All ETDs from UAB

Advisory Committee Chair

John F Kearney

Advisory Committee Members

David E Briles

David D Chaplin

Claude H Steele

Casey T Weaver

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The incidence of asthma has increased dramatically among children living in developed countries, and the hygiene hypothesis suggests that this is the result of decreased neonatal exposure to microbes. Microbes and allergens can bear similar antibody-reactive epitopes, and exposure to microbes bearing these epitopes during early life can permanently alter the frequency and clonality of the antigen-specific B cell repertoire. The objective of this dissertation was to determine if B cells stimulated by microbes during early life could suppress the development of respiratory allergies during adult life. Both Streptococcus pneumoniae (pneumococcus) and house dust mite (HDM) express antibody-reactive phosphorylcholine (PC) epitopes, therefore we began by investigating whether neonatal exposure to PC-bearing pneumococcus could suppress the development of HDM-induced allergic disease. Our results demonstrated that, compared to mice that received a PC-deficient pneumococcus, neonatal mice that were immunized with a PC-bearing pneumococcus had an increased frequency of PC-specific B cells in their lung following challenge with HDM and exhibited suppressed development of allergic disease. We were also able to demonstrate that anti-PC IgM antibodies in the lung inhibited the engagement of HDM with PC-specific receptors, CD36 or platelet activating factor receptor (PAFR), on APCs. Additionally, levels of anti-PC IgM antibodies in the plasma of asthmatic children were significantly decreased compared to non-asthmatic children, suggesting these antibodies are possibly immunoprotective. We were next interested in determining whether this mechanism would be observed if the epitope shared between the microbe and the allergen is a glycan. Both Enterobacter cloacae (strain MK7) and cockroach allergen express antibody-reactive α-1,3-glucan epitopes. We started by investigating whether neonatal exposure to MK7 could suppress the development of cockroach allergy. Our result demonstrated that neonatal, but not adult, mice immunized with MK7 were protected against cockroach allergy. We further identified a unique population of α-1,3-glucan-specific IgA-secreting B cells from the lungs of mice that had been immunized with MK7 as neonates, but not adults, that was responsible for suppressing the development of cockroach allergy. Thus, B cells stimulated as a result of early microbial exposure are protective against the development of allergic disease during adult life.

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