 samples. All 30 bead sets in this multiplex assay detected 5 ng/mL of food allergen and gluten with responses greater than background. In addition, 26 of the bead sets displayed signal/noise ratios of five or greater. The bead-based design makes this 30-plex assay expandable to incorporate new antibodies and capture/detector methodologies by ascribing these new detectors to any of the unassigned bead sets that are commercially available.
Dunachie, Susanna; Hill, Adrian V.S.; Fletcher, Helen A.
A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research. PMID:26256528
Dunachie, Susanna; Hill, Adrian V S; Fletcher, Helen A
A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research.
D'Amato, G; Cecchi, L; Bonini, S; Nunes, C; Annesi-Maesano, I; Behrendt, H; Liccardi, G; Popov, T; van Cauwenberge, P
The allergenic content of the atmosphere varies according to climate, geography and vegetation. Data on the presence and prevalence of allergenic airborne pollens, obtained from both aerobiological studies and allergological investigations, make it possible to design pollen calendars with the approximate flowering period of the plants in the sampling area. In this way, even though pollen production and dispersal from year to year depend on the patterns of preseason weather and on the conditions prevailing at the time of anthesis, it is usually possible to forecast the chances of encountering high atmospheric allergenic pollen concentrations in different areas. Aerobiological and allergological studies show that the pollen map of Europe is changing also as a result of cultural factors (for example, importation of plants such as birch and cypress for urban parklands), greater international travel (e.g. colonization by ragweed in France, northern Italy, Austria, Hungary etc.) and climate change. In this regard, the higher frequency of weather extremes, like thunderstorms, and increasing episodes of long range transport of allergenic pollen represent new challenges for researchers. Furthermore, in the last few years, experimental data on pollen and subpollen-particles structure, the pathogenetic role of pollen and the interaction between pollen and air pollutants, gave new insights into the mechanisms of respiratory allergic diseases.
Birmingham, Neil; Thanesvorakul, Sirinart; Gangur, Venu
Food allergies affect 6 to 8% of children and 2% of adults in the United States. For reasons that are not clear, eight types of food account for a vast majority (approximately 90%) of food-induced hypersensitivity reactions. In this study, C57Bl/6 mice were used to test the hypothesis that commonly allergenic foods are intrinsically more immunogenic than rarely allergenic or nonallergenic foods in allergy-susceptible hosts. Groups of mice (n = 4 to 5) were injected intraperitoneally with the protein extracts (plus alum as an adjuvant) from chicken eggs, peanuts, almonds, filberts-hazelnuts, walnuts, soybeans, and wheat (commonly allergenic foods) and coffee, sweet potatoes, carrots, white potatoes, cherries, lettuce, and spinach (rarely allergenic and nonallergenic foods). Primary and secondary immune responses (as measured by specific IgG1 antibody serum levels) were measured by an enzyme-linked immunosorbent assay. Proteins from peanuts, almonds, filberts, sweet potatoes, cherries, and spinach elicited robust primary and/or secondary immune responses. Proteins from eggs, walnuts, and lettuce elicited poor primary responses but significant secondary responses. In contrast, wheat, soybeans, coffee, carrots, and white potatoes elicited barely detectable to poor primary and secondary immune responses. The order of the immunogenicity levels of these foods in mice is as follows: almonds = filberts > spinach (Rubisco) > peanuts > or = sweet potatoes > cherries > lettuce > walnuts > chicken eggs > carrots > or = white potatoes > wheat = coffee = soybeans. In summary, these data demonstrate for the first time that: (i) foods vary widely with regard to their relative immunogenicity in allergy-susceptible hosts and (ii) intrinsic immunogenicity in mice does not distinguish commonly allergenic foods from rarely allergenic or nonallergenic foods.
Dotson, G. S.; Maier, A.; Siegel, P. D.; Anderson, S. E.; Green, B. J.; Stefaniak, A. B.; Codispoti, C. D.; Kimber, I.
