Abstract | OBJECTIVE: Patients with hypomorphic mutations in DNase II develop a severe and debilitating autoinflammatory disease. This study was undertaken to compare the disease parameters in these patients to those in a murine model of DNase II deficiency, and to evaluate the role of specific nucleic acid sensors and identify the cell types responsible for driving the autoinflammatory response. METHODS: To avoid embryonic death, Dnase2-/- mice were intercrossed with mice that lacked the type I interferon (IFN) receptor (Ifnar-/- ). The hematologic changes and immune status of these mice were evaluated using complete blood cell counts, flow cytometry, serum cytokine enzyme-linked immunosorbent assays, and liver histology. Effector cell activity was determined by transferring T cells from Dnase2-/- × Ifnar-/- double-knockout (DKO) mice into Rag1-/- mice, and 4 weeks after cell transfer, induced changes were assessed in the recipient mice. RESULTS: In Dnase2-/- × Ifnar-/- DKO mice, many of the disease features found in DNase II-deficient patients were recapitulated, including cytopenia, extramedullary hematopoiesis, and liver fibrosis. Dnase2+/+ × Rag1-/- mice (n > 22) developed a hematologic disorder that was attributed to the transfer of an unusual IFNγ-producing T cell subset from the spleens of donor Dnase2-/- × Ifnar-/- DKO mice. Autoinflammation in this murine model did not depend on the stimulator of IFN genes ( STING) pathway but was highly dependent on the chaperone protein Unc93B1. CONCLUSION: Dnase2-/- × Ifnar-/- DKO mice may be a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation similar to that seen in DNASE2-hypomorphic patients. In this 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-/- mouse T cells to transfer disease to Rag1-/- mice suggests that T cells may be a relevant therapeutic target in patients with IFN-related systemic autoinflammatory diseases.
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Authors | Sudesh Pawaria, Kerstin Nündel, Kevin M Gao, Stephanie Moses, Patricia Busto, Kevin Holt, Rohit B Sharma, Michael A Brehm, Ellen M Gravallese, Merav Socolovsky, Anette Christ, Ann Marshak-Rothstein |
Journal | Arthritis & rheumatology (Hoboken, N.J.)
(Arthritis Rheumatol)
Vol. 72
Issue 2
Pg. 359-370
(02 2020)
ISSN: 2326-5205 [Electronic] United States |
PMID | 31464028
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2019, American College of Rheumatology. |
Chemical References |
- Interferon Type I
- Interferon-gamma
- Endodeoxyribonucleases
- deoxyribonuclease II
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Topics |
- Animals
- Autoimmune Diseases
(etiology)
- Disease Models, Animal
- Endodeoxyribonucleases
(deficiency)
- Inflammation
(immunology)
- Interferon Type I
- Interferon-gamma
(biosynthesis)
- Mice
- Mice, Inbred C57BL
- Th1 Cells
(metabolism)
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