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Dectin-1 is a critical negative regulator of allergic asthma
Author Info
Gour, Naina
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1413472037
Abstract Details
Year and Degree
2014, PhD, University of Cincinnati, Medicine: Immunology.
Abstract
Asthma is a chronic inflammatory disease of the airways, driven by an inappropriate Type-2 immune response to innocuous allergens in susceptible individuals. Among the allergens, sensitization to house dust mites constitutes a major risk factor for the development of asthma. Despite this recognition, the mechanisms driving initiation of skewed type 2 cell responses following allergen exposure in asthmatics remains unknown. Recent evidence suggests that the recognition of allergens by pattern recognition receptors (PRRs) expressed on lung epithelial cells and antigen-presenting cells (APCs) dictates the nature and magnitude of the effector T cell response. PRRs trigger the inflammatory response upon recognition of specific conserved structures known as Pathogen Associated Molecular Patterns (PAMPs) through germline-encoded PRRs expressed by the host. Recently, the carbohydrate moiety-sensing family of PRRs, the C-type lectin receptor family (CLRs) has been implicated in the development of Type 2 immune responses. Based on our earlier published findings that dust-mite contains an active non-mammalian expressed carbohydrate (ß-glucan), we hypothesized that the putative ß-glucan receptor, dectin -1 may mediate allergic airway responses. Contrary to our initial hypothesis, utilizing multiple approaches, we report that dectin- 1 strongly inhibits the magnitude of asthmatic severity (AHR, eosinophilia and severe mucus plugging of the airways). Mechanistically, we report for the first time that dectin-1 expressed on lung structural cells, instead of on hematopoietic cells, inhibits the production of the type-2 promoting cytokine, IL-33, which in turns inhibits type 2 iii cytokine production from non-CD4+ innate lymphoid type 2 cells (ILC2s). Collectively, these results suggest that constitutive dectin-1 expression normally serves to dampen type 2 mediated immune responses at the airway surface-thereby maintaining homeostasis. Importantly, we demonstrate that this pathway is dysregulated in the bronchial epithelial cells of asthmatics as compared to healthy individuals suggesting that the loss of dectin-1-mediated inhibition of the IL-33-ILC2 pathway may be an important determinant of asthma susceptibility. These studies suggest that modulation of this pathway may provide a promising new therapeutic avenue for the treatment of this ever-increasing disease.
Committee
Marsha Wills-Karp , Ph.D. (Committee Chair)
Simon Hogan, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
Ronald Schnaar, Ph.D. (Committee Member)
Yui-Hsi Wang, Ph.D. (Committee Member)
Pages
203 p.
Subject Headings
Immunology
Keywords
immunology
;
asthma
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Mendeley
Citations
Gour, N. (2014).
Dectin-1 is a critical negative regulator of allergic asthma
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1413472037
APA Style (7th edition)
Gour, Naina.
Dectin-1 is a critical negative regulator of allergic asthma.
2014. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1413472037.
MLA Style (8th edition)
Gour, Naina. "Dectin-1 is a critical negative regulator of allergic asthma." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1413472037
Chicago Manual of Style (17th edition)
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Document number:
ucin1413472037
Download Count:
376
Copyright Info
© 2014, some rights reserved.
Dectin-1 is a critical negative regulator of allergic asthma by Naina Gour is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.