Chemical allergens represent a significant health burden in the workplace. Exposures to such chemicals can cause the onset of a diverse group of adverse health effects triggered by immune-mediated responses. Common responses associated with workplace exposures to low molecular weight (LMW) chemical allergens range from allergic contact dermatitis to life-threatening cases of asthma. Establishing occupational exposure limits (OELs) for chemical allergens presents numerous difficulties for occupational hygiene professionals. Few OELs have been developed for LMW allergens because of the unique biological mechanisms that govern the immune-mediated responses. The purpose of this article is to explore the primary challenges confronting the establishment of OELs for LMW allergens. Specific topics include: (1) understanding the biology of LMW chemical allergies as it applies to setting OELs; (2) selecting the appropriate immune-mediated response (i.e., sensitization versus elicitation); (3) characterizing the dose (concentration)-response relationship of immune-mediated responses; (4) determining the impact of temporal exposure patterns (i.e., cumulative versus acute exposures); and (5) understanding the role of individual susceptibility and exposure route. Additional information is presented on the importance of using alternative exposure recommendations and risk management practices, including medical surveillance, to aid in protecting workers from exposures to LMW allergens when OELs cannot be established. PMID:26583909
Grass pollen allergens are shown to remain associated with protein material and a yellow pigment during paper chromatography and during dialyses and ultrafiltrations of various types. Dialysable* allergens comprise only a fraction of 1 per cent of the total activity and the amount of activity extractable by diethylene glycol (DEG) and similar solvents is of the same order. Besides the allergens, the DEG and aqueous extracts contain large amounts of inositol, glucose and fructose, also some yellow pigments and phosphates. Larger amounts of free and combined amino acids are found in the aqueous than in the DEG extracts, but the reverse is true for sucrose. In addition the DEG extracts contain a yellow glucoside different from the dactylen of the aqueous extracts, a glucosan and an arabinose-galactose-pigment complex, only the latter being associated with any activity. The spontaneous release of the crystalline dactylen from originally clear aqueous pollen extracts is found not to be caused by enzymes. The washed crystals are found to be chromatographically and electrophoretically homogeneous and devoid of allergenic activity. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7 PMID:13640676
Science Teacher, 2005
Researchers at National Jewish Medical and Research Center have demonstrated that dilute bleach not only kills common household mold, but may also neutralize the mold allergens that cause most mold-related health complaints. The study, published in the Journal of Allergy and Clinical Immunology, is the first to test the effect on allergic…
Food allergies have become a major public health issue in many countries. In the U.S. it is estimated that approximately 150 individuals die each year from accidental ingestion of an allergic food. As a result, the federal government recently passed the food allergen labeling law which went into ef...
Chruszcz, Maksymilian; Mikolajczak, Katarzyna; Mank, Nicholas; Majorek, Karolina A.; Porebski, Przemyslaw J.; Minor, Wladek
Background Albumins are multifunctional proteins present in the blood serum of animals. They can bind and transport a wide variety of ligands which they accommodate due to their conformational flexibility. Serum albumins are highly conserved both in amino acid sequence and three-dimensional structure. Several mammalian and avian serum albumins (SAs) are also allergens. Sensitization to one of the SAs coupled with the high degree of conservation between SAs may result in cross-reactive antibodies in allergic individuals. Sensitivity to SA generally begins with exposure to an aeroallergen, which can then lead to cross-sensitization to serum albumins present in food. Scope of Review This review focuses on the allergenicity of SAs presented in a structural context. Major Conclusions SA allergenicity is unusual taking into account the high sequence identity and similarity between SA from different species and human serum albumin. Cross-reactivity of human antibodies towards different SAs is one of the most important characteristics of these allergens. General Significance Establishing a relationship between sequence and structure of different SAs and their interactions with antibodies is crucial for understanding the mechanisms of cross-sensitization of atopic individuals. Structural information can also lead to better design and production of recombinant SAs to replace natural proteins in allergy testing and desensitization. Therefore, structural analyses are important for diagnostic and treatment purposes. PMID:23811341
Science Teacher, 2005
Researchers at National Jewish Medical and Research Center have demonstrated that dilute bleach not only kills common household mold, but may also neutralize the mold allergens that cause most mold-related health complaints. The study, published in the Journal of Allergy and Clinical Immunology, is the first to test the effect on allergic…
Prisco, Antonella; De Berardinis, Piergiuseppe
Abstract A crucial challenge for vaccine development is to design vaccines that induce a long-lasting protective immune response, i.e., immune memory. The persistence of antigen-specific antibody titers over a protective threshold, and the ability to exibit a 'recall response' to a subsequent encounter with an antigen have long been the only measurable correlates of vaccine take and immune memory development, suffering from the disadvantage of relying on long-term monitoring of the immune response. In the last few years, advances in the technologies for the identification and characterization of the cell subsets and molecular pathways involved in the immune response to vaccination have allowed innovative approaches to the identification of early correlates of immune memory. In this review, we discuss recent data and hypotheses on early correlates of the development of immune memory, with special emphasis on the gene expression signatures that underlie the self-renewal ability of some lymphocyte subsets, and their similarities with gene expression signatures in stem cells.
Gangl, K; Niederberger, V; Valenta, R
Grass pollen allergy affects approximately 40% of allergic patients. Subcutaneous allergen immunotherapy (SCIT) is the only allergen-specific and disease-modifying treatment available. Currently available therapeutic vaccines for the treatment of grass pollen allergy are based on natural grass pollen extracts which are either made from pollen of one cross-reactive grass species or from several related grass species. Clinical studies have shown that SCIT performed with timothy grass pollen extract is effective for the treatment of grass pollen allergy. Moreover, it has been demonstrated that recombinant timothy grass pollen allergens contain the majority of relevant epitopes and can be used for SCIT in clinical trials. However, recent in vitro studies have suggested that mixes consisting of allergen extracts from several related grass species may have advantages for SCIT over single allergen extracts. Here, we review current knowledge regarding the disease-relevant allergens in grass pollen allergy, available clinical studies comparing SCIT with allergen extracts from timothy grass or from mixes of several related grass species of the Pooideae subfamily, in vitro cross-reactivity studies performed with natural allergen extracts and recombinant allergens and SCIT studies performed with recombinant timothy grass pollen allergens. In vitro and clinical studies performed with natural allergen extracts reveal no relevant advantages of using multiple grass mixes as opposed to single grass pollen extracts. Several studies analysing the molecular composition of natural allergen extracts and the molecular profile of patients' immune responses after SCIT with allergen extracts indicate that the major limitation for the production of a high quality grass pollen vaccine resides in intrinsic features of natural allergen extracts which can only be overcome with recombinant allergen-based technologies. © 2013 John Wiley & Sons Ltd.
