Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus.
Hanna KimGina A Montealegre SanchezRaphaela Goldbach-ManskyPublished in: Journal of molecular medicine (Berlin, Germany) (2016)
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.
Keyphrases
- systemic lupus erythematosus
- dendritic cells
- immune response
- nucleic acid
- disease activity
- early onset
- signaling pathway
- oxidative stress
- circulating tumor
- end stage renal disease
- cell free
- single molecule
- chronic kidney disease
- late onset
- newly diagnosed
- gene expression
- ejection fraction
- peritoneal dialysis
- multiple sclerosis
- genome wide
- poor prognosis
- squamous cell carcinoma
- neoadjuvant chemotherapy
- epithelial mesenchymal transition
- dna methylation
- cell proliferation
- prognostic factors
- long non coding rna
- genome editing
- induced apoptosis
- crispr cas
- patient reported outcomes
- african american
- reactive oxygen species