Joseph Holoshitz, M.D.
University of Michigan
NIEHS grantees have identified how a specific genetic variant may interact with environmental pollutants, such as dioxin, to increase the risk of developing rheumatoid arthritis (RA).
The shared epitope (SE), a five-amino acid sequence coded by a specific variant of the gene human leukocyte antigen (HLA), is the single largest genetic risk factor for RA. Based on cell studies, the researchers showed that the SE signaling pathway interacts with another pathway in the body — the aryl-hydrocarbon receptor (AhR) pathway — which leads to enhanced creation of osteoclast cells, which break down bone tissue.
To investigate this relationship in mice, the researchers exposed them to dioxin, which can bind to AhR and initiate a greater signaling response. Common sources of dioxins, which are byproducts of combustion, include cigarette smoke and vehicle exhaust. In dioxin-exposed mice with the HLA gene variant, the researchers saw an increase in arthritis severity and in hyperactivity of osteoclasts, which led to excessive bone destruction.
According to the authors, this study identified a previously unrecognized mechanism to explain the interaction between SE and some environmental pollutants in the development and progression of RA.
Citation: Fu J, Nogueira SV, Drongelen VV, Coit P, Ling S, Rosloniec EF, Sawalha AH, Holoshitz J. 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(18):4755–4760.