Riascos, John J; Weissinger, Sandra M; Weissinger, Arthur K; Kulis, Michael; Burks, A Wesley; Pons, Laurent
Soybean is a common allergenic food; thus, a comprehensive characterization of all the proteins that cause allergy is crucial to the development of effective diagnostic and immunotherapeutic strategies. A cDNA library was constructed from seven stages of developing soybean seeds to investigate candidate allergens. We searched the library for cDNAs encoding a seed-specific biotinylated protein (SBP) based on its allergenicity in boiled lentils. A full-length cDNA clone was retrieved and expressed as a 75.6-kDa His-tagged recombinant protein (rSBP) in Escherichia coli. Western immunoblotting of boiled bacterial extracts demonstrated specific IgE binding to rSBP, which was further purified by metal affinity and anion exchange chromatographies. Of the 23 allergic sera screened by ELISA, 12 contained IgEs specific to the purified rSBP. Circular dichroism spectroscopy revealed a predominantly unordered structure consistent with SBP's heat stability. The natural homologues (nSBP) were the main proteins isolated from soybean and peanut embryos after streptavidin affinity purification, yet they remained low-abundance proteins in the seed as confirmed by LC-MS/MS. Using capture ELISAs, the soybean and peanut nSBPs were bound by IgEs in 78 and 87% of the allergic sera tested. The soybean nSBP was purified to homogeneity and treatments with different denaturing agents before immunoblotting highlighted the diversity of its IgE epitopes. In vitro activation of basophils was assessed by flow cytometry in a cohort of peanut-allergic children sensitized to soybean. Stronger and more frequent (38%) activations were induced by nSBP-soy compared to the major soybean allergen, Gly m 5. SBPs may represent a novel class of biologically active legume allergens with the structural resilience to withstand many food-manufacturing processes.
Protease activity is a characteristic common to many allergens. Allergen source-derived proteases interact with lung epithelial cells, which are now thought to play vital roles in both innate and adaptive immune responses. Allergen source-derived proteases act on airway epithelial cells to induce disruption of the tight junctions between epithelial cells, activation of protease-activated receptor-2, and the production of thymic stromal lymphopoietin. These facilitate allergen delivery across epithelial layers and enhance allergenicity or directly activate the immune system through a nonallergic mechanism. Furthermore, they cleave regulatory cell surface molecules involved in allergic reactions. Thus, allergen source-derived proteases are a potentially critical factor in the development of allergic sensitization and appear to be strongly associated with heightened allergenicity. PMID:22523502
Kelly, Elizabeth A. B.; Koziol, Cynthia; Clay, Kathryn J.; Liu, Linying; Bates, Mary Ellen; Bertics, Paul J.; Jarjour, Nizar N.
The primary function of IL-7 is to promote maturation and survival of T cells. Through microarray expression analysis, we previously observed that human blood eosinophils express mRNA for IL-7Rα (CD127) and its common gamma chain (γc, CD132). The purpose of this study was to determine if eosinophils have functional IL-7 receptors and to assess the potential contribution of IL-7 to eosinophilic airway inflammation by evaluating its presence in bronchoalveolar lavage (BAL) fluid of subjects with atopic asthma before and after segmental bronchoprovocation with allergen. Immunoblot analysis revealed that CD127 is present in highly purified human blood eosinophils. Furthermore, eosinophils responded to IL-7 with phosphorylation of STAT5, upregulation of the activation marker CD69, and prolonged survival. Neutralization of GM-CSF, but not IL-5, significantly blunted these functional responses, suggesting that IL-7 mediates its effects by promoting eosinophil release of autologous GM-CSF. Notably, the suppressive effect of anti-GM-CSF on STAT5 phosphorylation occurred within 10 min of eosinophil exposure to IL-7. Thus, IL-7 likely activates eosinophil release of preformed, rather than newly synthesized GM-CSF. The biological relevance of IL-7 to eosinophilia in vivo was implicated in a study of airway allergen challenge in allergic asthmatics. IL-7 concentrations in BAL fluid increased significantly 48 h after segmental allergen challenge and were highly correlated with BAL eosinophils (r=0.7, p<0.001). In conclusion, the airway response to allergen is associated with the generation of IL-7, which may contribute to airway inflammation by promoting enhanced eosinophil activation and survival. Activation of eosinophils is a novel function for IL-7. PMID:19155487
Bush, R.K.; Schroeckenstein, D.; Meier-Davis, S.; Balmes, J.; Rempel, D.
