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HP Turns 17: T Helper 17 Cell Response During Hypersensitivity

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HP Turns 17: T Helper 17 Cell Response During Hypersensitivity University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2012 HP Turns 17: T helper 17 cell response during hypersensitivity pneumonitis (HP) and factors controlling it Hossam Abdelsamed University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Immunology Commons, Medical Microbiology Commons, and the Medical Molecular Biology Commons Recommended Citation Abdelsamed, Hossam , "HP Turns 17: T helper 17 cell response during hypersensitivity pneumonitis (HP) and factors controlling it" (2012). Theses and Dissertations (ETD). Paper 6. http://dx.doi.org/10.21007/etd.cghs.2012.0002. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. HP Turns 17: T helper 17 cell response during hypersensitivity pneumonitis (HP) and factors controlling it 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. DOI 10.21007/etd.cghs.2012.0002 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/6 HP TURNS 17: T HELPER 17 CELL RESPONSE DURING HYPERSENSITIVITY PNEUMONITIS (HP) AND FACTORS CONTROLLING IT A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Hossam Abdelsamed May 2012 Portions of Chapter 3 © 2012 by BioMed Central Ltd. All other materials © 2012 by Hossam Abdelsamed. All rights reserved. ii DEDICATION I dedicate this work to my parents, Aly Abdelsamed and Salwa Fahmy, to my wife, Amira Ahmed and to my future students. iii 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 TNFD 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. iv TABLE OF CONTENTS CHAPTER 1. INTRODUCTION .....................................................................................1 TYPES OF HYPERSENSITIVITY REACTIONS .........................................................1 NAÏVE CD4+ T CELL DIFFERENTIATION ................................................................2 GRANULOMA F ORMATION .......................................................................................6 Definition .....................................................................................................................6 Requirements ...............................................................................................................6 Granuloma as a Dynamic Environment .......................................................................8 Fate of Granuloma .......................................................................................................8 HYPERSENSITIVITY P NEUMONITIS ........................................................................9 History ..........................................................................................................................9 Different Types and Etiological Agents of HP ............................................................9 Classification, Clinical Diagnosis, and Epidemiology ..............................................11 Immunopathogenesis .................................................................................................13 CHAPTER 2. HP AND TH17 .........................................................................................18 INTRODUCTION .........................................................................................................18 Th17 Cell as a Distinct CD4+ T Helper Cell ..............................................................18 Effector Function of Th17 Cytokines ........................................................................19 Is HP a Th1/Th17-Mediated Disease? .......................................................................20 MATERIALS AND METHODS ...................................................................................20 Bacterial Preparation and Exposure Protocol ............................................................20 Cell Culture Medium .................................................................................................21 Bronchoalveolar Lavage (BAL) and Lung Cell Isolation ..........................................21 RNA Extraction and Semi-Quantitative RT-PCR .....................................................22 Flow Cytometry .........................................................................................................22 Histology ....................................................................................................................24 Statistical A nalysis .....................................................................................................24 RESULTS ......................................................................................................................26 Characterization of BAL Composition during Acute HP ..........................................26 Expression of IL-17 and CXCL2 during Acute Phase of HP ....................................26 Acute HP Is Associated with Th17 Differentiation and Effector Cytokines .............27 Characterization of BAL Composition during Granulomatous HP ...........................27 Granuloma Formation during Granulamatous HP .....................................................30 Granulomatous HP Is Associated with Activated CD4+ T Cells ...............................30 Granulomatous HP Is Associated with Th17 Immune Response ..............................31 Characterization of BALF during Chronic HP ..........................................................35 Chronic HP Is Associated with Granuloma Formation .............................................35 Chronic HP Is Associated with Activated CD4+ and CD8+ T Cells ..........................35 Chronic HP Is Associated with a Th17 Immune Response .......................................38 DISCUSSION ................................................................................................................42 Acute HP: Neutrophilic Alveolitis and IL-17 Expression .........................................42 Granulomatous HP and the Th17 Response ..............................................................42 Chronic HP and Th17 Response ................................................................................44 v Th17 Response and HP: A Correlation Not a Cause and Effect Study .....................45 CHAPTER 3. T-BET IN HP ...........................................................................................47 INTRODUCTION .........................................................................................................47 MATERIALS AND METHODS ...................................................................................48
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