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A20 edits ubiquitin and autoimmune paradigms

Nature Genetics volume 43, pages 822–823 (2011)Cite this article

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Complex autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, psoriasis and inflammatory bowel disease have different pathological presentations but have overlapping genetic susceptibility variants. A new study using mice lacking Tnfaip3, whose ortholog is linked to autoimmune disease in humans, leads to insights in the role of one molecular driver of varied clinical symptomatology in disparate autoimmune disorders.

Over the last decade, a large number of common genetic variants have been associated with human autoimmune diseases. TNFAIP3, which encodes the ubiquitin-editing enzyme A20 is associated with rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes, Crohn's disease and psoriasis1,2. A20 functions as a brake on the immune system by regulating the termination of a number of proinflammatory signals initiated by pathogen products through Toll-like receptors, NOD-like receptors and effector cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)3. A20-deficient mice show a spontaneous and profound activation of their immune system, characterized by multiorgan inflammation and cachexia, with death occurring within 2 weeks of birth4. In an article published in this issue of Nature Genetics, Dirk Elewaut, Rudi Beyaert, Geert van Loo and colleagues report the unexpected finding that mice lacking A20 only in their macrophages develop spontaneous arthritis with some resemblance to human rheumatoid arthritis5.

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Figure 1: A20 deficiency in specific cell types in mice leads to different phenotypes that suggest mechanisms of human autoimmune disease physiopathology.

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Authors and Affiliations

  1. Flavius Martin is in the Department of Immunology, Genentech, South San Francisco, California, USA.,

    Flavius Martin

  2. Vishva M. Dixit is in the Department of Physiological Chemistry, Genentech, South San Francisco, California, USA.,

    Vishva M Dixit

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  1. Flavius Martin
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  2. Vishva M Dixit
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Correspondence to Flavius Martin or Vishva M Dixit.

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Competing interests

F.M. and V.M.D. are employees of Genentech, a member of the Roche group.

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Martin, F., Dixit, V. A20 edits ubiquitin and autoimmune paradigms. Nat Genet 43, 822–823 (2011). https://doi.org/10.1038/ng.916

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