A 43-year-old woman developed asthma 6 years after beginning work in a food-processing plant in which soybean flour was used as a protein extender. Symptoms of sneezing, coughing, and wheezing would begin within minutes of exposure to soybean flour and resolve 2 hours after exposure ceased. Skin tests were positive to a soy extract prepared from the flour. Airway hyperreactivity was confirmed by a positive bronchial challenge to methacholine. Bronchial challenge with soybean flour produced an immediate increase in specific airway resistance from 5.0 to 22.7 L. cm of H2O/L/sec. There was no response to challenge with lactose. The patient's allergic response to soy-flour extract was further characterized by several immunologic methods. IgE binding to soy-flour protein by direct RAST was 5.98 times that of a normal control serum. The soy-flour extract was separated by dodecyl sulfate-polyacrylamide gel electrophoresis. Twenty-four protein bands were detected in the crude soy-flour extract. After immunoblotting and subsequent autoradiography, nine proteins with molecular weights ranging from 54,500 to 14,875 were found. Cross-reactivity studies with other legumes demonstrated apparent immunologic identity between a component in green pea extract and a soybean protein with a molecular weight of 17,000. The clinical significance of this cross-reactivity is not known. We conclude that in this case of occupational asthma to soybean flour, multiple allergens were involved. Immunoblotting may be useful in identifying the allergens involved in occupational asthma.
Baek, Kwang Je; Cho, Jae Youn; Rosenthal, Peter; Alexander, Laura E. Crotty; Nizet, Victor; Broide, David H.
Whether hypoxia contributes to airway inflammation and remodeling in asthma is unknown. In this study we used mice exposed to a hypoxic environment during allergen challenge (simulating hypoxia during an asthma exacerbation) to investigate the contribution of hypoxia to airway inflammation and remodeling. Although neither hypoxia alone, nor OVA allergen alone, induced significant neutrophil influx into the lung, the combination of OVA and hypoxia induced a synergistic 27 fold increase in peribronchial neutrophils, enhanced expression of HIF-1α and one of its target genes, the CXC-family neutrophil chemokine KC. The combination of hypoxia and OVA allergen increased eotaxin-1, peribronchial eosinophils, lung TGB-β1 expression, and indices of airway remodeling (fibrosis and smooth muscle) compared to either stimulus alone. As hypoxia is present in >90% of severe asthma exacerbations, these findings underscore the potential of hypoxia to potentiate the airway inflammatory response, remodeling, and accelerate the decline of lung function in asthma exacerbations. PMID:23499929
Engebretsen, Kristiane Aasen; Thyssen, Jacob Pontoppidan
The skin is an important barrier protecting us from mechanical insults, microorganisms, chemicals and allergens, but, importantly, also reducing water loss. A common hallmark for many dermatoses is a compromised skin barrier function, and one could suspect an elevated risk of contact sensitization (CS) and allergy following increased penetration of potential allergens. However, the relationship between common dermatoses such as psoriasis, atopic dermatitis (AD) and irritant contact dermatitis (ICD) and the development of contact allergy (CA) is complex, and depends on immunologic responses and skin barrier status. Psoriasis has traditionally been regarded a Th1-dominated disease, but the discovery of Th17 cells and IL-17 provides new and interesting information regarding the pathogenesis of the disease. Research suggests an inverse relationship between psoriasis and CA, possibly due to increased levels of Th17 cells and its associated cytokines. As for AD, a positive association to CS has been established in epidemiological studies, but is still unresolved. Experimental studies show, however, an inverse relationship between AD and CS. The opposing and antagonistic influences of Th1 (CS) and Th2 (AD) have been proposed as an explanation. Finally, there is convincing evidence that exposure to irritants increases the risk of CS, and patients with ICD are, therefore, at great risk of developing CA. Skin irritation leads to the release of IL-1 and TNF-α, which affects the function of antigen-presenting cells and promotes their migration to local lymph nodes, thus increasing the probability of CS and ultimately the development of CA.
Paulissen, Geneviève; El Hour, Mehdi; Rocks, Natacha; Guéders, Maud M; Bureau, Fabrice; Foidart, Jean-Michel; Lopez-Otin, Carlos; Noel, Agnès; Cataldo, Didier D
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.
Groenewoud, G C M; de Graaf in 't Veld, C; vVan Oorschot-van Nes, A J; de Jong, N W; Vermeulen, A M; van Toorenenbergen, A W; Burdorf, A; de Groot, H; Gerth van Wijk, R
Protection against thrips, a common pest in bell pepper horticulture is effectively possible without pesticides by using the commercially available predatory mite Amblyzeius cucumeris (Ac). The prevalence of sensitization to Ac among exposed greenhouse employees and its clinical relevance was studied. Four hundred and seventytwo employees were asked to fill in a questionnaire and were tested on location. Next to RAST, skin prick tests (SPTs) were performed with common inhalant allergens, the storage mite Tyrophagus putrescentiae (Tp) which serves as a temporary food source during the cultivation process and Ac. Furthermore, nasal challenge tests with Ac were carried out in 23 sensitized employees. SPTs positive to Ac were found in 109 employees (23%). Work-related symptoms were reported by 76.1%. Sensitization to Tp was found in 62 employees of whom 48 were also sensitized to Ac. Immunoglobulin (Ig)E-mediated allergy to inhalant allergens appeared to be an important risk factor for sensitization to Ac. Employees with rhinitis symptoms showed a significantly higher response to all Ac doses during the nasal challenge test compared with employees without rhinitis symptoms. The predatory mite Ac is a new occupational allergen in horticulture which can cause an IgE-mediated allergy in exposed employees. It is biologically active on the mucous membranes of the nose and therefore clinically relevant for the development of work-related symptoms.
