Epidemiology of dust-mite-related disease

For many years it has been suggested that allergens derived from the house dust mite played a major role in the pathogenesis of asthma, eczema and some cases of allergic rhinitis. Recently, house dust mite allergens have been purified and specific immunoassays developed with which exposure to house dust mites and their allergens can be more easily determined. Using these tools, epidemiological studies have provided confirmatory evidence that not only is house dust mite exposure associated with the majority of cases of asthma in children and young adults, but that it is causally related to the development of asthma.     

Allergen exposure and control

Allergens produced by the house dust mites (family Pyroglyphidae) are probably the single most important allergens associated with asthma world wide. If exposure to these allergens in houses could be sufficiently reduced, then asthma symptoms may be markedly reduced and even prevented from being initiated. Only about half of the many attempts to reduce mite allergens in houses have shown any clinical benefit. One reason may be that exposure was not reduced enough-however exposure to mite allergens has never been measured in any trial. This review summarises previous allergen control trials and then provides an outline of allergen exposure, including the nature of exposure, the analytical methods available and the recognised risks of allergen exposure. This provides a perspective to evaluate the individual methods used to kill mites and to reduce exposure to the allergens. The object is to provide a framework to improve and develop allergen avoidance as an effective component of asthma management.The author is supported by a project grant from the National Heath and Medical Research Council of Australia.     

Laboratory animal allergens

Allergic sensitivity to laboratory animals can pose a significant occupational hazard to anyone with regular animal contact. Reactions to mice and rats are most common although all furred animals produce allergens that can lead to sensitization and disease. Most of the relevant allergens of laboratory animals have been defined and characterized, which has revealed that these allergens are typically small, acidic glycoproteins and that many of them are members of a superfamily of extracellular proteins called lipocalins. In addition to understanding their molecular characteristics, the identification of these allergens has also made it possible to measure their distribution in laboratory environments and to relate exposure levels to sensitization and symptoms. These studies have shown that the major laboratory animal allergens are carried on small particles that are both capable of remaining airborne for extended periods and penetrating into the lower airways of exposed workers. These advances in the understanding of these important occupational allergens will allow for the development of better methods of diagnosis and avoidance for affected workers and others who may be at risk for future difficulties.     

Early Exposure to Respiratory Allergens by Placental Transfer and Breastfeeding

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.     

New immunodiagnostic system

We have developed a new immunodiagnostic system whichmeasures personal allergen exposure and which can beused to identify allergens.Personal exposure is directly sampled using inertialimpaction filters which fit just inside the nose andcollect particles (mainly >5 µm) inhaled duringnormal respiration. These samplers provide both anindex of personal exposure as well as being aninexpensive and portable sampling system.The particles are captured on adhesive tapes which arethen laminated with a protein-binding membrane. Theallergens eluting from the particles are bound by the membrane in theperiphery of each particle. The systemthen uses either allergen-specific monoclonalantibodies or the subject's IgE as primary probes toimmuno-label the `halo' of allergen around individualallergen-containing particles. Such an assay is verysensitive and can detect a single particle carryingallergens. In addition, the system providesinformation on the size, shape and allergen content ofthe particles. Because the particles carryingallergens can be seen, high resolution video images ofpollen grains and fungal spores can be subjected to atraditional morphological study or a range of featureextraction routines. This information can be comparedto a database of some known allergenic pollen grainsand fungal spores which we have also assembled tofacilitate their identification.When using monoclonal antibodies as the probe, thesystem determines the amount of allergen the subjectis exposed to and the characteristics of the particles(size, shape, etc). When using the subject's IgE as theprobe, the system allows visualisation of the allergensources that an individual is allergic to. The systemmay have clinical applications in quantifying personalexposure as well as identifying allergens anddetermining exposure to unsuspected allergens.     

Structure and Function of the Peanut Panallergen Ara h 8

The incidence of peanut allergy continues to rise in the United States and Europe. Whereas exposure to the major allergens Ara h 1, 2, 3, and 6 can cause fatal anaphylaxis, exposure to the minor allergens usually does not. Ara h 8 is a minor allergen. Importantly, it is the minor food allergens that are thought to be responsible for oral allergy syndrome (OAS), in which sensitization to airborne allergens causes a Type 2 allergic reaction to ingested foods. Furthermore, it is believed that similar protein structure rather than a similar linear sequence is the cause of OAS. Bet v 1 from birch pollen is a common sensitizing agent, and OAS results when patients consume certain fruits, vegetables, tree nuts, and peanuts. Here, we report the three-dimensional structure of Ara h 8, a Bet v 1 homolog. The overall fold is very similar to that of Bet v 1, Api g 1 (celery), Gly m 4 (soy), and Pru av 1 (cherry). Ara h 8 binds the isoflavones quercetin and apigenin as well as resveratrol avidly.     

