The mechanisms governing genetic and environmental risk factors in rheumatoid arthritis (RA) are presently unknown. This laboratory has recently gained novel mechanistic insights into the mode of action of the main genetic risk factor in RA, the shared epitope (SE). The investigators have recently demonstrated that the SE, a 5-amino acid sequence motif in the HLA-DR ? chain shared by the majority of RA patients, acts as an innate immune system ligand, which triggers oxidative stress, facilitates differentiation of Th17 cells (T helper cells that produce IL-17), and induces pro-osteoclastogenic effects both in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a well-studied transcription factor that mediates the xenobiotic effects of many pollutants, has been shown by others to activate similar biologic effects. Prompted by the parallels between the mode of action of AhR and the SE ligand, and the epidemiologically well-documented synergism between the SE and exposure to environmental pollutants in RA disease risk, the investigators carried out preliminary experiments to determine whether the SE and AhR pathways interact in autoimmune arthritis. The findings demonstrate that the SE ligand and AhR pathway agonists produce additive or multiplicative biologic effects, which lead to enhanced osteoclast differentiation, Th17 polarization and more severe erosive arthritis. Additionally, preliminary findings suggest that the SE activates the nuclear factor kappa B (NF-?B) pathway. In this project the investigators will determine the hierarchy and inter-dependence of the two respective pathways as an exploratory phase before embarking on detailed characterization of the molecular mechanisms involved in SE- AhR interaction in the future. Successful completion of the research proposed here could open the door to advancing our understanding of the mechanisms involved in environmental pollutants-associated autoimmunity.

Public Health Relevance

The project proposed here will examine a novel hypothesis pertaining to the complementing roles of genes and environmental pollutants in autoimmune arthritis. If confirmed, the new hypothesis could provide important insights into the mechanism of interaction between genes and environmental factors in autoimmunity, which is a significant public health problem. In the long run the results of the study could help identify new therapies for human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES024428-01
Application #
8768943
Study Section
Special Emphasis Panel (ZES1-JAB-J (AU))
Program Officer
Humble, Michael C
Project Start
2014-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$233,188
Indirect Cost
$83,188
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109