The studies proposed in this grant are designed to provide new understanding of the role of both indoor allergen exposure and IgE antibodies specific for these proteins in relation to the prevalence and severity of asthma. Our recent investigation of a novel form of anaphylaxis identified IgE antibodies specific for the oligosaccharide galactose-?-1,3-galactose (alpha-gal) that are induced by tick bites. Those responses are common in the southeastern United States and are associated with delayed anaphylaxis following 3-4 hours after consumption of red meat. In keeping with that, the experiments proposed here take advantage of the fact that there are two allergens (alpha-gal and peanut) where sensitization appears to have become more common and which i) give rise to high titer IgE antibodies, ii) are thought to induce IgE antibodies by going through the skin, and iii) are not associated with asthma. Our central hypothesis is that IgE antibodies to protein antigens are an important contributor to asthma if they are chronically inhaled, and also that higher titers of these IgE antibodies increase that risk. The proposed experiments address several aspects of the problem from: I. Studies in developing or """"""""pre-hygiene"""""""" regions, designed to understand why children in those countries do not have either high titer IgE antibodies to inhalant allergens or allergic asthma. These studies will include a comparison of home environments, allergic sensitization, clinical symptoms, and stool microbiome in Ecuador, Costa Rica, and Virginia. II. Studies within a Western """"""""post-hygiene"""""""" environment focused on the evidence that different routes of exposure influence IgE antibody responses. These studies will investigate the effects of allergens on the skin in inducing Th2-related responses, with or without disruption of the skin barrier. The studies will also address the question whether changes in the skin due to excessive cleaning of infants could have contributed to the increase in IgE antibodies. III. We will use two different approaches to investigate the relevance of high titer IgE antibodies to understanding acute exacerbations of asthma. Those studies will first study children presenting with acute exacerbations to the hospital emergency room, and second, carry out RV challenges on adult subjects with asthma, using a new RV-16 pool. These studies will focus on the mechanisms by which Rhinovirus acts to cause exacerbation of allergic asthma. Taken together, the experiments proposed here have the potential to: i) explain the effects of high titer on prevalence and severity of asthma, ii) identify targets for treatment designed to reduce the severity of disease and the risk of exacerbations, and iii) provide information about why allergic diseases are continuing to increase in prevalence.

Public Health Relevance

Immediate hypersensitivity to common inhaled allergens is strongly associated with asthma in western countries. This form of sensitization can be quantified by measurement of serum IgE antibodies and recent evidence has shown that the risk of asthma is directly related to the titer of these antibodies. Identifying the factors that influence high titer IgE antibodies to different allergens with help, to identify children who are t risk, to explain how route of exposure influences IgE production, and to understand the mechanism by which high titers of IgE antibodies are related to acute exacerbations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020565-30
Application #
8642608
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Minnicozzi, Michael
Project Start
1984-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
30
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Muehling, Lyndsey M; Turner, Ronald B; Brown, Kenneth B et al. (2018) Single-Cell Tracking Reveals a Role for Pre-Existing CCR5+ Memory Th1 Cells in the Control of Rhinovirus-A39 After Experimental Challenge in Humans. J Infect Dis 217:381-392
Schuyler, Alexander J; Tripathi, Anubha; Workman, Lisa J et al. (2018) Underestimation of specific IgE measurements using extract-based assays on undiluted sera revealed through dilution. J Allergy Clin Immunol Pract 6:1070-1072.e4
Lawrence, Monica G; Palacios-Kibler, Thamiris V; Workman, Lisa J et al. (2018) Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID). J Clin Immunol 38:225-233
Hoyt, Alice E W; Chapman, Martin D; King, Eva M et al. (2018) Food allergen component proteins are not detected in early-childhood vaccines. J Allergy Clin Immunol Pract 6:677-679
Wilson, Jeffrey M; Workman, Lisa; Schuyler, Alexander J et al. (2018) Allergen sensitization in a birth cohort at midchildhood: Focus on food component IgE and IgG4 responses. J Allergy Clin Immunol 141:419-423.e5
Schuyler, Alexander J; Wilson, Jeffrey M; Tripathi, Anubha et al. (2018) Specific IgG4 antibodies to cow's milk proteins in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol 142:139-148.e12
Smith, Anna R; Knaysi, George; Wilson, Jeffrey M et al. (2017) The Skin as a Route of Allergen Exposure: Part I. Immune Components and Mechanisms. Curr Allergy Asthma Rep 17:6
Erwin, Elizabeth A; Rhoda, Dale A; Redmond, Margaret et al. (2017) Using Serum IgE Antibodies to Predict Esophageal Eosinophilia in Children. J Pediatr Gastroenterol Nutr 65:520-525
Wilson, Jeffrey M; Schuyler, Alexander J; Schroeder, Nikhila et al. (2017) Galactose-?-1,3-Galactose: Atypical Food Allergen or Model IgE Hypersensitivity? Curr Allergy Asthma Rep 17:8
Knaysi, George; Smith, Anna R; Wilson, Jeffrey M et al. (2017) The Skin as a Route of Allergen Exposure: Part II. Allergens and Role of the Microbiome and Environmental Exposures. Curr Allergy Asthma Rep 17:7

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