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47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

04.09. - 07.09.2019, Dresden

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STING-associated vasculopathy in mice requires adaptive immunity but not type I interferon or cGAS

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  • Hella Luksch - Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden
  • Alexander Gerbaulet - Institut für Immunologie, Medizinische Fakultät der TU Dresden, Immunologie, Dresden
  • Alexander Stinson - Department of Pathology and Immunology, Washington University in St. Louis, Rheumatology, St. Louis, USA
  • Derek J. Platt - Department of Molecular Microbiology, Washington University in St. Louis, Rheumatology, St. Louis, USA
  • Wei Qian - Department of Medicine, Washington University in St. Louis, Rheumatology, St. Louis, USA
  • Gowri Kalugotla - Department of Medicine, Rheumatology, St. Louis, USA
  • Catherine A. Miner - Department of Medicine, Rheumatology, St. Louis, USA
  • Brock G. Bennion - Department of Pathology and Immunology, Washington University in St. Louis, Rheumatology, St. Louis, USA
  • Jonathan Miner - Division of Rheumatology, Washington University in St. Louis, Rheumatology, St. Louis, USA
  • Angela Rösen-Wolff - Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, TU Dresden, Experimentelle Pädiatrie, Dresden

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Gesellschaft für Kinder- und Jugendrheumatologie. 47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR). Dresden, 04.-07.09.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocET.12

doi: 10.3205/19dgrh134, urn:nbn:de:0183-19dgrh1347

Published: October 8, 2019

© 2019 Luksch et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Background: It is assumed that monogenic interferonopathies are mediated by type I interferon (IFN) inducing autoinflammation. For instance, it has been shown that gain-of-function mutation in STING (STING N153S) upregulated type I IFN-stimulated genes (ISGs) and results in perivascular inflammatory lung disease in mice. The corresponding mutation in humans also causes lung disease. It is thought that signaling via the cGAS-STING pathway and subsequent activation of IFN regulatory factors (IRF) 3/7, type I IFN, and ISGs are involved.

Methods: We crossed STING N153S mice to animals lacking cGAS, IRF3, IRF7, IFNAR1, adaptive immunity, alph/beta T cells, and mature B cells. As read out we evaluated the mice for development of spontaneous inflammatory lung disease. In addition we generated bone marrow chimeric mice and examined severity of the lung disease and survival of the transplanted animals for 322 days.

Results: We found that spontaneous inflammatory lung disease in STING N153S mice developed independently of cGAS, IRF3, IRF7, and type I IFN signaling. Bone marrow transplantation experiments revealed that certain aspects of STING N153S-associated disease are intrinsic to the hematopoietic system. In additon, we discovered that Rag1-/- STING N153S mice have histologically normal lungs without perivascular infiltrates. Tcr beta-/- STING N153S animals developed a mild lung phenotype.

Conclusion: Spontaneous inflammatory lung disease in STING N153S mice develops independently of cGAS and type I IFN signaling. STING N153S depends on adaptive immunity to induce inflammatory lung disease in mice.