By Merin C. MacDonald | Date published: September 17, 2024
Study from Fitzgerald and Rothstein Labs Reveals Insights on How STING Initiates Autoimmunity Development
Immune dysregulation has been shown to enhance the likelihood of developing adaptive autoimmunity in a mouse model of STING Associated Vasculopathy with onset in Infancy (SAVI). SAVI, an autoinflammatory disease, is caused by increased activation of the cGAS-STING pathway which mediates innate immune responses. Pediatric patients with SAVI possess activating mutations in STING, resulting in persistent innate immune responses. SAVI patients typically present with interstitial lung disease (ILD) which progresses to respiratory failure. The lack of effective therapies for patients with SAVI ILD and other connective tissue disease-associated ILDs creates a need to better understand how inflammatory lung pathology arises in these disorders. Although SAVI is an autoinflammatory disease, patients often have signs of ongoing autoimmune responses.
In a study from the labs of Kate Fitzgerald, PhD, the Worcester Foundation for Biomedical Research Chair III, professor of medicine, associate vice provost for basic science research, vice chair of research in the Department of Medicine, chief of the Division of Innate Immunity and director of the Program in Innate Immunity, and Ann Marshak-Rothstein, PhD, professor of medicine in the Division of Rheumatology and a faculty member in the Program in Innate Immunity, published in JCI Insight, investigators used a mouse model of SAVI to investigate the role of adaptive autoimmunity in the disease. They found that otherwise healthy lymphocytes that develop within a host expressing a constitutively active STING mutation can become autoreactive against lung tissue self-antigens.
“Our findings provide insight into how STING activation within stromal and parenchymal tissues initiates the development of autoimmunity and highlights the need to further investigate how the engagement of cGAS-STING and other innate immune sensing pathways within non-hematopoietic cells may contribute to the pathogenesis of autoimmunity,” said Kevin Gao, an MD/PhD student in the Fitzgerald and Rothstein labs and lead author on the study.
Along with Gao, Fitzgerald, and Rothstein, the study team included Kristy Chiang, a PhD candidate at UMass Chan, Sharon Subramanian, an MD candidate at UMass Chan, Kerstin Nundel, PhD, assistant professor of medicine in the Division of Rheumatology, and Paul Utz, MD, of Stanford University School of Medicine.