The "shared epitope" (SE) - a HLA-DRB1-encoded 5-amino acid sequence motif carried by the vast majority of rheumatoid arthritis (RA) patients - is associated with severe disease. The mechanistic basis of RA-SE association is unknown. In prior studies, this laboratory has demonstrated that the SE acts as a signal transduction ligand that activates nitric oxide (NO) production in other cells. SE signaling is transduced by cell surface calreticulin (CRT), a known innate immunity receptor previously implicated in immune regulation, autoimmunity and angiogenesis. To better understand the pathogenic role of the SE in RA, we have begun characterizing SE signaling events in RA-related cells. Preliminary data demonstrate that in dendritic cells (DCs) the SE is a potent inhibitor of regulatory T (Treg) cells and enhancer of pro-angiogenic, IL-17- producing T (Th17) cells. In endothelial cells (ECs), the SE triggers production of the pro-angiogenic factors, IL-8, IL-6 and monocyte chemotactic protein-1 (MCP-1). Additionally, it was found the CRT is over- citrullinated in the synovium of RA patients and citrullinated CRT showed markedly higher affinity to the SE and transduced much more potent signals than the unmodified protein. Thus, the SE triggers angiogenesis- relevant functional events that could account for its effect in RA. The main goal of the research proposed here is to characterize the effect of the SE in angiogenesis, a key pathgenetic mechanism in several autoimmune conditions, including RA. Specifically, we propose to: 1. Characterize the functional effect of SE-mediated Th17 polarization using mouse models of tolerance and collagen-induced arthritis (CIA);2. Determine the effect of the SE-CRT on EC activation in experimental mouse models of angiogenesis and CIA;3. Determine the role of CRT citrullination in SE-activated pro- angiogenic effect in mouse ECs Collectively, these studies offer an examination of a novel paradigm that provides a unifying explanation for several important mechanistic aspects of RA. In the long run, the new knowledge gained in this project could provide a basis for designing novel therapeutic strategies.

Public Health Relevance

This project will investigate a novel hypothesis regarding the mechanism of rheumatoid arthritis (RA). At the center on this project is a process called angiogenesis (new blood vessel formation). It has been previously noted that angiogenesis plays a central role in RA. The project proposed here will examine the hypothesis that certain gene products that are known to characterize RA, but their mechanism of action is unknown, are directly involved in promoting angiogenesis. If confirmed, the studies proposed here could improved understanding of RA and other autoimmune conditions, and may open the door to the design of new anti- angiogenesis treatment strategies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR059085-04
Application #
8699012
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Fu, Jiaqi; Ling, Song; Liu, Ying et al. (2013) A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis. J Immunol 191:2096-103
Ling, Song; Cline, Erika N; Haug, Timothy S et al. (2013) Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum 65:618-26
Holoshitz, Joseph; Liu, Ying; Fu, Jiaqi et al. (2013) An HLA-DRB1-coded signal transduction ligand facilitates inflammatory arthritis: a new mechanism of autoimmunity. J Immunol 190:48-57
Naveh, Shirly; Tal-Gan, Yftah; Ling, Song et al. (2012) Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads. Bioorg Med Chem Lett 22:493-6