The Journal of Allergy and Clinical Immunology
Volume 123, Issue 3 , Pages 575-578, March 2009

Advances in environmental and occupational disorders in 2008

  • Robert K. Bush, MD

      Affiliations

    • Department of Medicine, Section of Allergy, Immunology, Pulmonary, Critical Care, and Sleep Medicine, University of Wisconsin, Madison, Wis
    • Corresponding Author InformationReprint requests: Robert K. Bush, MD, K4/910 CSC 9988, 600 Highland Ave, Madison, WI 53792.
    • ,
  • David B. Peden, MD

      Affiliations

    • Department of Pediatrics, Division of Allergy, Immunology, Rheumatology, and Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, NC

Received 26 January 2009; accepted 28 January 2009.

Article Outline

Substantial progress in understanding the role of environmental factors in allergic disease and asthma has been made in the past year. A number of new allergens have been described, and the impact of exposure to indoor allergens in the development of allergic respiratory disease is further confirmed. Exposures to environmental pollutants, particularly tobacco smoke in children, have furthered our knowledge of the detrimental effects of these exposures. This review highlights key advances in environmental and occupational exposures that contribute to the burden of allergic respiratory disease.

Key words: Allergens, molds, allergic sensitization, diagnostic approaches, therapeutic approaches

Abbreviations used: BAL, Bronchoalveolar lavage, CCD, Cross-reactive carbohydrate determinant, MDI, Methylene diphenyl diisocyanate, sCD14, Soluble CD14, TDI, Toluene diisocyanate

 

Allergic disease arises from immune responses to various environmental exposures. We review the significant articles published in the Journal in the past year, emphasizing the critical nature of the allergens and other exposures such as pollutants and other factors that affect the development of allergic disease (Table I).

Table I. Key advances in environmental and occupational disorders in 2008
1.Global warming may markedly modify pollination patterns, with potentially wide-ranging impact on allergic disease.
2.Exposure to indoor allergens, including mouse allergen, continues to be an important factor in pathogenesis of allergic disease.
3.Sensitization to allergens alone does not necessarily predict disease, whether in occupational or domestic settings.
4.Molecular techniques have catalyzed identification of specific allergens derived from environmental and occupational sources.
5.Tobacco smoke is an important TH2 adjuvant in development and expression of allergic disease.
6.Airway endotoxin and innate immune processes may have an important impact on responsiveness of patients with asthma to corticosteroids.

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Allergens 

Although controversial, climate change (global warming) is a potentially significant factor that will contribute to allergic disease burden in the future. An excellent review by Shea et al1 describes how these climate changes can not only affect exposure to pollens but also contribute to air pollution, and describes weather patterns that may have significant impact on asthma and other allergic diseases.

Basagaña et al2 identified cross-reactivity between dog dander allergens and human prostate-specific antigen, which may be a factor in enhanced risk for individuals to develop sensitivities to human seminal plasma. Although rare, this is an important issue for some patients.

Wagner et al3 examined various isoforms of the major birch pollen allergen, Bet v 1. Of the various isotypes, 2, Bet v 1.0401 and Bet v 1.1001, induce only minimal IgE responses. Bet v 1.0101 acts as the principal sensitizing agent. The identification of these hypoallergenic isotypes may lead to improved vaccine therapies in the future.

Jin et al4 examine the affinity of IgE for cross-reactive carbohydrate determinants (CCDs) on plant and insect glycoproteins. Although there is low affinity for these determinants by IgE, this is not the principal reason for the observed clinical insignificance of IgE in patients so sensitized. The affinity of IgG to CCDs is higher than to protein allergens and therefore may serve as a blocking antibody. This has significance in terms of explaining the lack of significant reactions to these molecules, even though they can be demonstrated with in vitro testing.

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Molds 

Three submissions were of note. Rabito et al5 reported on children residing in New Orleans whose homes were affected by Hurricane Katrina. Amongst these individuals, there was an overall decrease in indoor fungal levels over a 6-month period, and any respiratory symptoms present at the time of the hurricane also diminished. At the end of the period, these children had normal lung functions. This study suggests that exposure to indoor fungi does not impair long-term lung function in these individuals.

Horner et al6 produced an excellent review regarding the interpretation of reports from inspections or investigations of indoor molds in home environments. This article should be of great practical benefit to the practicing allergist.

