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

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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.

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Acknowledgments

This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. The authors would like to thank Dr. Ann Marschuk-Rothstein and Dr. Adriana Almeida de Jesus for helpful discussions.

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Authors and Affiliations

  1. Lawrence Shulman Scholar in Translational Research, Pediatric Translational Research Branch, National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA

    Hanna Kim

  2. Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases (NIAID), and NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA

    Gina A. Montealegre Sanchez & Raphaela Goldbach-Mansky

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  1. Hanna Kim
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  2. Gina A. Montealegre Sanchez
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  3. Raphaela Goldbach-Mansky
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Correspondence to Hanna Kim or Raphaela Goldbach-Mansky.

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HK does not have any disclosures. GMS has received study support from SOBI, Regeneron, and Lilly. RGM has received study support from SOBI, Novartis, Regeneron and Lilly.

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Kim, H., Sanchez, G.A.M. & Goldbach-Mansky, R. Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus. J Mol Med 94, 1111–1127 (2016). https://doi.org/10.1007/s00109-016-1465-5

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