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

Abstract

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.

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

“…9,10 Based on the similarities and differences in phenotypes and immunopathogenesis of numerous monogenic autoinflammatory disorders, including CANDLE syndrome and monogenic form SLE, recent suggestion argues for grouping these disorders as interferonopathies. 11,12 This work demonstrates the heterogeneity of phenotypic and genotypic features of the first three cases of CANDLE syndrome in an Arab population and the overlap with some features of monogenic form of SLE, namely C1q deficient SLE.…”

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

“…While this disease is characterized by the presence of autoantibodies and therefore classify as an autoimmune disease, it presents also autoinflammatory features involving innate immune pathways. Monogenic mutations in the DNA nucleases ( DNASE1 and DNASE1L3 ), which function in the rapid clearance of DNA from apoptotic cells, drive a monogenic SLE (monoSLE) that is characterized by autoinflammation and autoimmunity including positive anti‐dsDNA antibodies . This indicates that over‐activation of innate immune sensors of DNA may trigger an autoinflammation that could also contribute to autoimmunity in this disease.…”

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

“…However, whilst IL1b-associated autoinflammatory diseases display little if any involvement of adaptive immunity, interferonopathies can associate with secondary activation of B cells and production of autoantibodies. Thus, the dogma that autoinflammatory diseases are not characterized by autoimmune phenomena does not apply to all the interferonopathies, which may include autoinflammatory disorders as well as diseases with more prominent autoimmune features [26].…”