Allergic airway diseases such as rhinitis, asthma, and chronic rhinosinusitis are responsible for causing a huge economic burden on patients and society. Patients suffering from asthma often have allergies to pollen, dust mite, and mold. Interestingly, studies have shown that there is a correlation between severe asthma and sensitization to fungi including Aspergillus, Alternaria, Cladosporium, and Penicillium. This project has been focused on studying the innate immunomodulatory activities of the major allergen Alt a 1, from the ubiquitous airborne fungus, Alternaria alternata. In several studies, 90-100% of allergic patients who are sensitized to Alternaria, have Alt a 1 specific IgE antibodies indicating that it is a major and clinically relevant allergen. Although progress has been made over the past few decades regarding elucidating the mechanistic underpinnings of allergic inflammation, more research needs to be done, especially in regards to innate immunity and its role in the sensitization and exacerbation aspects of allergic diseases. Published studies have increasingly made it clear that Toll-like receptors (TLRs) are key players in innate immunity to several allergens. For example, the dust mite allergen, Der p 2, has been shown to mimic the activity of human and mouse MD2 in the presence of LPS to trigger a response through TLR4. Bet v 1, an allergen from Birch tree, has been shown to enter and be transported through lung epithelium in patient cells. It is hypothesized that transcytosis of allergens like Bet v 1 may contribute to sensitization and exacerbation in atopic individuals. This project was focused on two primary aims; (1) Characterize the innate immune response of Alt a 1 in human airway epithelial cells, and (2) Identify if and how Alt a 1 can enter human airway cells. We found that Alt a 1 was able to stimulate innate immune responses in bronchial epithelial cells and this was dependent upon TLR2, TLR4 and the downstream adaptor proteins MyD88 and TIRAP. We also found in our studies that Alt a 1 rapidly enters bronchial epithelial cells. Furthermore, our data suggests that endocytosis of Alt a 1 may be partially dependent upon interaction with phosphatidyl-inositol-3-phosphate (PI-3-P). / Ph. D. / Allergic airway diseases such as rhinitis, asthma, and chronic rhinosinusitis are responsible for causing a huge economic burden on patients and society. Patients suffering from asthma often have allergies to pollen, dust mite, and mold. Interestingly, studies have shown that there is a correlation between severe asthma and allergy to several fungal species including Aspergillus, Alternaria, Cladosporium, and Penicillium. This project has been focused on studying how the allergen, Alt a 1, from the fungus, <i>Alternaria alternata</i>, can cause an allergic response in the human airways. In several studies, 90-100% of allergic patients who have allergy to Alternaria, have proteins in their bloodstream that specifically recognize Alt a 1. This indicates that they are allergic to Alt a 1. Though we know that these patients have allergy to Alt a 1, we do not know how this protein causes the characteristic symptoms of allergy, such as a runny nose, watery eyes, hives, and breathing difficulty. Published studies have increasingly made it clear that molecules on the surface of cells that line the airways are important players in the body’s response to allergens. A dust mite allergen, Der p 2, can interact with one such receptor on human cells. The receptor may not be the only way that allergens can cause a response. Studies have shown that allergens can directly enter human cells. For example, a Birch tree allergen, Bet v 1, has been shown to enter human lung cells. This project was focused on two primary aims; (1) Identify how human airway cells response to Alt a 1, and (2) Identify if and how Alt a 1 can enter human airway cells. We found that Alt a 1 was able to cause human airway cells to produce several molecules that lead to the characteristic symptoms of allergy, and that this response was dependent on a receptor on human airway cells. We also found that Alt a 1 rapidly enters human airway cells.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/85399 |
| Date | 25 April 2017 |
| Creators | Hayes, Tristan Alonzo |
| Contributors | Biological Sciences, Lawrence, Christopher B., Li, Liwu, Schubot, Florian D., Kale, Shiv D., Capelluto, Daniel G. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
Page generated in 0.0021 seconds