Deregulated Type I IFN Response in TREX1-Associated Familial Chilblain Lupus

Peschke, Katrin; Friebe, Franziska; Zimmermann, Nick; Wahlicht, Tom; Schumann, Tina; Achleitner, Martin; Berndt, Nicole; Luksch, Hella; Behrendt, Rayk; Lee‐Kirsch, Min Ae; Roers, Axel; Günther, Claudia

doi:10.1038/jid.2013.496

Cited by 43 publications

(38 citation statements)

References 15 publications

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“…In line with previous observations 15 we detected an upregulation of ISGs in the blood of 2 affected members of the family in the present report, supporting a pathogenic role of type I IFN in familial chilblain lupus. Furthermore, the high prevalence of systemic clinical manifestations in this family suggests that TREX1-associated familial chilblain lupus is a systemic disease with prominent cutaneous involvement.…”

Section: Discussionsupporting

confidence: 94%

Familial Chilblain Lupus Due to a Novel Mutation in the Exonuclease III Domain of 3′ Repair Exonuclease 1 (TREX1)

et al. 2015

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This case further implicates type I interferon-dependent innate immune activation in the pathogenesis of TREX1-associated familial chilblain lupus. Unlike previously reported TREX1 mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial chilblain lupus.

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Section: Discussionsupporting

confidence: 94%

Familial Chilblain Lupus Due to a Novel Mutation in the Exonuclease III Domain of 3′ Repair Exonuclease 1 (TREX1)

et al. 2015

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“…In fact, TREX1 has even been shown to have nuclease independent activities in the regulation of oligosaccharyltransferase that contributes to its role in immune regulation23. Moreover, studies have shown that deregulation of TREX1 can mediate inflammation3839. Our observations demonstrate another unique but critical role for TREX1 downstream of miR-103 in promoting EC death and dysfunction in response to radiation.…”

Section: Discussionmentioning

confidence: 65%

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

et al. 2016

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Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.

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“…In most patients with FCL the positive ANA antibody titers fluctuate over time, and anti-dsDNA Abs or immune-complex mediated kidney disease have not been described [67, 71]. Upregulation of IFN-stimulated genes in peripheral blood from FCL patients and increased expression of IFN-inducible IFN myxovirus resistance protein A (MxA) and CXCL10 in lesional skin biopsies from FCL patients have been seen [71, 73]. Cold-induced skin features of FCL resemble the cutaneous features in SAVI in some [74] and a distinct TMEM173 mutation identified in a single kindred has the phenotype of FCL [70], but no lung disease in FCL has been reported as seen in SAVI.…”

Section: Familial Chilblain Lupus (Fcl) Retinal Vasculopathy With Cementioning

confidence: 99%

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

2016

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Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of “autoinflammatory” and “autoimmune” interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.

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Deregulated Type I IFN Response in TREX1-Associated Familial Chilblain Lupus

Cited by 43 publications

References 15 publications

Familial Chilblain Lupus Due to a Novel Mutation in the Exonuclease III Domain of 3′ Repair Exonuclease 1 (TREX1)

Familial Chilblain Lupus Due to a Novel Mutation in the Exonuclease III Domain of 3′ Repair Exonuclease 1 (TREX1)

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

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