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Arthritis Rheumatol. 2019 Aug 28. doi: 10.1002/art.41090. [Epub ahead of print]

The Role of IFNγ-Producing Th1 Cells in a Type I IFN-Independent Murine Model of Autoinflammation Resulting from DNase II-Deficiency.

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Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
Institute of Innate Immunity, University Hospital Bonn, 53127, Bonn, Germany.



Patients with hypomorphic mutations in DNase II develop a severe and debilitating autoinflammatory disease. The objectives of this study were to compare disease parameters of these patients to a murine model of DNase II deficiency, evaluate the role of specific nucleic acid sensors and identify cell types responsible for driving the autoinflammatory response.


To rescue Dnase2-/- mice from embryonic lethality, they were intercrossed with mice that lacked the type I IFN receptor. Hematological and immune status of these mice was evaluated by CBC, flow cytometry, serum cytokine ELISAs and liver histology. Effector cell activity was determined by transferring cells from Dnase2-/- Ifnar-/- mice into Rag1-/- recipients and assessing induced changes four weeks post-transfer.


Dnase2-/- Ifnar-/- mice were shown to recapitulate many features of the DNase II-deficient patients including cytopenia, extramedullary hematopoiesis and liver fibrosis. An unusual IFNγ-producing T cell subset present in Dnase2-/- Ifnar-/- spleens could transfer hematological disorders to Dnase2+/+ Rag1-/- mice (n>22). Autoinflammation did not depend on the STING pathway but was highly dependent on Unc93B1.


Dnase2-/- Ifnar-/- mice are a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation that develops in DNASE2-hypomorphic patients. In the murine model, IFNγ is required for T cell activation and the development of clinical manifestations. The role of IFNγ in DNASE2-deficient patient populations remains to be determined, but the ability of Dnase2-/- T cells to transfer disease to Rag1-/- recipients points to T cells as a relevant therapeutic target in patient populations. This article is protected by copyright. All rights reserved.


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