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Advisory Committee Chair

John F Kearney

Advisory Committee Members

Robbina G Lorenz

David D Chaplin

Claude H Steele

Hubert M Tse

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The incidence of asthma, allergies and autoimmune diseases has increased dramatically in developed countries. The hygiene hypothesis postulates that excessively sanitary conditions lead to a lack of critical immune stimulation during early life, leading to inappropriate responses to self or harmless antigens later in life. Many bacteria and potential allergens share common polysaccharide epitopes. We investigated the ability of antibodies against these shared polysaccharides to dampen the immune response to the ubiquitous fungus and potent allergen, Aspergillus fumigatus. We found that antibodies against these polysaccharides, specifically of the IgM isotype, induced by neonatal bacterial immunization or passive antibody transfer, dampened the development of a mouse model of A. fumigatus - induced allergic airway disease. We further show that these antibodies block the binding and uptake of A. fumigatus, resulting in a decrease in chemokine and cytokine production, innate immune cell influx into the lungs and the antigen-specific CD4 T cell responses in the lung. Studies into the mechanisms of the modulation of the adaptive immune response revealed that the anti-polysaccharide antibodies lead to a decrease of antigen uptake and presentation by antigen presentation cells to CD4 T cells. Further studies into the roles of the polysaccharides expressed by A. fumigatus in the generation of the immune response revealed critical roles for these polysaccharides. CD36 in a scavenger receptor, expressed on a wide variety of cells and binds polysaccharides expressed on A. fumigatus, including ß-glucans. CD36-/- mice have decreased uptake of A. fumigatus and display a defect in the development and maintenance of the A. fumigatus -specific CD4 T cell response. Taken together, these studies demonstrate a previously unrecognized role for anti-polysaccharides IgM antibodies generated against conserved bacterial polysaccharides in the modulation of the immune response and the development of allergic airway disease.

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