Scheurer, Stephan; Sonnewald, Sophia
Food allergies are a major health concern in industrialized countries. Since a specific immunotherapy for food allergies is not available in clinical routine praxis till now, reduction of allergens in foods, either by food processing or genetic engineering are strategies to minimize the risk of adverse reactions for food allergic patients. This review summarizes biotechnological approaches, especially the RNA interference (RNAi) technology, for the reduction of selected allergens in plant foods. So far, only a limited number of reports showing proof-of-concept of this methodology are available. Using RNAi an impressive reduction of allergen accumulation was obtained which was stable in the next generations of plants. Since threshold doses for most food allergens are not known, the beneficial effect has to be evaluated by oral challenge tests in the future. The article critically addresses the potential and limitations of genetic engineering, as well as of alternative strategies to generate "low allergic" foods.
According to the so-called "26 allergens rule" 26 supposedly allergenic fragrances must be specified on the containers of cosmetic products if they are present above 0.001% in leave-on products and, 0.01% in rinse-off products. This declaration is meant to inform the consumers of potential risks of skin sensitizers in the products. As many consumers of deodorants suffer from allergic or irritant contact dermatitis in the axillae, the presence of allergens in deodorants deserves special attention. The objective of this study was to find answers to the following questions: Does compulsory labeling lead to omission of strong allergenic fragrances in deodorants? Is there a difference in the use patterns of strong and weak allergens? What is the quantitative exposure to fragrances by deodorants? Is the situation in Germany different from other European countries? Is there a difference between deodorants for men and for women? I tested the implementation of the "26 allergens rule" and compiled which allergenic fragrances are specified on the containers of deodorants. Three market studies were conducted in Germany in 2008, 2010 and 2011. The labels of a total number of 374 deodorants were analyzed as to whether any of the "26 allergens" were listed. The frequency of each allergen in the deodorants was compared with results from previous studies by other authors. It was found that up to 83% of the deodorants contain at least one of the "26 allergens" and that up to 30% of all products contain strong allergens above the threshold for labeling (0.001% in the product). The most frequently listed allergens are medium or weak allergens. In comparison with other authors, the frequency of the "26 allergens" in products is slightly smaller in these recent studies for the German market. There is no significant difference between deodorants for men and women, as far as the labeling of the "26 allergens" is concerned. The results show that the mandatory labeling procedure as designed
van't Hof, W; van den Berg, M; Driedijk, P C; Aalberse, R C
The fine specificity of IgE antibody binding to peptide 65-78 of the house dust mite major allergen Der p II was examined by comparison with binding to two peptides in which the cysteines corresponding to cys73 and cys78 in Der p II were substituted by serines and methionines. Differences in binding behavior indicated that at least three different subpopulations of IgE antibodies bound to peptide 65-78. Even at the level of such a small fragment the IgE response in individual donors proved to be polyclonal.
Basketter, David A; English, John
p-Phenylenediamine (PPD) is an important hair dye allergen, but there remains a reasonable suspicion that other hair dye chemicals may also be responsible for a proportion of the clinical burden of hair dye allergy. To assess to what extent presently assessed additional patch test agents contribute to the diagnosis of non-PPD hair dye allergy. A retrospective analysis was conducted of patch test results with hair dye allergens, focusing on the extent to which patients who were positive for allergic reactions to other hair dye allergens also had a concomitant positive reaction to PPD. For the hair dye allergens other than p-toluenediamine (PTD), reactions in the absence of a concomitant positive reaction to PPD were very rare. Positive reactors to PTD were also positive for reactions to PPD in 5 of every 6 cases. Pyrogallol positives often occurred in the absence of a PPD positive, but were never judged to be of clinical relevance. Hair dye chemicals other than PPD may be of importance, but the presently tested materials, with the possible exception of PTD, are normally positive only when a PPD-positive reaction is also present, suggesting that their use in patch testing in hair dye allergy is likely to be of limited value.
Danos, Nicole; Lauder, George V
Escape responses of fishes have long been studied as a model locomotor behavior in which hypothesized maximal or near-maximal muscle power output is used to generate rapid body bending. In this paper we present the results of experiments that challenged zebrafish (Danio rerio) to perform escape responses in water of altered viscosity, to better understand the effects that the fluid mechanical environment exerts on kinematics. We quantified escape kinematics using 1000 frames s(-1) high-speed video, and compared escape response kinematics of fish in three media that differed in viscosity: 1 mPa s (normal water), 10 mPa s and 20 mPa s (20 times normal water viscosity). We hypothesized that because viscosity is increased but not density there will be a different effect on kinematic variables resulting from unsteady (acceleration-dependent) hydrodynamic forces and steady (velocity-dependent) ones. Similarly, we hypothesized that the kinematics of stage 1 will be less affected by viscosity than those of stage 2, as higher angular velocities are reached during stage 1 resulting in higher Reynolds numbers. Our results showed a significant overall effect of viscosity on escape response kinematics but the effect was not in accordance with our predictions. Statistical tests showed that increasing viscosity significantly decreased displacement of the center of mass during stage 1 and after 30 ms, and decreased maximum velocity of the center of mass, maximum angular velocity and acceleration during stage 1, but increased time to maximum angular acceleration and time to maximum linear velocity of the center of mass. Remarkably, increasing water viscosity 20 times did not significantly affect the duration of stage 1 or stage 2.