Schmechel et al7 examine polyclonal antibodies used for assaying levels of Alternaria antigens by immunoassays. Their studies indicate that these polyclonal antibodies cross-react with a broad variety of fungi such as Aspergillus, Penicillin, Fusarium, and Cladosporium. This suggests the use of polyclonal antibodies to detect antigen levels in indoor environments cannot reflect necessarily the specific fungus but can indicate exposure to a broader range of fungi.

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Allergic sensitization 

Kim et al8 examined a large population of individuals residing in rural China. Sensitization was found in 47% to 1 or more allergens involved in the study. The most common sensitizers were shellfish, dust mites, and cockroaches, but fewer than 1% of these individuals had self-reported food allergy or asthma. This demonstrates a discrepancy between sensitization and actual disease. Further, Yang et al9 also examined reported differences in allergic sensitizations by self-reported race and genetic ancestry. The race and location of residence appear to be more important predictors of allergic sensitization than genetic ancestry, suggesting that disparities in allergic sensitization by race may be result of environmental rather than genetic factors.

The importance of indoor allergens' relationship to asthma was again verified by the study of Salo et al,10 in which a national study of homes in the United States demonstrated that exposure to multiple allergens was common in US homes. Fifty-one percent had at least 6 detectable allergens and 45% had at least 3 allergens exceeding a predetermined criterion for increased levels. In atopic individuals, high allergen burden increased the risk of asthma symptoms, again confirming the contribution of the indoor environment to allergic disease.

Chew et al11 examined the allergen levels of cockroach in homes and their association with the development of IgE sensitization. Bla g 2 levels greater than 1 U/g in children's bedroom and kitchen samples were associated with the development of cockroach-specific IgE. Therefore, this appeared to a specific factor in sensitization in children. Donohue et al12 confirmed the importance of both cockroach and mouse antigens as being associated with early wheeze and atopy in an inner-city birth cohort, further demonstrating the concerns of these indoor allergens and their significant effect on human health.

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Diagnostic and therapeutic approaches 

Chapman et al13 reported on the European Union CREATE (Development of Certified Reference Materials for Allergenic Products and Validation of Methods for their Quantification) Project, which is a model for the development of allergen vaccines and standardization based on recombinant allergen molecules. Of the various recombinant allergens, several were certified as potential reference materials, but only 1 recombinant allergen was considered unsuitable. This provides evidence that improvements in allergen and vaccine standardization can and should be achievable.

Platts-Mills14 argued that the use of meta-analyses for assessing control methods for environmental exposure to house dust mite allergens may have certain flaws and that these need to be addressed in such analyses for house dust mite avoidance. Brandt et al15 discussed their evaluation of allergists' attitudes toward environmental controls as an approach to relief of allergic symptoms. Enthusiasm for environmental controls was lessened by concerns for cost and lack of immediate benefits. Patient adherence also contributes to the control failure of such measures and to their widespread adaptation.

Calabria et al16 address the effect of glycerin added to immunotherapy vaccines and its effect on local reactions to immunotherapy. Increasing concentrations of glycerin did not appear to affect the size or rate of local reactions to the vaccine, but rather reaction rates increased with higher allergen concentration, number, and volume. Unfortunately the article did not address the issue of pain at the injection site induced by glycerin.

Finally, Severino et al17 presented a proof-of-concept study of the use of sublingual immunotherapy for large local reactions to Hymenoptera stings. Sublingual immunotherapy was shown to reduce the extent of large local reactions and had a good safety profile. Although large local reactions are not an indication for immunotherapy, the study suggests that further investigation of SLIT in hymenoptera allergy is merited in patients with a systemic reactions.

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Occupational allergy 

A number of intriguing studies employing state of the art molecular biology in occupational allergy reported in the Journal in 2008. In a study of baker's asthma, Bittner et al18 sought to identify and characterize unknown wheat allergens related to this disease. They used a wheat cDNA phage display library to screen for IgE binding to wheat proteins with pooled sera from patients with baker's asthma, with 1 being identified as an αβ gliadin. Serum IgE antibodies to the recombinant allergen were found in 12% of bakers with occupational asthma, and in bakers with asthma, 33% showed sensitization to native total gliadin.

Vanoirbeek et al19 used a murine model of toluene diisocyanate sensitization to examine the relationship between immune responses to toluene diisocyanate (TDI) and TDI-related pathophysiology. They observed that TDI challenge would cause changes in respiratory tract pathophysiology (decreased lung function, increased nonspecific reactivity, and increased respiratory tract inflammation) as long as 50 days after challenge. Immunologic changes in lymph nodes (decreased helper and suppressor T lymphocyte and increased B-lymphocyte populations, as well as increased IL-4 and IFN-γ levels) would persist for 20 days, whereas TDI specific IgE, IgG1, and IgG(2a) were increased as long as 90 days after challenge. Because serology persisted long after loss of symptomatic response, the authors suggested that changes in serum TDI antibodies may persist long after disease abates.

