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A correction to this article has been published: Lech et al., J. Exp. Med. 205 (9) 2179
Published online
doi:10.1084/jem.20072646
The Journal of Experimental Medicine, Vol. 205, No. 8, 1879-1888
The Rockefeller University Press, 0022-1007 $30.00
© Lech et al.
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ARTICLE

 Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens

Maciej Lech1, Onkar P. Kulkarni1, Stephanie Pfeiffer1, Emina Savarese2, Anne Krug2, Cecilia Garlanda3, Alberto Mantovani3,4, and Hans-Joachim Anders1

1 Medical Policlinic, University of Munich, 80336 Munich, Germany
2 Department of Medicine, Technical University of Munich, 80333 Munich, Germany
3 Istituto Clinico Humanitas and Fondazione Humanitas per la Ricerca, I-20089 Rozzano, Italy
4 University of Milan, 20126 Milan, Italy

CORRESPONDENCE Hans-Joachim Anders: hjanders{at}med.uni-muenchen.de

The Sigirr gene (also known as Tir8) encodes for an orphan receptor of the Toll-like receptor (TLR)/interleukin 1 receptor family that inhibits TLR-mediated pathogen recognition in dendritic cells. Here, we show that Sigirr also inhibits the activation of dendritic cells and B cells upon exposure to RNA and DNA lupus autoantigens. To evaluate the functional role of Sigirr in the pathogenesis of systemic lupus erythematosus (SLE), we generated Sigirr-deficient C57BL/6-lpr/lpr mice. These mice developed a progressive lymphoproliferative syndrome followed by severe autoimmune lung disease and lupus nephritis within 6 mo of age as compared with the minor abnormalities observed in C57BL/6-lpr/lpr mice. Lack of Sigirr was associated with enhanced activation of dendritic cells and increased expression of multiple proinflammatory and antiapoptotic mediators. In the absence of Sigirr, CD4 T cell numbers were increased and CD4+CD25+ T cell numbers were reduced. Furthermore, lack of Sigirr enhanced the activation and proliferation of B cells, including the production of autoantibodies against multiple nuclear lupus autoantigens. These data identify Sigirr as a novel SLE susceptibility gene in mice.

Abbreviations used: dsDNA, double-stranded DNA; LE, lupus erythematosus; PAS, periodic acid-Schiff; SIGIRR, single IG IL-1–related receptor; SLE, systemic LE; Sm, Smith; TIR8, Toll–IL-1 receptor 8; TLR, Toll-like receptor.

© 2008 Lech 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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