title: Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens.
abstract: 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.
authors.affiliation: Medical Policlinic, University of Munich, 80336 Munich, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kulkarni
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pfeiffer
authors.forename: Emina
authors.initials: E
authors.lastname: Savarese
authors.forename: Anne
authors.initials: A
authors.lastname: Krug
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D017931:DNA Primers; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse