Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease

Abstract

Summary The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense, but is also associated with specific autoimmune diseases. Mutations in the human 3′ repair exonuclease 1 (Trex1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to non-hematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

“…The twofold to fourfold induction of ISGs we observed in Rnaseh2b A174T/A174T heart tissue is comparable to the fourfold to sevenfold induction seen in Samhd1 −/− mouse tissue (Rehwinkel et al , 2013). While an overt inflammatory phenotype is seen in Trex1 −/− mice (Morita et al , 2004; Gall et al , 2012), pathological signs of neuroinflammation are not evident, although ISG upregulation in brain tissue can be detected (Pereira‐Lopes et al , 2013). Given that the autoinflammatory process appears to initiate in the Trex1 −/− heart (Gall et al , 2012), there are similarities between the pattern of inflammation in Trex1 −/− mice and the ISG tissue expression pattern in Rnaseh2b A174T/A174T mice.…”

“…Samhd1 −/− mice, like Rnaseh2b A174T/A174T mice, display an ISG response in the absence of detectable pathology (Behrendt et al , 2013; Rehwinkel et al , 2013). In contrast a strong ISG response in Adar1 null or editing‐deficient mice is associated with embryonic lethality (Mannion et al , 2014; Liddicoat et al , 2015; Pestal et al , 2015), and with autoinflammatory cardiomyopathy and multi‐tissue involvement in Trex1 −/− mice (Morita et al , 2004; Stetson et al , 2008; Gall et al , 2012). The variation in severity between different AGS gene mouse models remains unexplained, although it may be meaningful that mutations in human RNASEH2B are associated with the least severe disease course, with AGS onset generally in infancy, in contrast to the prenatal/neonatal onset more commonly seen in TREX1 patients (Crow et al , 2015).…”

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

“…One of the characteristic features of Aicardi-Goutières syndrome, which is also being recognized as a central pathogenic event in driving the phenotype of the disease, is an excessive production of type I IFNs. Recent studies in TREX1-deficient mice have established the inappropriate expression of type I IFNs leading to a fatal T cell and B cell-driven autoimmune response (13,14). This continuous type I IFN response was shown to depend on chronic activation of STING-dependent signaling (14).…”

“…Recent studies in TREX1-deficient mice have established the inappropriate expression of type I IFNs leading to a fatal T cell and B cell-driven autoimmune response (13,14). This continuous type I IFN response was shown to depend on chronic activation of STING-dependent signaling (14). In fact, TREX1-deficient mice devoid of STING or IRF3 were completely protected from autoimmune pathology and mortality.…”

DNA sensing unchained

“…Conditions, in which cytosolic DNA sensing has already been linked to STING activation, will be top on the list. As such, disease models with specific deficiencies in DNA degrading enzymes (e.g., TREX1 and DNase II alpha) and a documented role of STING-driven sterile inflammation will be of great interest [9,10]. Assuming that cGAS is required for DNA-dependent inflammation under these conditions, targeting cGAS synthetase activity or the binding of its product cGAMP to STING using a small molecule inhibitor could open new avenues in anti-inflammatory therapy.…”