Ann Marshak-Rothstein

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..Thus, strategies to preferentially block innate activation through TLRs in autoimmune B cells may be preferred over non-selective B-cell depletion...

..In this context, they likely play a key role in the development of systemic autoimmune diseases...

..These data have important implications regarding the therapeutic application of TLR9 inhibitors to the treatment of systemic autoimmune diseases...

..In the case of antinuclear antibodies, it seems that DNA itself can serve as an endogenous adjuvant. Similar to many of the microbial adjuvants, mammalian DNA mediates its effect through a Toll-like receptor--in this case, TLR9...

..As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers...

..In conclusion, our data indicate that the function of FasL on intraocular tumors is determined by the microenvironment in conjunction with the form and level of FasL expressed...

..The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE...

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..This system may also prove useful for the study of receptors and signaling pathways used by immune complexes in other human diseases...

..The data demonstrate that only certain nucleic acid sequences or structures can induce autoreactive B-cell proliferation, even when delivery to the appropriate TLR compartment is facilitated by uptake through the B-cell receptor (BCR)...

..Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I IFN production...

..We found that spontaneous and defined DNA ICs activated RAGE+ and RAGE(- ) AM14 B cells to a comparable extent. These results suggest that HMGB1 promotes B cell responses to endogenous TLR9 ligands through a RAGE-independent mechanism...

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..These data identify direct and indirect mechanisms by which BCR engagement facilitates access of exogenous ligands to TLR9-associated compartments and subsequent B cell activation...

..These results demonstrate that FcγRIIB can effectively modulate both BCR/TLR9 and BCR/TLR7 endosomal-dependent activation of autoreactive B cells...

..Membrane-bound FasL induces powerful Fas-mediated signals because it possesses both Fas-focusing and signal-transducing functions...

..These reagents reveal an important role for nucleic acid sequence, even when the ligand is mammalian DNA...

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..These data indicate that autoreactive B cells, stimulated by a combination of BCR and TLR9 ligands, acquire functional properties that may contribute to the activation of additional cells involved in the autoimmune disease process...

..We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage...

..However, the precise details of the interactions and the extent to which they may contribute to the pathogenesis of human disease remain to be clarified...

..Additionally, although the precise nature of the neoantigen is not known, the T cells described in this report may provide a useful tool for examining the role of T cells in the RF autoantibody response...

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..These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors...

..These results highlight subtle differences in the IFN dependence of TLR7 responses compared with other TLR-mediated B cell responses...

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..In this context, autoreactive B cells can respond robustly to common autoantigens. These findings have important implications for the role of B cells in vivo in the pathology of SLE...

..The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells...

..CONCLUSIONS: Bioactive membrane FasL microvesicles coinjected with tumor cells induce a potent inflammatory response that terminates immune privilege, eliminates ocular tumors, and prevents metastatic disease...

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..Further understanding of the role of specific receptors, cell subsets, and inhibitory signals that govern these TLR-associated pathways will enable future therapeutics to be tailored to specific categories of autoimmune disease...

..By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma...

..Discussed here are the experimental situations, possible mechanisms, and pathways that mediate this response...

..These results identify parameters that define specific mammalian RNAs as ligands for TLRs...

..The development of clinical trials using therapeutic agents that target components of the innate immune system suggests that these advances may soon culminate in new medications for treating patients with systemic lupus erythematosus...

..Two papers in this issue of Immunity provide important insights into the contribution of Toll-like receptors in systemic autoimmune disease (Berland et al., 2006; Christensen et al., 2006)...

..This study could lead to significant insights into the factors that trigger the development of SSc and strategies that might prove useful in limiting the progression of disease in afflicted patients. ..

..The results of this proposal should eventually have clinical application with regard to the control of the basic immunoregulatory defects involved in autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis...

..The results of the studies will provide important information regarding the development of novel therapies for the treatment of systemic diseases such as SLE. ..

..Moreover, this experimental strategy should also have direct relevance to human clinical syndromes associated with excessive RF production. ..

..A better understanding of the events that contribute to the initial activation of these autoreactive B cells will be critical to the development of more effective and less toxic therapies. ..

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..A better understanding of the events that contribute to the initial activation of these autoreactive B cells will be critical to the development of more effective and less toxic therapies. ..

..The better understanding of the etiology of autoimmunity gained from these studies should be directly applicable to the treatment of human disease. ..