Plasmacytoid dendritic cells (PDCs), which produce IFN-␣ in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients.In this study, we show that murine PDCs are activated by purified U1snRNP/ anti-Sm ICs to produce IFN-␣ and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-␣ and IL-6 by U1snRNPs in murine bone marrow-derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm IntroductionSystemic lupus erythematosus (SLE) is a prototypic autoimmune disorder affecting approximately 1 in 2000 people. The etiology of the disease is unknown. Genetic susceptibility and environmental factors play a role. Defects in tolerance, apoptosis, clearance of immune complexes (ICs), or generation of regulatory cells lead to uncontrolled hyperactivity of self-reactive T-and B-lymphocytes and to the sustained production of tissue-damaging autoantibodies and ICs. The presence of high levels of circulating autoantibodies against nuclear antigens is the immunologic hallmark of SLE. Anti-dsDNA antibodies are found in 70% of patients, and high titers correlate with disease severity. Thirty percent of patients with SLE also have circulating anti-Smith (Sm) antibodies recognizing the 7 Sm proteins (B, D1, D2, D3, E, F, G), which are common to all small nuclear ribonucleoproteins (snRNPs) and which associate with U snRNA (U1, 2, 4, 5). In addition, 40% of SLE patients have anti-RNP antibodies, which specifically bind to the A and C and the 70-kDa proteins within U1snRNPs. 1 It has been demonstrated that ICs containing nucleic acids can directly activate murine B lymphocytes and conventional DCs as well as human plasmacytoid DCs, thus contributing to the development of full-blown SLE. [2][3][4] Type I interferon (IFN-␣/␤), which is induced by SLE ICs in vitro, is found at high levels in the sera of most patients with active SLE. Microarray analysis in peripheral blood mononuclear cells of patients with SLE revealed the typical "IFN signature" of gene expression, which correlates with disease activity. 5,6 There is strong evidence for a central role of IFN-␣/␤ in SLE pathogenesis from studies in the New Zealand Black (NZB)/New Zealand White (NZW) mouse model of lupus, 7,8 whereas conflicting results were obtained in the Fas lpr mouse model of lupus-like disease. 9,10 The SLE-promoting role of IFN-␣/␤ may be attributed to the support of B-cell differentiation and antibody production 11,12 and to the induction of dendritic cell (DC) differentiation and maturation. 13 Plasmacytoid DCs (PDCs), whi...

Objective. The detection of high titers of antibodies against small nuclear ribonucleoproteins (snRNP) is a diagnostic finding in patients in whom systemic lupus erythematosus (SLE) is suspected. Endogenous RNA molecules within snRNP trigger Toll-like receptor 7 (TLR-7) activation in B cells and dendritic cells, leading to anti-snRNP antibody production, which is associated with the development of immune complex nephritis in SLE. The purpose of this study was to investigate the role of TLR-7 in anti-snRNP antibody production and renal disease in SLE induced by an exogenous factor in the absence of genetic predisposition, using the pristane-induced murine lupus model.Methods. Serum autoantibodies, IgG isotypes, and cytokine levels in pristane-treated wild-type and TLR-7-deficient mice were analyzed by enzyme-linked immunosorbent assay. Histopathologic changes in mouse kidneys were determined by light immunofluorescence microscopy. Cell subsets in splenocytes and peritoneal lavage cells from the mice were examined by flow cytometry.Results. We found that anti-snRNP antibody production induced by pristane treatment was entirely dependent on the expression of TLR-7, whereas antidouble-stranded DNA antibody production was not affected by a lack of TLR-7. Impaired anti-snRNP antibody production in TLR-7-deficient mice was paralleled by lower levels of glomerular IgG and complement deposits, as well as less severe glomerulonephritis.Conclusion. TLR-7 is specifically required for the production of RNA-reactive autoantibodies and the development of glomerulonephritis in pristane-induced murine lupus, a model of environmentally triggered SLE in the absence of genetic susceptibility to autoimmunity. Specific interference with TLR-7 activation by endogenous TLR-7 ligands may therefore be a promising novel strategy for the treatment of SLE.The immunologic hallmark of systemic lupus erythematosus (SLE) is the presence of high levels of circulating antinuclear autoantibodies, which develop several years before manifestation of the disease and which are thought to be critically involved in its pathogenesis (1). Recent data indicate that Toll-like receptors (TLRs) recognizing self nucleic acids may be critically involved in breaking peripheral tolerance against nuclear antigens and allowing the generation of a destructive autoimmune response in SLE. By activating Tolllike receptor 9 (TLR-9) and TLR-7/8, endogenous DNA and RNA sequences contained within nuclear autoantigens in circulating autoimmune complexes act as "autoadjuvants" for efficient priming and boosting of the autoimmune response in SLE (2). By simultaneous

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 Sigirrdefi cient 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 proinfl ammatory 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.

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 Sigirrdefi cient 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 proinfl ammatory 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.