Georgetown University LogoGeorgetown University Library LogoDigitalGeorgetown Home
    • Login
    View Item 
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Biomedical Graduate Education
    • Department of Biochemistry and Molecular & Cellular Biology
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
    • View Item
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Biomedical Graduate Education
    • Department of Biochemistry and Molecular & Cellular Biology
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    THE CX3CR1+ LAMINA PROPRIA DENDRITIC CELL: MASTER SENTINEL OF THE TERMINAL ILEUM

    Cover for THE CX3CR1+ LAMINA PROPRIA DENDRITIC CELL: MASTER SENTINEL OF THE TERMINAL ILEUM
    View/Open
    View/Open: Lough_georgetown_0076D_11523.pdf (3.1MB) Bookview

    Creator
    Lough, Denver Matthew
    Advisor
    Gallicano, Ian
    Crooke, Elliott
    Abstract
    The CX3CR1+ lamina propria dendritic cell (LPDC) of the terminal ileum provides a unique sentinel role, critical for intestinal health. Here, we demonstrate that three Crohn's disease associated single nucleotide polymorphisms within the muramyl dipeptide receptor (MDP), NOD2, appear to alter the physical phenotype and transcriptome of the LPDC within the small intestine. Among the alterations described here, is a LPDC that is unable to extend its defining trans-epithelial dendrites (TEDs) into the lumen of the bowel despite (1) increased expression of the CX3CR1 receptor, (2) the presence of increased bacteria adherent to the mucosal wall and (3) the increased expression of the stress fractalkine, CX3CL1, all of which are directly associated with TED extension. In addition, the mRNA and protein expression profiles of the LPDC are also significantly distorted, including under-expression of genes within the TLR, ICAM and MIF families. There is also over expression of some inflammatory cytokines, such as IFN-ã and TNF-á, when comparing NOD2 mutants to wild types. Finally, the NOD2 mutation within the CX3CR1+ LPDC appears to depress Wnt5a expression both in vivo and in response to ex vivo MDP stimulation. In vivo observation of the Wnt5a/disheveled-2 axis showed reduced activation within the epithelium when in communication with the NOD2 mutant LPDC. However, once removed from the lamina propria compartment, the epithelium responded to Wnt5a stimulation by augmenting the transcription of Tcf4, a Paneth cell dependent transcription factor involved directly in the expression of human alpha defensin 5. We propose that Wnt5a participates in a novel homeostatic circuit involving the LPDC, epithelium, and Paneth cell and that a mutation in the NOD2 receptor within this LPDC alters its ability to communicate with its immunologic epithelial counterparts allowing for bacterial infiltration of the mucosal niche.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/557511
    Date Published
    2012
    Subject
    Bacteria; CX3CR1; Dendritic Cell; Intestinal Transplant; NOD2; Transepithelial Dendrite; Medicine; Cytology; Molecular biology; Medicine; Cellular biology; Molecular biology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    148 leaves
    Collections
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
    Metadata
    Show full item record

    Related items

    Showing items related by title, author, creator and subject.

    • Cover for Cell Subsets and Pathogen Recognition Requirements Involved in the Innate Response of Primary Human Monocytes and Dendritic Cells to Toxoplasma gondii

      Cell Subsets and Pathogen Recognition Requirements Involved in the Innate Response of Primary Human Monocytes and Dendritic Cells to Toxoplasma gondii 

      Tosh, Kevin Wayne (Georgetown University, 2015)
      As a major natural host for Toxoplasma gondii, the mouse is widely used for the study of the immune response to this medically important protozoan parasite. However, murine innate recognition of toxoplasma depends on the ...
    Related Items in Google Scholar

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility
     

     

    Browse

    All of DigitalGeorgetownCommunities & CollectionsCreatorsTitlesBy Creation DateThis CollectionCreatorsTitlesBy Creation Date

    My Account

    Login

    Statistics

    View Usage Statistics

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility