The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20090585
The Journal of Experimental Medicine, Vol. 206, No. 8, 1661-1671
The Rockefeller University Press, 0022-1007 $30.00
© Espinosa et al.
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BRIEF DEFINITIVE REPORT

 Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23–Th17 pathway

Alexander Espinosa1, Valerie Dardalhon4, Susanna Brauner1, Aurelie Ambrosi1, Rowan Higgs5, Fransisco J. Quintana4, Maria Sjöstrand1, Maija-Leena Eloranta6, Joan Ní Gabhann5, Ola Winqvist1, Birgitta Sundelin2, Caroline A. Jefferies5, Björn Rozell3, Vijay K. Kuchroo4, and Marie Wahren-Herlenius1

1 Department of Medicine, 2 Department of Oncology and Pathology, and 3 Department of Laboratory Medicine, Karolinska Institute, Stockholm SE-171 77, Sweden
4 Center for Neurological diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
5 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
6 Department of Rheumatology, Uppsala University, Uppsala SE-751 05, Sweden

CORRESPONDENCE Marie Wahren-Herlenius: marie.wahren{at}ki.se

Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52–/–), which appear phenotypically normal if left unmanipulated. However, Ro52–/– mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52–/– mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23–Th17 pathway.

A. Espinosa, V. Dardalhon, and S. Brauner contributed equally to this paper.

Abbreviations used: ANA, antinuclear antibody; IRF, IFN regulatory factor; SLE, systemic lupus erythematosus; TLR, toll-like receptor.

© 2009 Espinosa et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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