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    Molecular Players in Lupus: Leads from Proteomic Screens

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    ORME-DISSERTATION-2016.pdf (6.817Mb)
    Date
    2014-05-23
    Author
    Orme, Jacob Jennings
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    Abstract

    Systemic Lupus Erythematosus is a multifactorial systemic autoimmune disorder marked by anti-nuclear antibodies (ANA), rashes and photosensitivity, joint inflammation, nephritis, and other clinical criteria. SLE develops through the breakdown of three major checkpoints: adaptive immune tolerance, peripheral innate responsiveness, and end-organ inflammation. Adaptive immune dysfunction produces autoantibodies leading to immune complex formation and deposition in the skin, joints, and kidneys. Innate immunity plays an important role in determining disease severity and progression. Molecular markers in patient blood and urine improve diagnosis and treatment of SLE. Proteomic screens identify such markers and provide important clues about disease pathogenesis. We have discovered that soluble Axl receptor tyrosine kinase, the Wnt/β-catenin pathway-related factors, and rare fibrinogen alpha chain variant A-α-E are elevated in the serum of patients with SLE. Here I explore these factors and their contributions to disease. I find that Axl tyrosine kinase is sheared from the surface of lupus-prone and SLE CD19+ and CD11b+/CD14+ leukocytes by proteases ADAM10 and TACE (ADAM17) to abrogate macrophage anti-inflammatory signaling through Twist. I further find that β-catenin is dysregulated in SLE but the deletion of β-catenin in lupus-prone macrophages does not appreciably change disease course. Lastly, I find that fibrinogen alpha chain isoform Aα-E may be associated with aPL-negative thrombotic complications in SLE.

    Subject
    ADAM10 Protein
    ADAM17 Protein
    Lupus Erythematosus, Systemic
    Proto-Oncogene Proteins
    Receptor Protein-Tyrosine Kinases
    URI
    https://hdl.handle.net/2152.5/5282
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    UT Southwestern Health Sciences Digital Library and Learning Center | 5323 Harry Hines Boulevard, Dallas, Texas 75390-9049
    Telephone 214-648-2001 | Email
    Library Home | UT Southwestern Home
    DSpace software copyright © 2002-2016  DuraSpace
    Contact Us | Send Feedback
    TDL
    Theme by 
    Atmire NV