Hur et al20 conducted challenge with methylene diphenyl diisocyanate (MDI) in sensitized persons and unexposed control volunteers, and used proteomic analysis of recovered bronchoalveolar lavage (BAL) fluid to identify novel biomarkers of disease. Unique changes in 23 proteins were observed in persons with symptomatic response to MDI. Among these changes were downregulation of ferritin and upregulation of transferrin expression. Serum levels of ferritin and transferrin were examined, and when changes in both proteins were considered together, they had a sensitivity of 71.43% and specificity was 85.71% for MDI occupational asthma. Together, these studies demonstrate that modern molecular techniques will be useful in identifying novel nonantibody measures of occupational disease.

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Development of airway biomarkers for environmental disease 

There were also studies in which airway samples were used to assess the impact of environmental agents on airway inflammation. Examination of induced sputum for changes in inflammation was reported by Yacoub21 to be a useful method for documenting occupational asthma. Romieu et al22 examined the use of malondialdehyde in exhaled breath condensate as a biomarker of exposure to ambient air pollutants in children with asthma in Mexico City. They found that increased exposure to particulate matter and O3 was linked to increased malondialdehyde and decreased lung function. These studies demonstrate that markers of airway inflammation can be developed as useful measures of the impact of occupational and environmental agents in asthma.

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Innate immunity and asthma 

There continues to be great interest in the role of innate immune responses to environmentally encountered bacterial products in asthma. Vogel et al23 used an animal model to examine the effect of exposure to Bacillus licheniformis spores on the development of atopy. Bacillus was chosen as this was the most common bacteria identified in assessment of dust from farm and bedding samples. In vitro assessment of monocyte response to B licheniformis revealed a TH1 cytokine expression profile. Animal experiments demonstrated that these spores induce a long-lasting immune activation that inhibits development of eosinophilia and goblet cell hyperplasia, but a promotes lung neutrophilia.

LeVan et al24 examined the effect of endotoxin challenge with 20 μg endotoxin in 88 healthy volunteers genotyped for CD14 protomer polymorphisms at the -1619, -1359, and -159 loci, focusing on systemic leukocyte, C-reactive protein, LPS-binding protein, and soluble CD14 (sCD14) responses to challenge. Homozygotes for the -1619G, -1359G, and -159T alleles had higher baseline levels of sCD14. Although challenge resulted in significant increases in white cells, C-reactive protein, LPS-binding protein, and sCD14 levels, no influence of CD14 genotype on these responses was noted.

Pacheco et al25 conducted questionnaire surveys of 335 laboratory workers who use animals, of whom 21% were sensitized to animals and 29% reported symptoms with exposure. These volunteers were genotyped for the Toll-like receptor 4/8551 polymorphism. The G variant, which is associated with decreased responsive to endotoxin, was detected in 9% and was significantly associated with atopy and sensitization to laboratory animals. Interestingly, workers with the G variant spent significantly longer hours in high endotoxin/animal allergen tasks compared with those with the AA variant. In multivariate analyses, the G variant and longer animal research hours increased the risk of laboratory animal sensitization.

Goleva et al26 authored a very intriguing report on the impact of airway endotoxin in severe asthma. They identified persons who were responsive to oral prednisone, as defined by improvement in FEV1 after 1 week of treatment. They found that BAL cells recovered from persons with steroid-resistant asthma had increased levels expression of proinflammatory genes. This was associated with increased levels of endotoxin in the BAL samples of steroid-resistant volunteers. Furthermore, in vitro studies of prolonged exposure to LPS resulted in functional steroid resistance to dexamethasone in normal human monocytes. These studies suggest that airway endotoxin, perhaps resulting from either bacterial colonization of the airway or inhalation of environmental endotoxin, influences steroid response in asthma.

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Indoor air pollution, tobacco smoke, and asthma 

A review article provided by Bernstein et al27 outlined the role of exposure to nonoccupational environmental agents on airway disease. A number of the agents noted included, many usually thought of as outdoor ambient pollutants, including ozone and particulate matter, are also relevant in indoor environments. In addition, well known indoor sources like tobacco smoke remain significant triggers of disease, despite increased public awareness of the adverse effects of tobacco.

