B cells isolated from the B cell receptor (BCR) transgenic model AM 14 recognize a prototypic autoantigen, lgG2a, with relatively low affinity, and are relatively unresponsive to most lgG2a-containing immune complexes (IC). However, these rheumatoid factor producing B cells proliferate vigorously in response to IC consisting of lgG2a bound to DNA- or RNA-associated autoantigens via a mechanism that involves sequential engagement of the BCR located on the plasma membrane and Toll-like receptor 9 (TLR9) or TLR7, located in a cytoplasmic compartment. This experimental system has clearly implicated TLR7 and TLR9 in the activation of autoreactive B cells and shown that these receptors are specific for CG-rich dsDNA - potent endogenous DNA ligands include CpG islands. Importantly, we have shown that the functions elicited by physiologically relevant ICs cannot be reproduced with artificial ligands. However the exact role played by TLR7 and TLR9 in disease onset and progression is still unclear, and very little is known about the distinct functions elicited by TLR9 compared to TLR7 triggered pathways. 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 in this project include: (1) what are the natural sources of endogenous TLR ligands and when do they become available to the immune system;(2) what structural features of RNA determine TLR7 reactivity;(3) can TLR7 and TLR9 form functional heterodimers that detect DNA/RNA autoantigens;(4) which cellular compartments are involved in the detection of TLR7 and TLR9 ligands and how does the specific compartment regulate function;(5) how do type 1 interferons modulate the autoantibody repertoire and autoreactive B cell function;and (6) what functional outcomes distinguish BCR/TLR9 from BCR/TLR7 activation. The results of the studies will provide important information regarding the development of novel therapies for the treatment of systemic diseases such as 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 #
8504902
Study Section
Special Emphasis Panel (ZAR1-EHB-D)
Project Start
2013-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$7,183
Indirect Cost
$1,281
Name
University of Massachusetts Medical School Worcester
Department
Type
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

Showing the most recent 10 out of 33 publications