Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens.
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.
Lech
Maciej
M
Medical Policlinic, University of Munich, 80336 Munich, Germany.
Kulkarni
Onkar P
OP
Pfeiffer
Stephanie
S
Savarese
Emina
E
Krug
Anne
A
Garlanda
Cecilia
C
Mantovani
Alberto
A
Anders
Hans-Joachim
HJ
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
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D017931:DNA Primers; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse