Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1181136696.pdf (5.44 MB)

ETD Abstract Container

Abstract Header

Immunological Consequences of HLA-B27 Misfolding: Implications for Spondyloarthropathy Pathogenesis

Turner, Matthew Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1181136696

Abstract Details

2007, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
The Human Leukocyte Antigen (HLA)-B27 is a Major Histocompatibility Complex (MHC) Class I allele that is highly associated with spondyloarthropathy. Biochemical studies have shown that HLA-B27 heavy chains are prone to misfold in the endoplasmic reticulum (ER). Here we provide evidence that misfolding of HLA-B27 generates ER-stress, resulting in activation of the unfolded protein response (UPR) in cells from HLA-B27 transgenic rats, an animal model of spondyloarthropathy. This response is specific for HLA-B27 and strongly correlated with the magnitude of HLA-B27 expression, which could account for the lack of UPR activity in some cells and robust activation of this pathway in others. Strong UPR activation occurs in HLA-B27 transgenic rat macrophages. This, in turn, augments the expression of the inflammatory cytokines, IL-23 p19 and IFN-beta, when these cells are stimulated with LPS or other TLR ligands. IL-23 and its downstream target, IL-17, were both shown to be elevated, concurrent with the development of colitis in HLA-B27 transgenic rats. These findings suggest a novel pathogenic mechanism of disease, with HLA-B27 misfolding as the root cause of inflammation. Our studies also identify a novel immunologic effect of the UPR that could provide the critical link to explain how protein misfolding can cause inflammatory disease. Future studies will focus on testing the model set forth by this work and the relevance of our findings to human disease.
Dr. Robert Colbert (Advisor)
157 p.
HLA-B27; Unfolded Protein Response; Misfolding; Disulfide-linked; Spondyloarthropathy; Spondyloarthritis; ER-stress; Macrophage; UPR-TLR synergy; XBP-1

Recommended Citations

Citations

  • Turner, M. J. (2007). Immunological Consequences of HLA-B27 Misfolding: Implications for Spondyloarthropathy Pathogenesis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1181136696

    APA Style (7th edition)

  • Turner, Matthew. Immunological Consequences of HLA-B27 Misfolding: Implications for Spondyloarthropathy Pathogenesis. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1181136696.

    MLA Style (8th edition)

  • Turner, Matthew. "Immunological Consequences of HLA-B27 Misfolding: Implications for Spondyloarthropathy Pathogenesis." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1181136696

    Chicago Manual of Style (17th edition)

ucin1181136696
548
© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.