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.

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

“…Finally, the analysis of two publicly available datasets (Liu et al, 2012;Rodero et al, 2017) demonstrated a significant overlap (P < 10 -10 ) between the genes that are upregulated in GPP and those that are over-expressed in autoinflammatory syndromes caused by abnormal activation of IFN-I responses ( Figure 1f). Notably, no overlap was found with the upregulated genes detected in cryopyrin associated periodic syndrome (CAPS), a disease caused by excessive IL-1 activity, which was analyzed as a negative control (Supplementary Figure S1).…”

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

“…A list of candidate immune function genes was curated from the following main sources: genome-wide study of rare copy number variants in 70 PML cases (Dis cohort) that impact immune function genes (data not shown), genes from the ClinVar database (43) using search terms "immune deficiency" and "immunodeficiency, " IUIS and other immunodeficiency reviews (29,30,(44)(45)(46)(47)(48)(49)(50), type I interferon pathway genes (51)(52)(53)(54)(55)(56)(57)(58), complement pathway genes (59), and JCV or PML linked biology (23,26,33,(60)(61)(62)(63)(64). The full list of 711 unique genes were cross-checked against genes that were found with DV-called variants in the Dis and/or Rep cohorts.…”

A STING to inflammation and autoimmunity

“…The deficiency of DNase II, an enzyme localized in lysosomes that clears DNA of dead cells and DNA expelled from nuclei, also increases the activation of STING signaling and the generation of type 1 IFNs causing systemic autoinflammation . The STING signaling is also responsible for the acrid bone accumulation in the long bones and spleens, sites of erythropoiesis, and the potent DNA accrual in DNase II/IFNaR double deficient (double knockout [DKO]) mice .…”