Two studies from the same laboratory by Yu et al28 and Wang et al29 using a rhesus monkey model found that exposure of pregnant animals to tobacco smoke resulted in a distinct skewing toward a TH2 immune response in the offspring. These included increased respiratory tract TH2 cytokines and increased mast cell and eosinophils influx into tissues. Infant monkeys born to smoke-exposed mothers also had increased plasma endotoxin levels.

In studies of adults with allergic rhinitis, smoking was found to have a notable effect on the development of asthma. Polosa et al30 examined data from 325 patients collected over a 10-year period and found a dose-related effect of smoking with development of asthma in patients with allergic rhinitis. A history of 1 to 10 pack-years resulted in an odds ratio of 2.05 for incident asthma, with an odds ratio of 3.7 and 5.05 for 11 to 20 and >20 pack-years, respectively. In a study of the effect on montelukast in children with asthma, Rabinovitch31 found a baseline relationship between urinary leukotriene E4 levels and albuterol use that was significantly decreased by montelukast. Of note, the effect of montelukast was significantly greater in children with an increased urinary cotinine level, suggesting that leukotrienes play an important role in smoking-induced exacerbations of asthma.

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Summary 

An exciting concept that is emerging to explain the effects of a variety of environmental influences on allergic disease is the role of oxidant stress on inflammatory processes. The effects of oxidants and variation of responses attributed to genetic variation in antioxidant defenses was outlined in a review by Ciencewicki et al.32 Continued examination of the biology of innate immune responses, oxidant stress, and the interaction between these 2 processes shows great promise to an improved general understanding of the biology of allergic disease. Coupled with examination of novel environmental and occupational allergens, allergen immunotherapy, and the impact of the global environment on allergic disease, we anticipate that studies will be of central importance to the allergy community in coming years and will remain an important content area for the Journal.

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References 

  1. Shea KM, Truckner RT, Weber RW, Peden DB. Climate change and allergic disease. J Allergy Clin Immunol. 2008;122:443–453
  2. Basagaña M, Bartolome B, Pastor C, Torres F, Alonso R, Vivanco F, et al. Allergy to human seminal fluid: cross-reactivity with dog dander. J Allergy Clin Immunol. 2008;121:233–239
  3. Wagner S, Radauer C, Bublin M, Mann-Sommergruber KH, Kopp T, Greisenegger EK, et al. Naturally occurring hypoallergenic Bet v 1 isoforms fail to induce IgE responses in individuals with birch pollen allergy. J Allergy Clin Immunol. 2008;121:246–252
  4. Jin C, Hantusch B, Hemmer W, Stadimann J, Altmann F. Affinity of IgE and IgG against cross-reactive carbohydrate determinants on plant and insect glycoproteins. J Allergy Clin Immunol. 2008;121:185–190
  5. Rabito FA, Iqbal S, Kiernan MP, Holt E, Chew GL. Children's respiratory health and model levels in New Orleans after Katrina: a preliminary look. J Allergy Clin Immunol. 2008;121:622–625
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  28. Yu M, Zheng X, Peake J, Joad JP, Pinkerton KE. Perinatal environmental tobacco smoke exposure alters the immune response and airway innervation in infant primates. J Allergy Clin Immunol. 2008;122:640–647
  29. Wang L, Joad JP, Zhong C, Pinkerton KE. Effects of environmental tobacco smoke exposure on pulmonary immune response in infant monkeys. J Allergy Clin Immunol. 2008;122:400–406
  30. Polosa R, Knoke JD, Russo C, Piccillo G, Caponnetto P, Sarva M, et al. Cigarette smoking is associated with a greater risk of incident asthma in allergic rhinitis. J Allergy Clin Immunol. 2008;121:1428–1434
  31. Rabinovitch N, Strand M, Stuhlman K, Gelfand EW. Exposure to tobacco smoke increases leukotriene E4-related albuterol usage and response to montelukast. J Allergy Clin Immunol. 2008;121:1365–1371
  32. Ciencewicki J, Trivedi S, Kleeberger SR. Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol. 2008;122:456–468

 Disclosure of potential conflict of interest: R. K. Bush has received research support from the National Institutes of Health and Greer Laboratories. D. B. Peden has received research support from the National Institutes of Health and the US Environmental Protection Agency, has provided legal consultation or expert witness testimony in court cases related to air quality, and is a consultant for GlaxoSmithKline and Funxional Therapeutics.

PII: S0091-6749(09)00215-2

doi:10.1016/j.jaci.2009.01.062

The Journal of Allergy and Clinical Immunology
Volume 123, Issue 3 , Pages 575-578, March 2009