Date of Award

Fall 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

David Artis

Abstract

Allergic diseases have reached pandemic levels and represent a significant source of morbidity, mortality and healthcare cost. These chronic inflammatory diseases are characterized by interleukin (IL)-4, IL-5, IL-9 and IL-13 production by CD4+ T helper type 2 (TH2) cells, immunoglobulin E (IgE) production by B cells, and the recruitment of effector cells to sites of tissue inflammation. In addition to host genetic polymorphisms and environmental triggers, studies in patients and model systems suggest that commensal bacterial-derived signals influence susceptibility to TH2 cytokine-mediated allergic inflammation. For example, patients with allergies display altered commensal bacterial populations and antibiotic treatment increases allergy susceptibility. However, the influence of antibiotic treatment on intestinal bacterial communities, and subsequent effects on innate immune cells that influence the development of allergic inflammation, are poorly defined. Chapter 2 describes the development and characterization of a new murine antibiotic treatment model using 454 deep sequencing techniques and details antibiotic-induced temporal and spatial alterations to bacterial communities colonizing the murine intestine. Having characterized the effects of antibiotic treatment on commensal populations, Chapter 3 and Chapter 4 examine the cellular and molecular mechanisms through which innate immune cells respond to commensal-derived signals and regulate TH2 cytokine-mediated allergic responses. Data in Chapter 3 describe antibiotic-induced steady-state elevations in serum IgE levels and circulating basophil populations, an innate granulocyte implicated in contributing to allergic TH2 cell responses, as well as exaggerated basophil-mediated inflammation in models of allergic disease. Data in Chapter 4 indicate that circulating basophil populations correlate with serum IgE levels in mice and patients with hyper-IgE syndrome, and that B cell-intrinsic MyD88 expression limits murine IgE levels and basophil responses. These results provide novel mechanistic insights into how commensal bacterial-derived signals influence TH2 cytokine-mediated allergic inflammation, and have implications for the development of new preventative or therapeutic interventions for allergic disease.

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