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.

Public Health Relevance

SLE is a chronic life threatening autoimmune disorder that afflicts up to 2 million individuals within the United States. Current therapeutic options can moderate disease severity but often have deleterious side effects that limit their extended use. Insights gained from this proposal should facilitate the development of drugs that specifically target the relevant immune effector mechanisms without the debilitating side effects of now associated with standard treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR050256-11
Application #
8504899
Study Section
Special Emphasis Panel (ZAR1-EHB-D (M2))
Program Officer
Mancini, Marie
Project Start
2004-09-30
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$1,310,545
Indirect Cost
$233,556
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Ericson, Jeffrey A; Duffau, Pierre; Yasuda, Kei et al. (2014) Gene expression during the generation and activation of mouse neutrophils: implication of novel functional and regulatory pathways. PLoS One 9:e108553
Yasuda, Kei; Watkins, Amanda A; Kochar, Guneet S et al. (2014) Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2. PLoS One 9:e103478
Pelka, Karin; Phulphagar, Kshiti; Zimmermann, Jana et al. (2014) Cutting edge: the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms. J Immunol 193:3257-61
Watkins, Amanda A; Bonegio, Ramon G B; Rifkin, Ian R (2014) Evaluating the role of nucleic acid antigens in murine models of systemic lupus erythematosus. Methods Mol Biol 1169:143-58
Aprahamian, Tamar R; Bonegio, Ramon G; Weitzner, Zachary et al. (2014) Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus. Immunology 142:363-73
Teichmann, Lino L; Schenten, Dominik; Medzhitov, Ruslan et al. (2013) Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus. Immunity 38:528-40
Bossaller, Lukas; Rathinam, Vijay A K; Bonegio, Ramon et al. (2013) Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. J Immunol 191:2104-14
Yasuda, Kei; Nundel, Kerstin; Watkins, Amanda A et al. (2013) Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2. Int Immunol 25:295-306
Nickerson, Kevin M; Christensen, Sean R; Cullen, Jaime L et al. (2013) TLR9 promotes tolerance by restricting survival of anergic anti-DNA B cells, yet is also required for their activation. J Immunol 190:1447-56
Nickerson, Kevin M; Cullen, Jaime L; Kashgarian, Michael et al. (2013) Exacerbated autoimmunity in the absence of TLR9 in MRL.Fas(lpr) mice depends on Ifnar1. J Immunol 190:3889-94

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