Navarro, S; Lazzari, A; Kanda, A; Fleury, S; Dombrowicz, D; Glaichenhaus, N; Julia, V
Allergic asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), lung infiltration of Th2 cells, and high levels of IgE. To date, allergen-specific immunotherapy (SIT) is the only treatment that effectively alleviates clinical symptoms and has a long-term effect after termination. Unfortunately, SIT is unsuitable for plurisensitized patients, and highly immunogenic allergens cannot be used. To overcome these hurdles, we sought to induce regulatory CD4(+) T cells (Treg) specific to an exogenous antigen that could be later activated as needed in vivo to control allergic responses. We have established an experimental approach in which mice tolerized to ovalbumin (OVA) were sensitized to the Leishmania homolog of receptors for activated c kinase (LACK) antigen, and subsequently challenged with aerosols of LACK alone or LACK and OVA together. Upon OVA administration, AHR and allergic airway responses were strongly reduced. OVA-induced suppression was mediated by CD25(+) Treg, required CTLA-4 and ICOS signaling and resulted in decreased numbers of migrating airway dendritic cells leading to a strong impairment in the proliferation of allergen-specific Th2 cells. Therefore, inducing Treg specific to a therapeutic antigen that could be further activated in vivo may represent a safe and novel curative approach for allergic asthma.
Pishdadian, Abbas; Varasteh, Abdolreza; Gholamin, Mehran; Nasiraie, Leila Roozbeh; Hosseinpour, Mitra; Moghadam, Malihe; Sankian, Mojtaba
Objective(s): Sublingual allergen-specific immunotherapy is a safe and effective method for treatment of IgE-mediated respiratory allergies; however, the underlying mechanisms are not fully understood. This study was planned to test whether sublingual immunotherapy (SLIT) can exert epigenetic mechanisms through which the airway allergic responses can be extinguished. Materials and Methods: BALB/c mice were sensitized intraperitoneally and challenged intranasally. Then, they received sublingual treatment with recombinant Che a 2 (rChe a 2), a major allergen of Chenopodium album. After SLIT, allergen-specific antibodies in sera, cytokine profiles of spleen cell cultures, mRNA and protein expression of lung-derived IL-33, IL-25, and TSLP (thymic stromal lymphopoietin), and histone modifications of these three genes were assessed. Results: Following Immunotherapy, systemic immune responses shifted from Th2 to Th1 profile as demonstrated by significant decrease in IgE and IL-4 and substantial increase in IgG2a and IFN-γ. At local site, mRNA and protein levels of lung-derived pro-inflammatory cytokines IL-33 and TSLP were markedly down-regulated following SLIT that was associated with marked enrichment of trimethylated lysine 27 of histone H3 at promoter regions of these two cytokines. Conclusion: In our study, sublingual immunotherapy with recombinant allergen effectively attenuated allergic immune responses, at least partly, by induction of distinct histone modifications at specific loci. Additionally, the lung-derived pro-allergic cytokines IL-33 and TSLP could be promising mucosal candidates for either monitoring allergic conditions or therapeutic approaches. PMID:27096066
Gomes Câmara Camacho, Irene
This review aims to present in a simple manner the work performed in Portugal regarding the identification of the most prevalent aeroallergens in the country and the sensitization levels in Portuguese patients. Much of the data was summarized in tables and illustrated on maps, enabling the community of clinicians, researchers, and patient organizations to access the knowledge about the research performed. This study provides an overview about the distribution of aeroallergens in Portugal, signaling regions and critical periods of exposure of the sensitized population. The illustrated data can help the community of allergy specialists to view the temporal and spatial distribution of aeroallergens across the country. In addition, this information can guide clinicians to select the most appropriate allergens for allergy diagnostic testing, treatment, and allergen avoidance.
