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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZES1-JAB-J (AU))
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Humble, Michael C
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Fu, Jiaqi; Nogueira, Sarah V; Drongelen, Vincent van et al. (2018) Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis. Proc Natl Acad Sci U S A 115:4755-4760
van Drongelen, Vincent; Holoshitz, Joseph (2017) Human Leukocyte Antigen-Disease Associations in Rheumatoid Arthritis. Rheum Dis Clin North Am 43:363-376
Van Drongelen, Vincent; Holoshitz, Joseph (2017) A reciprocal HLA-Disease Association in Rheumatoid Arthritis and Pemphigus Vulgaris. Front Biosci (Landmark Ed) 22:909-919
Gehlot, Prashasnika; Volk, Sarah L; Rios, Hector F et al. (2016) Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-coding HLA-DRB1 allele. RMD Open 2:e000349