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Type I interferon-mediated autoinflammation due to DNase II deficiency.

ABSTRACT: Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.

SUBMITTER: Rodero MP

PROVIDER: S-EPMC5736616 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Type I interferon-mediated autoinflammation due to DNase II deficiency.

Rodero Mathieu P MP Tesser Alessandra A Bartok Eva E Rice Gillian I GI Della Mina Erika E Depp Marine M Beitz Benoit B Bondet Vincent V Cagnard Nicolas N Duffy Darragh D Dussiot Michael M Frémond Marie-Louise ML Gattorno Marco M Guillem Flavia F Kitabayashi Naoki N Porcheray Fabrice F Rieux-Laucat Frederic F Seabra Luis L Uggenti Carolina C Volpi Stefano S Zeef Leo A H LAH Alyanakian Marie-Alexandra MA Beltrand Jacques J Bianco Anna Monica AM Boddaert Nathalie N Brouzes Chantal C Candon Sophie S Caorsi Roberta R Charbit Marina M Fabre Monique M Faletra Flavio F Girard Muriel M Harroche Annie A Hartmann Evelyn E Lasne Dominique D Marcuzzi Annalisa A Neven Bénédicte B Nitschke Patrick P Pascreau Tiffany T Pastore Serena S Picard Capucine C Picco Paolo P Piscianz Elisa E Polak Michel M Quartier Pierre P Rabant Marion M Stocco Gabriele G Taddio Andrea A Uettwiller Florence F Valencic Erica E Vozzi Diego D Hartmann Gunther G Barchet Winfried W Hermine Olivier O Bader-Meunier Brigitte B Tommasini Alberto A Crow Yanick J YJ

Nature communications 20171219 1

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both fam ...[more]

PMID: 29259162

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Project description:ObjectivePatients 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.MethodsTo 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.ResultsIn 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 IFN?-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.ConclusionDnase2-/- × 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, IFN? is required for T cell activation and the development of clinical manifestations. The role of IFN? 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.

Project description:BackgroundIn hereditary angioedema (HAE), diverse mutations in the C1-inhibitor gene may produce either normal C1-inhibitor protein in insufficient quantities (HAE type I), or a dysfunctional protein in normal or even excessive amounts (HAE type II). Previously, we have found strong association between baseline level of functional C1-inhibitor and severity of HAE. Our aim was to investigate complement activation products in HAE, during a follow-up period, and to analyze the relationship between these products and severity of disease.Methods107 HAE patients (96 HAE type I, 11 type II) and 113 healthy control subjects were included. C1rC1sC1-INH, C3bBbP, and SC5b-9 levels were determined using ELISA methods in single EDTA-plasma samples of controls and in 4 samples from patients taken in 4 subsequent years. Between-group differences were evaluated with the Mann-Whitney test, and correlations were calculated using non-parametric Spearman's correlation coefficients.ResultsMedian levels of C1rC1sC1-INH (60 U/mL [40–113] vs 8 U/mL [4–10]; P < 0.0001) and SC5b-9 (0.6 U/mL [0.4–1.2] vs 1.8[0.9–2.8]; P < 0.0001) differed between patients and controls. Significant differences were found between HAE type I and type II as regards median C1rC1sC1-INH level (54 U/mL [33–97] vs 31 U/mL [21–49], P < 0.0001), and in an opposite manner with C3bBbP median levels (6 U/mL [4–12] vs 10 U/mL [8–17], P = 0.0002). Level of C1rC1sC1-INH correlated with the number of attacks (r = 0.3546, P = 0.0004) in HAE type I, but not in HAE type II. Dividing the patients into 2 subgroups based on danazol therapy, significant association (r = 0.3705, P = 0.0026) was found between level of C1rC1sC1-INH and annual attack number only in patients not treated with danazol. Similar results were found as regards the number of C1-inhibitor vials administered, which correlated with the level of C1rC1sC1-INH only in HAE type I (r = 0.4288, P < 0.0001) and in patients not treated with danazol (r = 0.4783, P < 0.0001).ConclusionsMonitoring the level of C1rC1sC1-INH is mostly informative in HAE type I patients, who are not treated with danazol. No correlation was found in HAE type II patients between level of C1rC1sC1-INH and disease severity markers. As this observation may be explained by the small number of HAE type II patients, multicenter studies are needed, including more HAE type II patients.

Dataset Information

Type I interferon-mediated autoinflammation due to DNase II deficiency.

Publications

Type I interferon-mediated autoinflammation due to DNase II deficiency.

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