The human allergens of mesquite (Prosopis juliflora)

BACKGROUND: A computerized statistical analysis of allergy skin test results correlating patient reactivities initiated our interest in the cross-reactive allergens of mesquite tree pollen. In-vitro testing with mesquite-sensitized rabbits and a variety of deciduous tree pollens revealed so many cross-reactivities that it became apparent there could be more allergens in mesquite than previously described in the world literature. Our purpose was to examine the allergens of mesquite tree pollen (Prosopis juliflora) which elicit an IgE response in allergic humans so that future research could determine if these human allergens cross-react with various tree pollens in the same manner as did the mesquite antiserum from sensitized rabbits. METHODS: Proteins from commercial mesquite tree pollen were separated by polyacrylamide gel electrophoresis in the presence of sodium-dodecyl-sulphate. These mesquite proteins were subjected to Western blotting using pooled sera from ten mesquite-sensitive patients and goat anti-human IgE. The allergens were detected using an Amplified Opti-4-CN kit, scanned, and then interpreted by Gel-Pro software. RESULTS: Thirteen human allergens of mesquite pollen were detected in this study. CONCLUSION: The number of allergens in this study of mesquite exceeded the number identified previously in the literature. With the increased exposure to mesquite through its use in "greening the desert", increased travel to desert areas and exposure to mesquite in cooking smoke, the possible clinical significance of these allergens and their suggested cross-reactivity with other tree pollens merit further study.     

Laboratory animal allergy: a British perspective on a global problem

In the United Kingdom, laboratory animal allergy (LAA) has been recognized as an important occupational disease for nearly 25 years. However, introduction of health and safety legislation (e.g., the Control of Substances Hazardous to Health Regulations of 1988) and an increasing knowledge of the factors that contribute to the etiology of this disease have had surprisingly little impact on the prevalence and incidence of LAA over the last 10 to 20 yr. Studies of the relation between exposure to animal allergens and the development of LAA reveal that the risk of disease increases with increasing intensity of exposure. Current evidence suggests that animal allergens are very potent, and substantial decreases in allergen exposure are therefore necessary before a reduction in symptoms will be observed. In the United Kingdom, it is unlikely that an Occupational Exposure Limit will be set for animal allergens in the near future, partly because an adequately standardized assay for quantifying exposure is not yet available. Prevention of LAA in the future will probably be driven by the needs of the industry and will most likely rely on the adoption of guidelines describing " best practise" which incorporate sophisticated engineering methods of controlling exposure to animal allergens.     

Laboratory animal allergy: an update

Allergic reactions are among the most common conditions affecting the health of workers involved in the care and use of research animals. Between 11 and 44% of the individuals working with laboratory animals report work-related allergic symptoms. Of those who become symptomatic, 4 to 22% may eventually develop occupational asthma that can persist even after exposure ceases. Allergic symptoms consist of rashes where animals are in contact with the skin, nasal congestion and sneezing, itchy eyes, and asthma (cough, wheezing, and chest tightness). The generation of immunoglobulin E (IgE) antibodies is a prerequisite for the production of allergic symptoms. The mechanism by which IgE antibodies develop is becoming clearer. The propensity to produce IgE is genetically determined, and pre-existing allergy may be a risk factor for the development of laboratory animal allergy (LAA). However, exposure to animal allergens is the major risk factor for the development of LAA. Techniques to measure the airborne concentration of laboratory animal allergens have been developed. Research on animal allergens themselves indicates that many of the mouse and rat urinary proteins belong to a family of proteins called lipocalins, which share sequence homology with antigens of the parasitic agent that causes schistosomiasis. The fact that parasite infections also trigger IgE antibody responses may account for the development of LAA in persons who have never had any previous allergy. The prevention of LAA should be a major goal of an effective health and safety program in the animal research facility, and it can be accomplished by education and training of employees, reduction of exposure (including the use of personal protective gear), and changes in facility design. Medical surveillance programs can also play a role in improving health of individuals working with laboratory research animals. Early recognition of symptoms and evidence of sensitization can lead to interventions to reduce exposure and thereby avoid the long-term health consequences of LAA.     

Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study

ObjectiveTo investigate the importance of sensitisation and exposure to allergens and viral infection in precipitating acute asthma in adults resulting in admission to hospital.DesignCase-control study.SettingLarge district general hospital.Participants60 patients aged 17-50 admitted to hospital over a year with acute asthma, matched with two controls: patients with stable asthma recruited from the outpatient department and patients admitted to hospital with non-respiratory conditions (inpatient controls).ResultsViruses were detected in 31 of 177 patients. The difference in the frequency of viruses detected between the groups was significant (admitted with asthma 26%, stable asthma 18%, inpatient controls 9%; P=0.04). A significantly higher proportion of patients admitted with asthma (66%) were sensitised and exposed to either mite, cat, or dog allergen than patients with stable asthma (37%) and inpatient controls (15%; P<0.001). Being sensitised and exposed to allergens was an independent associate of the group admitted to hospital (odds ratio 2.3, 95% confidence interval 1.0 to 5.4; P=0.05), whereas the combination of sensitisation, high exposure to one or more allergens, and viral detection considerably increased the risk of being admitted with asthma (8.4, 2.1 to 32.8; P=0.002).ConclusionsAllergens and viruses may act together to exacerbate asthma.

What is already known on this topic

Studies on segmental allergen challenge of the lung and experimental rhinovirus infection show synergistic effects between allergens and respiratory virus infectionNo studies have investigated an interaction between sensitisation, exposure to allergens, and virus infections in real life exacerbations of asthma

What this study adds

Allergens and viruses may act together to exacerbate asthma, indicating that domestic exposure to allergens acts synergistically with viruses in sensitised patients, increasing the risk of hospital admissionStrategies to reduce the impact of asthma exacerbations in adults should include interventions directed at both viruses and reducing exposure to allergens     

Effects of food processing on the stability of food allergens

The ubiquitous presence of allergens in the human food supply coupled with increased awareness of food allergies warrants undertaking appropriate preventive measures to protect sensitive consumers from unwanted exposure to offending food allergens. Attempts to reduce or eliminate food allergenicity through food processing have met with mixed results. The rationale for using food processing to reduce/eliminate allergenicity and limitations to using this approach are discussed.     

A review of Alternaria alternata sensitivity

Sensitivity to fungi is a major risk factor for the development of asthma. However, the prevalence of fungal sensitivity in asthma is not completely understood. Nonetheless upward of 80% of asthmatic patients may be sensitized to one or more fungi. Fungal exposure occurs primarily from outdoors sources, but can occur in the indoor environment as well. Assessment of fungal exposure requires a multifaceted approach including measurement of airborne spores and culture techniques to identify the relevant organisms. Preventing intrusion of outdoor fungal spores into the indoor environment may be helpful in reducing allergic symptoms. Methods to abate indoor fungal growth include reduction of indoor humidity and removal of water sources. Patients with fungal sensitivity should be advised to avoid exposure as much as possible. For patients who have failed to respond to environmental control measures and appropriate medications, it may be reasonable to consider specific immunotherapy. The application of molecular biology techniques to the study of allergens has enhanced the researcher's ability to produce Alternaria allergens in quantity, to determine their biological relevance, as well as to evaluate mechanisms of Alternaria sensitivity. We look forward to new developments and improved treatments through modulation of the immune response with molecularly produced and well characterized fungal allergy.     

Endotoxin Exposure during Sensitization to Blomia tropicalis Allergens Shifts TH2 Immunity Towards a TH17-Mediated Airway Neutrophilic Inflammation: Role of TLR4 and TLR2

