It is becoming increasingly apparent that detection of auto antigens by components of the innate immune system can contribute to the pathogenesis of a variety of chronic inflammatory diseases. For example. Tolllike receptors 9 and 7 (TLR9, TLR7) can trigger responses to self nucleic acids. This proposal is based on recent studies that have identified TLR9, TLR7, and an associated downstream transcription factor, IRF5, as critical factors in the development of systemic lupus erythematosus (SLE). However the exact role played by these molecules is disease onset and progression is still unclear, and very little is known about the distinct functions elicited by TLR9 compared to TLR7. Both TLR9 and TLR7 contribute to autoantibody production and dendritic cell activation, but TLR9-deficiency exacerbates disease In autoimmune-prone mice while TLR7-deficiency reduces disease. Remarkably, reduced expression of IRF, a transcription factor downstream of both TLR7 and TLR9, is the most effective means of curing disease. The overall goal of the current application is to gain a better understanding of exactly how TLR9 and TLR7-expressing cell types contribute to SLE pathogenesis. Specific questions that will be addressed include: (1) why do TLR7 and TLR9 deficiency give discordant outcomes in autoimmune prone mice?;(2) can molecular interactions between TLR7 and TLR9 lead to attenuation of activity?;(3) how do type 1 interferons regulate TLR-elicited responses?;(4) what are the endogenous ligands that trigger TLR7 and TLR9?;and (5) when, where and how does IRF5 trigger the bioactivities that so critically regulate SLE disease pathogenesis. These questions can be best answered by a panel of program participants with diverse background and expertise - Marshak-Rothstein (immunoregulation and B cell activation);Latz (trafficking and structure/function analysis of TLR signaling);Viglianti (chromatin/RNA structure, retrovirology);Rifkin (dendritic cell biology and renal disease) and Shiomchik (animal models of SLE). The combined rigorous in vitro analysis of TLR-mediated activation and cell localization with the precise in vivo analysis of the impact of cell type specific TLR and deficiency or overexpression in animal models of autoimmune disease should provide important insights that will facilitate the development of non-invasive therapies for SLE.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZAR1-EHB-D (M2))
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Mancini, Marie
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University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
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Pawaria, Sudesh; Sharma, Shruti; Baum, Rebecca et al. (2017) Taking the STING out of TLR-driven autoimmune diseases: good, bad, or indifferent? J Leukoc Biol 101:121-126
Sindhava, Vishal J; Oropallo, Michael A; Moody, Krishna et al. (2017) A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens. J Clin Invest 127:1651-1663
Baum, Rebecca; Sharma, Shruti; Organ, Jason M et al. (2017) STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice. Arthritis Rheumatol 69:460-471
Roberts, Allison W; Lee, Bettina L; Deguine, Jacques et al. (2017) Tissue-Resident Macrophages Are Locally Programmed for Silent Clearance of Apoptotic Cells. Immunity 47:913-927.e6
Giles, Josephine R; Neves, Adriana Turqueti; Marshak-Rothstein, Ann et al. (2017) Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation. JCI Insight 2:e90870
Bossaller, Lukas; Christ, Anette; Pelka, Karin et al. (2016) TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus. J Immunol 197:1044-53
Garcia-Martinez, Irma; Santoro, Nicola; Chen, Yonglin et al. (2016) Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 126:859-64
Baum, Rebecca; NĂ¼ndel, Kerstin; Pawaria, Sudesh et al. (2016) Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice. J Immunol 196:1348-54
Moody, Krishna L; Uccellini, Melissa B; Avalos, Ana M et al. (2016) Toll-Like Receptor-Dependent Immune Complex Activation of B Cells and Dendritic Cells. Methods Mol Biol 1390:249-72
Pawaria, Sudesh; Moody, Krishna L; Busto, Patricia et al. (2015) An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual. Clin Exp Rheumatol 33:S70-3

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