All ETDs from UAB

Advisory Committee Chair

Robin G Lorenz

Advisory Committee Members

Casey Weaver

David Chaplin

Lisa Schwiebert

Chad Steele

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The inverse correlation between the industrialization and disease prevalence is termed the "hygiene hypothesis." Supporting this, immunological studies show Th1 cytokines modulate Th2 immune responses. Because the mucosa is essential in antigenic exposure, understanding bacterial sensing here is critical to addressing three foundations of this hypothesis: the role of bacterial exposure, relevance of noninvasive bacterial exposure, and influence of these exposures on immune responses. Key components of antigen sensing in the mucosa are toll-like receptors (TLRs) 2 and 4, which have been implicated in disease. The hypothesis of this thesis is, by globally knocking out one or both of these receptors, development of disease will be attenuated in a gastric inflammation model and exacerbated in an asthma model. Using a model with Helicobacter felis-induced gastristis, we show that bacteria acquisition after H. felis infection is imperative to switching the immune system from Th2 to Th1, as gnotobiotic mice infected with commensal-like bacteria and H. felis produce more anti-H.felis serum IgG1 than specific pathogen-free mice infected with H. felis, which produce more anti-H. felis serum IgG2a. In splenocytes, bone marrow derived dendritic cells, and peritoneal macrophages isolated from TLR2-/-, TLR4-/-, and TLR2/4-/- mice and C57BL/6 mice, in vitro recognition of H. felis was TLR2-dependent. However, H. felis pathogenesis was TLR2- and TLR4-independent in vivo, indicating alternative mechanisms of recognition responsible for H. felis recognition in vivo. Using a cockroach antigen acute asthma model in B6.TLR2-/-, B6.TLR4-/-, B6.TLR2/4-/-, and C57BL/6 mice, we determined TLR2 and TLR4 are not critical in this model of asthma, potentially playing a less significant role in the development of asthma than once proposed. This study demonstrates bacterial acquisition is important in shaping the adaptive immune response. H. felis recognition is TLR2- and TLR4-independent in vivo, despite conflicting in vitro data, which indicates recognition is mediated in vivo by an alternative mechanism. TLR2 and TLR4 were shown to be dispensable in our model of asthma induction, implicating other receptors as having a redundant function to TLR2 and TLR4. Future studies will address the role of these other innate sensing molecules in recognizing H. felis and in asthma induction.

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