Vandenplas, O; Froidure, A; Meurer, U; Rihs, H-P; Rifflart, C; Soetaert, S; Jamart, J; Pilette, C; Raulf, M
Recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergen components have been developed to assess the patients' allergen sensitization profile and to improve the diagnosis of NRL allergy. To examine whether the determination of specific IgE (sIgE) reactivity to a panel of recombinant allergen components would be helpful for diagnosing NRL-induced occupational asthma (OA) in predicting the outcome of a specific inhalation test. sIgE levels to NRL extract and 12 recombinant NRL allergen components were assessed in 82 subjects with OA ascertained by a positive specific inhalation challenge (SIC) with NRL gloves and in 25 symptomatic subjects with a negative challenge. The sensitivity, specificity, positive predictive value, and negative predictive value of a NRL-sIgE level ≥0.35 kUA /l as compared to the result of SICs were 94%, 48%, 86%, and 71%, respectively. The positive predictive value increased above 95% when increasing the cutoff value to 5.41 kUA /l. Subjects with a positive SIC showed a significantly higher rate of sIgE reactivity to rHev b 5, 6.01, 6.02, and 11 than those with a negative SIC. A sIgE sum score against rHev b 5 plus 6.01/6.02 ≥ 1.46 kUA /l provided a positive predictive value >95% with a higher sensitivity (79%) and diagnostic efficiency (Youden index: 0.67) as compared with a NRL-sIgE ≥5.41 kUA /l (49% and 0.41, respectively). In suspected OA, high levels of sIgE against rHev b 5 combined with rHev b 6.01 or 6.02 are the most efficient predictors of a bronchial response to NRL. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Bhalla, P L; Swoboda, I; Singh, M B
Hay fever and allergic asthma triggered by grass pollen allergens affect approximately 20% of the population in cool temperate climates. Ryegrass is the dominant source of allergens due to its prodigious airborne pollen production. Lol p 5 or group 5 is among the most important and widespread grass pollen allergen because it reacts with IgE antibodies of more than 90% of grass pollen-allergic patients, contains most of the grass pollen-specific IgE epitopes and elicits strong biological responses. Significant efforts have been made in developing diagnostic and therapeutic reagents for designing new and more effective immunotherapeutic strategies for treatment of allergic diseases. An alternative approach to this problem could be to reduce the amount of allergen content in the source plant. High velocity microprojectile bombardment was used to genetically engineer ryegrass. Antisense construct targeted to one of major allergen, Lol p 5, was introduced. The expression of antisense RNA was regulated by a pollen-specific promoter. Pollen was analysed for IgE reactivity. Analysis of proteins with allergen-specific monoclonal and polyclonal antibodies did not detect Lol p 5 in the transgenic pollen. The transgenic pollen showed remarkably reduced allergenicity as reflected by low IgE binding capacity of pollen extract as compared to control pollen. The transgenic ryegrass plants in which Lol p 5 gene expression is perturbed showed normal fertile pollen development. Our studies showed that it is possible to selectively 'switch off' allergen production in pollen of ryegrass demonstrating feasibility of genetic engineering of plants for reduced allergenicity. Copyright 2001 S. Karger AG, Basel
Marchei, P; Diverio, S; Falocci, N; Fatjó, J; Ruiz-de-la-Torre, J L; Manteca, X
In a previous experiment, the behaviour of Oriental/Siamese/Abyssinian (OSA) kittens was compared with that of Norwegian Forest kittens (NFO) in a repeated Open Field Test (OFT), and significant differences emerged. To further investigate such variations, we analyzed kittens' responses to a potentially threatening object (TO) during the OFT. It was a metal spring enveloped in a cotton case suddenly bouncing out of the cylinder after the first 6 min of OFT exposure, and the test lasted 6 more minutes. From the 4th to the 10th week of age, during each test, the response of 43 OSA kittens and 39 NFO kittens to the TO was analyzed. Heart rate (HR) before and after the test was recorded. Behaviours were recorded and analyzed by focal animal sampling. Behavioural modifications recorded after TO exposure confirmed our suggestions on slow limbic system development in NFO kittens, as previously suggested by poor habituation and poor memory retention of repeated OFT exposure. The evident avoiding response to the TO confirmed the adoption in NFO kittens of an active-coping strategy towards challenge, as indicated also by their high scores for exploration and escape attempts. Otherwise, poor TO influence on exploration observed in OSA kittens suggested the adoption of a passive coping strategy, as previously shown by low levels of exploration and intra-session reduction in the number of vocalizations. Nevertheless, some of the behaviours observed, and the evidence of emotional tachycardia in OSA kittens, suggested also that the low level of activity recorded could have been due to a low arousability predisposition in this breed. The perception of a poorly arousing potential in the experimental setting might have influenced the perception of danger and the behaviour adopted in OSA kittens.
Larenas Linnemann, Désirée; Arias Cruz, Alfredo; Guidos Fogelbach, Guillermo Arturo; Cid del Prado, Mari Lou
Immunotherapy is the only recognized causal treatment for allergies. It is prepared on an individual basis, based on the patient's clinical history and the result of the skin prick test (SPT). An adequate composition of the allergens with which to test the patient is crucial for an optimal diagnosis. To know allergens used in tests in allergy practices in Mexico. A national survey among all members of the Colegio Mexicano de Inmunología Clínica y Alergia (CMICA) and of the Colegio Mexicano de Pediatras Especialistas en Inmunología Clínica y Alergia (COMPEDIA) was carried out. In a second phase respondents were asked to send in the composition of a routine SPT in their clinic. The results are presented descriptively and the frequency is calculated by which certain allergen is tested in the interviewed practices. A survey response rate of 61 (17%) was obtained and 54% showed their SPT content. Weeds' representation in the SPT seems adequate; Atriplex is tested in all allergy practices. Some trees that show cross-reactivity might be eliminated from the SPT, but 20% doesn't test for Cynodon nor Holcus, and 25% doesn't for important allergens as cat, dog and cockroach. House dust and tobacco are still tested with certain frequency. The selection of which allergens to test in a SPT is based on multiple data, that change continuously with new investigations and discoveries. Our specialty is the most indicated--and obligated--to adjust constantly to these changes to have the best diagnostic tool to detect specific allergies.
