In vivo results with Tlr7-deficient lupusprone mice verify the pathological significance of TLR7 in SLE. In the absence of Tlr7, the generation of autoantibodies to RNA containing antigens was greatly impaired and the clinical diseases were much ameliorated. Analysis of the Y-linked autoimmune accelerator locus renders further support for such a point. Yaa is known to be a genetic modifier capable of increasing the severity of SLE. Recent studies revealed that this locus contained a duplication of Tlr7, and the majority of the autoimmune phenotype associated with Yaa appeared to be conferred by the two-fold increase in TLR7 expression. The in vivo effect of TLR9 on autoimmunity, on the other hand, is not fully congruent with expectations. In one initial study with the lupus model induced by anti-DNA BCR transgene and homozygous deficiency of the inhibitory receptor FccIIB, lack of Tlr9 was found to block class switching of autoreactive B cells to the pathogenic IgG2a and 2b subclasses with reduced pathology and mortality. Subsequent studies with the more commonly used MRL/Mplpr/lpr model, however, revealed that TLR9 could represent a protective factor as its deficiency resulted in increased immune activation and accelerated lupus nephritis and mortality. Thus, TLR7 and TLR9 appear to have divergent effect on the development of SLE. TLR signaling is normally under tight control by a number of negative regulators. They attenuate TLR signaling by acting as decoy receptors, interfering with the downstream signaling pathway, or facilitating the degradation of TLRs. Among them, SIGIRR is of particular interest for its close association with autoimmunity. SIGIRR is a member of the IL-1R like receptor family, which is characterized by a single extracellular immunoglobulin domain and a cytoplasmic TIR domain missing two well conserved residues essential for IL1R signaling. In vitro data demonstrate that enforced expression of SIGIRR inhibits IL-1R and TLR-induced NF-kB activation and cytokine production while lack of SIGIRR enhances the responses. In vivo, Sigirrdeficient C57BL/6lpr/lpr mice develop severe systemic autoimmunity as indicated by massive lymphoproliferation, production of autoantibodies against numerous lupus autoantigens and autoimmue tissue injury. Moreover, dendritic cells and B cells from such mice show much Ibrutinib enhanced responses to immune complexes containing RNA and DNA antigens. In another study, Sigirr deficiency is found to aggravate hydrocarbon oilinduced lupus, possibly due to hyperactivation of DCs by TLR7- mediated signal. Therefore, Sigirr may represent a novel SLE susceptibility gene. Despite the accumulating evidence that dysregulated TLR signaling contributes to the pathogenesis of lupus in animal models, limited information is currently available concerning its role in human diseases except for several recent reports on the upregulated expression of TLR7 and TLR9 in B cells from lupus patients. The functional consequence of their elevated expression, however, remains poorly understood. Even less known is the regulation of TLR signaling in human B cells, either in physiological or pathological conditions. The present study was therefore undertaken to characterize the responses of B cells from SLE patients to TLR7 and TLR9 stimulation and to explore the potential role of SIGIRR in the regulation of TLRmediated responses of SLE B cells. Several recent studies, using either flow cytometry or RT-PCR, have detected increased expression of TLR9 in CD19+ or CD20+ B cells from SLE patients.