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...