Date of Award

2012

Publisher

North Dakota State University

Document Type

Dissertation

Degree Awarded

Doctor of Philosophy (PhD)

Program

Cellular and Molecular Biology

Department

Cellular and Molecular Biology

College

Graduate and Interdisciplinary Studies

Faculty Advisor

Schuh, Jane

Description

In the world today, asthma affects more than 235 million people. The widespread prescription of inhaled corticosteroids—the current gold standard of asthma control medication—allows many asthmatics to live symptom-free and has significantly reduced the number of deaths due to asthma. However, when the disease is poorly controlled, for example due to ubiquitous exposure to airborne fungal conidia, this chronic inflammatory disease often results in lung dysfunction caused by airway architectural changes. The role of B lymphocytes in allergic asthma has been relegated to the production of IgE with relatively little being known about the trafficking of these cells in the tissues or their role(s) in the affected tissue. As a first step in ascertaining their function, the initial aim of this project was to characterize the recruitment and localization of B cells in the murine lung in response to Aspergillus fumigatus inhalation. We found that CD19+CD23+ B2 lymphocytes were recruited to the lungs after fungal inhalation and that IgA-, IgE-, IgG-producing cells localized around the large airways. The second aim of the project was to begin defining the impact that these B lymphocytes have on the allergic lung. By using mice that were deficient of conventional B cells, we were able to demonstrate that the allergic phenotype was retained, although the impact of tissue B1 B cells cannot yet be ruled out. We then investigated the ability of hyaluronic acid (HA), a major component of the extracellular matrix (ECM) generated at sites of chronic inflammation, to recruit and modulate B lymphocyte functions in allergic fungal disease. We found that B lymphocytes undergo chemotaxis in response to LMM HA, while HMM HA had little to no effect on B cell chemotaxis. Furthermore, HA-mediated B lymphocyte chemotaxis was significantly inhibited by blocking the CD44 HA receptor. We also demonstrated that LMM HA fragments elicit the production of the pro-fibrotic cytokines IL-10 and TGF-β1 by B lymphocytes. These observations suggest a previously unrecognized role for B lymphocytes and HA in the context of allergy and represent novel pathways by which B lymphocytes may contribute to airway inflammation and airway remodeling.

Rights

NDSU policy 190.6.2

Rights Link

https://www.ndsu.edu/fileadmin/policy/190.pdf

Handle Identifier

https://hdl.handle.net/10365/26663

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