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A Protein Coding Variant in IRF7 is associated with SLE Risk and Affects Production of Type IIinterferon

Fjellman, Ellen V. F.
http://orcid.org/0000-0002-1423-3783
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627662131455655

Abstract Details

2021, MS, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Systemic Lupus Erythematosus (SLE) is a debilitating autoimmune disorder characterized by system-wide inflammation and rampant production of autoantibodies. The most prominent and highly replicated set of dysregulated genes in the immune cells of patients with SLE are the type I interferons (IFN-I) and IFN-responsive genes. Plasmacytoid dendritic cells (pDCs) are the chief producers of IFN-I, and their ability to modulate IFN-I expression is directly regulated by the transcription factor interferon regulatory factor 7 (IRF7). While IRF7 is an established SLE risk locus, the variants responsible for disease pathology remain unknown. We hypothesized that an amino-acid changing SLE risk variant in the inhibitory domain of IRF7 (rs1131665) alters expression of disease-relevant IFN-I in clinically relevant cells to increase SLE risk. The functional consequences of the SLE-associated variant were assessed in human cell lines and in genome-edited mice with an introduced SLE-risk variant at Irf7. Our data demonstrate greater than 2-fold genotype-dependence in IFN-stimulated response element-driven luciferase activity and inflammatory cytokine secretion detected in the supernatant after toll-like receptor-7 stimulation. Gene expression differences in cells with IRF7/Irf7 risk variants are consistent with those dysregulated in SLE patients. In the present study, we demonstrate the functional consequences of a missense mutation in a critical type I interferon regulator. Understanding these mechanisms will enhance development of more effective clinical practices for autoimmune patients expressing the risk variant for IRF7.
Leah Claire Kottyan, Ph.D. (Committee Chair)
Brian Gebelein, Ph.D. (Committee Member)
Emily Miraldi, Ph.D. (Committee Member)
Stephen Waggoner, Ph.D. (Committee Member)
Matthew Weirauch, Ph.D. (Committee Member)
Aaron Zorn, Ph.D. (Committee Member)
37 p.
Genetics
IRF7; type I interferon; SLE; Lupus; rs1131665; Interferon Regulatory Factor 7

Recommended Citations

Citations

  • Fjellman, E. V. F. (2021). A Protein Coding Variant in IRF7 is associated with SLE Risk and Affects Production of Type IIinterferon [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627662131455655

    APA Style (7th edition)

  • Fjellman, Ellen. A Protein Coding Variant in IRF7 is associated with SLE Risk and Affects Production of Type IIinterferon. 2021. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627662131455655.

    MLA Style (8th edition)

  • Fjellman, Ellen. "A Protein Coding Variant in IRF7 is associated with SLE Risk and Affects Production of Type IIinterferon." Master's thesis, University of Cincinnati, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627662131455655

    Chicago Manual of Style (17th edition)

ucin1627662131455655
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This open access ETD is published by University of Cincinnati and OhioLINK.