期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 205, 期 8, 页码 1879-1888出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20072646
关键词
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资金
- Fritz Thyssen Foundation [10.04.2.140]
- Deutsche Forschungsgemeinschaft [AN372/8-1, GRK 1202]
- EU Integrated Project INNOCHEM [FP6-518167]
- MUGEN [LSHG-CT-2005-005203]
- Italian Ministero Universita e Ricerca (MIUR)
- Ministero della Salute
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.
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