Date of Award

5-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Medical Science)

Program

Microbiology, Molecular Biology and Biochemistry

Track

Microbial Pathogenesis, Immunology, and Inflammation

Research Advisor

Elizabeth A. Fitzpatrick, Ph.D.

Committee

David D. Brand, Ph.D. Fabio C. Re, Ph.D. Susan E. Senogles, Ph.D. Christopher M. Waters, Ph.D.

Keywords

Th17, T-bet, Hypersensitivity pneumonitis

Abstract

Hypersensitivity Pneumonitis (HP) is an interstitial lung disease caused by repeated inhalation of a wide range of environmental antigens. It is characterized by alveolitis, granuloma formation, and fibrosis. Since HP is a T cell-mediated disease, it is important to determine the type of T cell response associated with granuloma formation and the factors that control this response. We hypothesized that HP is associated with a predominant Th17 cell response where both T-bet and TLRs 2 and 9 are controlling T cell response during HP. The results demonstrated a predominant Th17 response associated with granuloma formation in the lungs of C57BL/6J mice during granulomatous and chronic HP. We also found that T-bet KO mice exposed to Saccharopolyspora rectivirgula (SR) were characterized by exacerbated Th17 cell response accompanied by an increase in granuloma formation and collagen production in the lungs compared to WT exposed mice. In an attempt to find other factors regulating Th17 development, previous studies in our lab showed that TLR2/9 double knockout (DKO) exposed mice were characterized by a decrease in the percentage of Th17 cells in their lungs compared to WT mice. Consequently, we hypothesized that the decrease in Th17 response is attributed to defect in phagocytosis, or cytokines production, or antigen presentation ability of TLR2/9 DKO antigen presenting cells (APCs). In vitro, we found no significant difference in the phagocytosis ability of both WT and TLR2/9 DKO BMDMs (Bone Marrow Derived Macrophages) or BMDCs (Bone Marrow Derived Dendritic Cells). In vivo, there was no significant difference in the phagocytosis ability of both WT and TLR2/9 DKO alveolar macrophages. Although we found that both TLRs 2 and 9 were regulating cytokine production e.g. IL-6, IL-10, and TNFα from BMDMs, we did not find a defect in antigen presentation ability of both WT and TLR2/9 DKO splenic APCs. In conclusion, these findings suggested the following: (1) Both granulomatous and chronic HP is associated with a predominant Th17 response and granuloma formation; (2) T-bet plays a role in controlling disease severity and Th17 development during HP; (3) TLR2 and 9 do not affect APCs’ ability to phagocytose SR but they affect cytokine production; and (4) Both WT and TLR2/9 DKO APCs are equally efficient in presenting SR antigen to T cells.

DOI

10.21007/etd.cghs.2012.0002

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