GSBS Dissertations and Theses

ORCID ID

0000-0003-0912-5478

Publication Date

2020-03-20

Document Type

Doctoral Dissertation

Academic Program

Immunology and Microbiology

Department

Department of Medicine, Division of Infectious Diseases and Immunology, Program in innate immunity

First Thesis Advisor

Kate Fitzgerald

Second Thesis Advisor

Ann Marshak Rothstein

Keywords

cGAS, STING, SAVI, LUPUS, Autoimmune, Auto-inflammatory, Type I Interferonopathies

Abstract

Cytosolic DNA sensing plays a key role in autoimmune and autoinflammatory diseases. STING is a cytosolic adaptor protein which upon activation leads to induction of type I interferons and inflammatory cytokines. Recently, gain-of-function mutations in STING have been identified in patients with an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). We compared two independent SAVI mutant mouse models and revealed a hierarchy of immune abnormalities which were dependent on SAVI mutation in lymphocytes. We also showed that bone marrow from the V154M mutant mice transfers disease to the wild-type host, whereas the N153S does not, indicating mutation-specific disease outcomes. Collectively, these mutant mice recapitulate disease features seen in SAVI patients and highlight mutation-specific functions of STING.

Other autoimmune mouse models such as DNAseII and DNAseIII-deficient mice, that fail to degrade DNA result in activation of the cGAS STING pathway. Deficiency of this pathway in these mouse models ameliorates lethality. By contrast, we previously reported that STING potently suppresses inflammation in a pristane-induced model of autoimmunity. In this model, we show that both cGAS- and STING-deficient mice exhibit exacerbated disease phenotypes compared to controls. We report that STING constrained TLR activation, and thereby limited autoimmune manifestations. Consistent with this premise, cGAS or STING deficient mice that lack a common TLR chaperone UNC93b develop less severe systemic autoimmunity than cGAS or STING deficient mice that are UNC93b sufficient. Overall, this study demonstrates that STING activation constrains systemic autoimmune disease and has important implications for cGAS STING-directed therapies.

DOI

10.13028/bpgs-qe55

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Saturday, May 14, 2022

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