Armentia, Alicia; Arranz, Eduardo; Hernandez, Nora; Garrote, Antonio; Panzani, Raphael; Blanco, Alfredo
Cereals are among the major foods in type I food hypersensitivity reactions. Hypoallergenic cereals and recombinant immunotherapy have been recently patented. In celiac disease, limited information is available regarding cereal allergens responsible for allergic reactions. The allergenic reactivity of ingested and inhaled cereal allergens in allergic and celiac people are discussed in the manuscript. Allergic sensitisation IgE mediated to cereals may be observed in celiac children. Inhalation and ingestion routes causing cereal allergy seem to involve similar allergens, but, in celiac disease specific response to CM3 may be important.
Wu, Weijia; Samoszuk, Michael K.; Comhair, Suzy A.A.; Thomassen, Mary Jane; Farver, Carol F.; Dweik, Raed A.; Kavuru, Mani S.; Erzurum, Serpil C.; Hazen, Stanley L.
Eosinophils promote tissue injury and contribute to the pathogenesis of allergen-triggered diseases like asthma, but the chemical basis of damage to eosinophil targets is unknown. We now demonstrate that eosinophil activation in vivo results in oxidative damage of proteins through bromination of tyrosine residues, a heretofore unrecognized pathway for covalent modification of biologic targets in human tissues. Mass spectrometric studies demonstrated that 3-bromotyrosine serves as a specific “molecular fingerprint” for proteins modified through the eosinophil peroxidase-H2O2 system in the presence of plasma levels of halides. We applied a localized allergen challenge to model the effects of eosinophils and brominating oxidants in human lung injury. Endobronchial biopsy specimens from allergen-challenged lung segments of asthmatic, but not healthy control, subjects demonstrated significant enrichments in eosinophils and eosinophil peroxidase. Baseline levels of 3-bromotyrosine in bronchoalveolar lavage (BAL) proteins from mildly allergic asthmatic individuals were modestly but not statistically significantly elevated over those in control subjects. After exposure to segmental allergen challenge, lung segments of asthmatics, but not healthy control subjects, exhibited a >10-fold increase in BAL 3-bromotyrosine content, but only two- to threefold increases in 3-chlorotyrosine, a specific oxidation product formed by neutrophil- and monocyte-derived myeloperoxidase. These results identify reactive brominating species produced by eosinophils as a distinct class of oxidants formed in vivo. They also reveal eosinophil peroxidase as a potential therapeutic target for allergen-triggered inflammatory tissue injury in humans. PMID:10811853
Kang, Min Gyu; Kim, Mi Yeong; Song, Woo Jung; Kim, Sujeong; Jo, Eun Jung; Lee, Seung Eun; Kwon, Jae Woo; Lee, Sang Min; Park, Chan Sun; Park, Hye Kyung; Park, Heung Woo; Chang, Yoon Seok; Lee, Jaechun; Lee, Young Min; Jee, Young Koo; Lee, Jong Myung; Choi, Inseon S; Cho, Sang Heon
Inhalant allergen sensitization is one of the major factors involved in the pathogenesis of allergic respiratory diseases. However, the sensitization is determined by interactions between genetic and environmental factors. Thus, testing panels of inhalant allergens may differ among geographical areas. Here we aimed to determine 10 common inhalant allergens in Korean adult patients with suspected respiratory allergies and to examine the variation between different geographical locations. A total of 28,954 patient records were retrieved for retrospective analysis, from 12 referral allergy clinics located in 9 different areas. Inclusion criteria were Korean adults (≥18 years old) who underwent the inhalant allergen skin prick test for suspected history of respiratory allergy. The primary outcome was inhalant allergen skin prick response. Demographic and clinical information were also collected. Positive skin prick responses to allergens were defined as allergen-to-histamine wheal ratio ≥1. Based on skin test results, the most prevalent aeroallergens were determined. The overall prevalence of allergic sensitization was 45.3%. Dermatophagoides farinae and Dermatophagoides pteronyssinus were the most commonly sensitized allergens. Other common inhalant allergens were cat epithelium (8.1%), birch (7.7%), mugwort (6.9%), alder (6.7%), hazel (6.7%), beech (6.7%), oak (6.6%), and Tyrophagus putres (6.2%), in decreasing order frequency. These 10 inhalant allergens explained 90% of inhalant allergen sensitization in the study participants. However, distinct patterns of the 10 inhalant sensitization were observed in patients living in Chungnam and Jeju. American cockroach, Gernam cockroach, and Trichophyton metagrophytes were unique in Chungnam. Orchard, Japanese cedar, and Velvet were unique in Jeju. The present analysis suggests a panel of 10 most common inhalant allergens in Korean adult patients with suspected respiratory allergies, which explained 90% of inhalant
Manning, Louise; Soon, Jan Mei
Protein components in food can trigger immune-mediated response in susceptible individuals. International law requires risk assessment to be undertaken by competent individuals to minimize food safety risk to consumers. Historically, allergen control legislation has been food focused and on the requirement for on pack labeling, and the need for formal food recalls in the event of misleading or inappropriate labeling. In order to develop a mechanism for decision makers when assessing allergenic risk from plant derived materials, the aim of this research was to consider a more holistic risk assessment method whereby rather than just using the food-based approach, an additive element in terms of considering the families of proteins is included. This approach reflects the need for food professionals to fully understand the role of proteins in triggering an allergic response to plant material and the health risk to individuals who show cross-reactivity to such proteins.