Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


30440.pdf (5.14 MB)

ETD Abstract Container

Abstract Header

Discover the Role of Dendritic Cell in Pulmonary Langerhans Cell Histiocytosis And Respiratory Syncytial Virus Infection

Liu, Huan
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535382725511759

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
Dendritic cells (DCs) are the most efficient antigen presentation cells and execute a pivotal role in the onset and regulation of innate and adaptive immune responses and the recruitment of a variety of leukocytes to the site of inflammation or injury. To counter the challenge of the non-stop exposure to exogenous pathogens, the lungs developed an intrigue and complex immunology defense orchestra that conducted by DCs. An increasing volume of research on DCs in recent years show that the disruption of DC equilibrium in the lung may result in different diseases. In this study, we used two different disease models to elucidate the importance of DC in disease pathogenesis. Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by focal DC accumulation, bronchiolocentric nodule formation, and cystic remodeling of the lung and occurs predominantly in active smokers. Approximately 50% of PLCH patients harbor somatic BRAF-V600E mutations identified mainly within the DC lineage. However, the rare nature of the disease and lack of animal models impedes the study of the pathogenic mechanisms of PLCH. We have established the first mouse model that recapitulates the hallmark characteristics of PLCH. In addition, we show that the BRAF-V600E mutation is associated with increased DC responsiveness towards multiple stimuli including the DC-chemokine CCL20. We provide evidence that DC accumulation in the lung is due to both increased viability and enhanced recruitment. Further evidence indicates that the accumulation of other inflammatory cells in PLCH is a secondary event driven by CCL7 secreted from DCs in a BRAF-V600E-dependent manner. Moreover, we demonstrate that the PLCH-like phenotype in the mouse model can be attenuated following smoking cessation and removal of BRAF-V600E DCs. Furthermore, we show PBMCs isolated from PLCH patients harboring the BRAF-V600E mutation produce CCL7. Collectively, our studies provide the first mechanistic insights into the role of DC BRAF-V600E mutation and CS exposure that mediate PLCH pathogenesis. Respiratory syncytial virus (RSV) is a common cause of respiratory tract infection in vulnerable populations. Natural killer (NK) cells and DC are important for the effector functions of inflammatory cells following infection. To investigate the importance of NKG2D pathway in regulating RSV infection, wild type and NKG2D deficient mice were infected with RSV. We found that NKG2D deficient mice exhibited greater lung pathology, marked by the accumulation of DCs following RSV infection. DCs isolated from NKG2D deficient mice had impaired responses towards TLR ligands. DCs expressed NKG2D ligands on their surface, which was further increased in NKG2D deficient mice and during RSV infection. Adoptive transfer of DCs isolated from WT mice into the airways of NKG2D deficient mice ameliorated the enhanced inflammation in NKG2D deficient mice after RSV infection. In summary, we discovered that the NKG2D-dependent interactions with DCs control the phenotype and function of DCs and play a critical role in pulmonary host defenses against RSV infection. Collectively, these results support the concept that the delicacy of DC-mediated lung equilibrium can be affected by both innate defects (BRAF-V600E mutation) and interaction of other cells in the local lung microenvironment (NKG2D-dependent editing). Our findings not only provide insights into the pathogenesis of PLCH and severe RSV infection but also broaden the knowledge of basic DC biology and shed light upon other DC-related disease and applications.
Michael Borchers, Ph.D. (Committee Chair)
Ian Paul Lewkowich, Ph.D. (Committee Member)
Francis McCormack, M.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
Kathryn Wikenheiser-Brokamp, M.D. Ph.D. (Committee Member)
158 p.
Surgery
DC; PLCH; NKG2D; RSV; Cigarette smoke; Lung

Recommended Citations

Citations

  • Liu, H. (2018). Discover the Role of Dendritic Cell in Pulmonary Langerhans Cell Histiocytosis And Respiratory Syncytial Virus Infection [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535382725511759

    APA Style (7th edition)

  • Liu, Huan. Discover the Role of Dendritic Cell in Pulmonary Langerhans Cell Histiocytosis And Respiratory Syncytial Virus Infection. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535382725511759.

    MLA Style (8th edition)

  • Liu, Huan. "Discover the Role of Dendritic Cell in Pulmonary Langerhans Cell Histiocytosis And Respiratory Syncytial Virus Infection." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535382725511759

    Chicago Manual of Style (17th edition)

ucin1535382725511759
212
© 2018, some rights reserved.Creative Commons License Discover the Role of Dendritic Cell in Pulmonary Langerhans Cell Histiocytosis And Respiratory Syncytial Virus Infection by Huan Liu is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.
Release 3.2.12