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New monogenic autoinflammatory diseases—a clinical overview

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Abstract

Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN’s as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases.

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Acknowledgments

This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the NIH

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Authors and Affiliations

  1. Autoinflammatory Pathogenesis Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bldg. 10, room 13c103, 10 Center Dr., Bethesda, MD, 20892, USA

    Scott W. Canna

  2. Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bldg. 10, room 6D47B, 10 Center Dr., Bethesda, MD, 20892, USA

    Raphaela Goldbach-Mansky

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  1. Scott W. Canna
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  2. Raphaela Goldbach-Mansky
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Correspondence to Scott W. Canna or Raphaela Goldbach-Mansky.

Additional information

This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases - Guest Editors: Seth L. Masters, Tilmann Kallinich, and Seza Ozen

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Canna, S.W., Goldbach-Mansky, R. New monogenic autoinflammatory diseases—a clinical overview. Semin Immunopathol 37, 387–394 (2015). https://doi.org/10.1007/s00281-015-0493-5

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