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
Baum, Rebecca; Sharma, Shruti; Organ, Jason M et al. (2016) STING regulates abnormal bone formation induced by deficiency of DNase II. Arthritis Rheumatol :
Baum, Rebecca; Nündel, 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
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
Giles, Josephine R; Kashgarian, Michael; Koni, Pandelakis A et al. (2015) B Cell-Specific MHC Class II Deletion Reveals Multiple Nonredundant Roles for B Cell Antigen Presentation in Murine Lupus. J Immunol 195:2571-9
Sharma, Shruti; Fitzgerald, Katharine A; Cancro, Michael P et al. (2015) Nucleic Acid-Sensing Receptors: Rheostats of Autoimmunity and Autoinflammation. J Immunol 195:3507-12
Pawaria, Sudesh; Moody, Krishna; Busto, Patricia et al. (2015) Cutting Edge: DNase II deficiency prevents activation of autoreactive B cells by double-stranded DNA endogenous ligands. J Immunol 194:1403-7
Nündel, Kerstin; Green, Nathaniel M; Shaffer, Arthur L et al. (2015) Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. J Immunol 194:2504-12
Baum, Rebecca; Sharma, Shruti; Carpenter, Susan et al. (2015) Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. J Immunol 194:873-7
Sharma, Shruti; Campbell, Allison M; Chan, Jennie et al. (2015) Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc Natl Acad Sci U S A 112:E710-7
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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