Experimental evidence and epidemiological studies indicate that exposure to endotoxin lipopolysaccharide (eLPS) or other TLR agonists prevent asthma. We have previously shown in the OVA-model of asthma that eLPS administration during alum-based allergen sensitization blocked the development of lung TH2 immune responses via MyD88 pathway and IL-12/IFN-γ axis. In the present work we determined the effect of eLPS exposure during sensitization to a natural airborne allergen extract derived from the house dust mite Blomia tropicalis (Bt). Mice were subcutaneously sensitized with Bt allergens co-adsorbed onto alum with or without eLPS and challenged twice intranasally with Bt. Cellular and molecular parameters of allergic lung inflammation were evaluated 24 h after the last Bt challenge. Exposure to eLPS but not to ultrapure LPS (upLPS) preparation during sensitization to Bt allergens decreased the influx of eosinophils and increased the influx of neutrophils to the airways. Inhibition of airway eosinophilia was not observed in IFN-γdeficient mice while airway neutrophilia was not observed in IL-17RA-deficient mice as well in mice lacking MyD88, CD14, TLR4 and, surprisingly, TLR2 molecules. Notably, exposure to a synthetic TLR2 agonist (PamCSK4) also induced airway neutrophilia that was dependent on TLR2 and TLR4 molecules. In the OVA model, exposure to eLPS or PamCSK4 suppressed OVA-induced airway inflammation. Our results suggest that B. tropicalis allergens engage TLR4 that potentiates TLR2 signaling. This dual TLR activation during sensitization results in airway neutrophilic inflammation associated with increased frequency of lung TH17 cells. Our work highlight the complex interplay between bacterial products, house dust mite allergens and TLR signaling in the induction of different phenotypes of airway inflammation.     

A DNA aptamer recognizes the Asp f 1 allergen of Aspergillus fumigatus

Allergies are caused by the binding of IgE antibodies onto specific sites on allergens. However, in the assessment of exposure to airborne allergens, current techniques such as whole spore counts fail to account for the presence of these allergenic epitopes that trigger allergic reactions. The objective of the research is to develop a DNA aptamer for the Asp f 1 allergen of the pathogenic fungus Aspergillus fumigatus, using an IgE-binding epitope of the allergen as the target for aptamer selection. Through in vitro SELEX, an aptamer has been produced that binds with nanomolar affinity to the Asp f 1 IgE-epitope. The aptamer is also able to recognize the native Asp f 1 allergen, and does not bind to allergenic proteins from non-target mold species such as Alternaria alternata. Production of this aptamer provides proof-of-principle that allergen measurement methods can be developed to indicate the potent fraction, or allergenicity, of allergens.     

Controlling exposure to laboratory animal allergens

Laboratory animal allergy (LAA) is a significant occupational disease that may affect up to one third of personnel exposed to laboratory animals. Research has characterized the relative risks of exposure, in terms of intensity, frequency, and duration, associated with given tasks and work areas in the animal facility. Studies have shown that reduced exposure to animal allergens can reduce the incidence of LAA and relieve symptoms among affected workers. A combination of measures to eliminate or control allergen exposure, including engineering and administrative controls and personal protective equipment, have been integral components of effective LAA management programs. The author provides a comprehensive review of exposure control options, considerations, and " best practices" relative to laboratory animal allergen in the context of traditional industrial hygiene methods.     

Proteinase-activated receptor-2 promotes allergic sensitization to an inhaled antigen through a TNF-mediated pathway

The reason why particular inhaled Ags induce allergic sensitization while others lead to immune tolerance is unclear. Along with a genetic predisposition to atopy, intrinsic characteristics of these Ags must be important. A common characteristic of many allergens is that they either possess proteinase activity or are inhaled in particles rich in proteinases. Many allergens, such as house dust mite and cockroach allergens, have the potential to activate the proteinase-activated receptor (PAR)-2. In this study, we report that PAR-2 activation in the airways at the same time as exposure to inhaled Ags induces allergic sensitization, whereas exposure to Ag alone induces tolerance. BALB/c mice were administered OVA with a PAR-2 activating peptide intranasally. Upon allergen re-exposure mice developed airway inflammation and airway hyperresponsiveness, as well as OVA-specific T cells with a Th2 cytokine profile when restimulated with OVA in vitro. Conversely, mice given OVA alone or OVA with a PAR-2 control peptide developed tolerance. These tolerant mice did not develop airway inflammation or airway hyperresponsiveness, and developed OVA-specific T cells that secreted high levels of IL-10 when restimulated with OVA in vitro. Furthermore, pulmonary dendritic cell trafficking was altered in mice following intranasal PAR-2 activation. Finally, we showed that PAR-2-mediated allergic sensitization was TNF-dependent. Thus, PAR-2 activation in the airways could be a critical factor in the development of allergic sensitization following mucosal exposure to allergens with serine proteinase activity. Interfering with this pathway may prove to be useful for the prevention or treatment of allergic diseases.     

Allergy to miscellaneous household arthropods

Of the various arthropods, humans have the greatest contact with mites and cockroaches, and as a result, allergies to these two groups have been the most frequently reported. Changes in lifestyle and living environment have encouraged the growth of arthropods other than mites and cockroaches, and consequently, human exposure to antigens derived from the new arthropods has increased. Although systematic approaches to and immunobiochemical studies of these arthropods are relatively sparse compared with those of mites and cockroaches, recent reports have shown that many species of household arthropods can elicit IgE-mediated reactions via inhalation, biting, or stinging. In this chapter, we review the other arthropods that can induce allergic reaction to human beings. Where the information exists, the frequency of sensitivity and clinical manifestation, and the characterization of the allergens are also reviewed. Virtually all species of arthropods may be sources of allergens that can sensitize and induce IgE-mediated allergic reactions in humans.     

Assessment of 3D models for allergen research

Allergenic proteins must crosslink specific IgE molecules, bound to the surface of mast cells and basophils, to stimulate an immune response. A structural understanding of the allergen–IgE interface is needed to predict cross‐reactivities between allergens and to design hypoallergenic proteins. However, there are less than 90 experimentally determined structures available for the approximately 1500 sequences of allergens and isoallergens cataloged in the Structural Database of Allergenic Proteins. To provide reliable structural data for the remaining proteins, we previously produced more than 500 3D models using an automated procedure, with strict controls on template choice and model quality evaluation. Here, we assessed how well the fold and residue surface exposure of 10 of these models correlated with recently published experimental 3D structures determined by X‐ray crystallography or NMR. We also discuss the impact of intrinsically disordered regions on the structural comparison and epitope prediction. Overall, for seven allergens with sequence identities to the original templates higher than 27%, the backbone root‐mean square deviations were less than 2 Å between the models and the subsequently determined experimental structures for the ordered regions. Further, the surface exposure of the known IgE epitopes on the models of three major allergens, from peanut (Ara h 1), latex (Hev b 2), and soy (Gly m 4), was very similar to the experimentally determined structures. For the three remaining allergens with lower sequence identities to the modeling templates, the 3D folds were correctly identified. However, the accuracy of those models is not sufficient for a reliable epitope mapping. © Proteins 2013. © 2012 Wiley Periodicals, Inc.     

Pectate Lyase Pollen Allergens: Sensitization Profiles and Cross-Reactivity Pattern

BackgroundPollen released by allergenic members of the botanically unrelated families of Asteraceae and Cupressaceae represent potent elicitors of respiratory allergies in regions where these plants are present. As main allergen sources the Asteraceae species ragweed and mugwort, as well as the Cupressaceae species, cypress, mountain cedar, and Japanese cedar have been identified. The major allergens of all species belong to the pectate lyase enzyme family. Thus, we thought to investigate cross-reactivity pattern as well as sensitization capacities of pectate lyase pollen allergens in cohorts from distinct geographic regions.MethodsThe clinically relevant pectate lyase pollen allergens Amb a 1, Art v 6, Cup a 1, Jun a 1, and Cry j 1 were purified from aqueous pollen extracts, and patients´ sensitization pattern of cohorts from Austria, Canada, Italy, and Japan were determined by IgE ELISA and cross-inhibition experiments. Moreover, we performed microarray experiments and established a mouse model of sensitization.ResultsIn ELISA and ELISA inhibition experiments specific sensitization pattern were discovered for each geographic region, which reflected the natural allergen exposure of the patients. We found significant cross-reactivity within Asteraceae and Cupressaceae pectate lyase pollen allergens, which was however limited between the orders. Animal experiments showed that immunization with Asteraceae allergens mainly induced antibodies reactive within the order, the same was observed for the Cupressaceae allergens. Cross-reactivity between orders was minimal. Moreover, Amb a 1, Art v 6, and Cry j 1 showed in general higher immunogenicity.ConclusionWe could cluster pectate lyase allergens in four categories, Amb a 1, Art v 6, Cup a 1/Jun a 1, and Cry j 1, respectively, at which each category has the potential to sensitize predisposed individuals. The sensitization pattern of different cohorts correlated with pollen exposure, which should be considered for future allergy diagnosis and therapy.