Environment and genetics factors interact in the course of rheumatoid arthritis.
Interaction between genes and environmental factors is widely believed to increase the risk for rheumatoid arthritis (RA), but until now scientists haven’t understood the nature of this interplay. Studies by researchers at the University of Michigan, Ann Arbor, have now uncovered a mechanism by which a particular variant of the HLA-DRB1 allele and exposure to environmental pollutants such as cigarette smoke or vehicle exhausts work together to increase RA risk and the severity of bone damage in patients with the disease.
“We found a particular enzyme that acts as a channel, or pathway, in the cell for a conversation between the two culprits, so they work together to do greater damage,” says research lead Joseph Holoshitz, M.D., professor of internal medicine and associate chief for research at the University of Michigan School of Medicine’s Division of Rheumatology, “Individually they are bad, but together, they’re worse.”
Reporting on their in vitro and in vivo studies in the Proceedings of the National Academy of Sciences, the University of Michigan team and collaborators at the University of Tennessee Health Science Center suggest that their findings could lead to the development of drugs that block the gene-activated pathway and so reduce the incidence of RA and severity of bone damage.
They describe their studies in a paper entitled “Shared Epitope–Aryl Hydrocarbon Receptor Crosstalk Underlies the Mechanism of Gene–Environment Interaction in Autoimmune Arthritis.”
About two-thirds of RA risk is attributed to genes, and the single most significant genetic risk factor for RA is the shared epitope (SE), a five-amino-acid sequence motif encoded by the RA-associated HLA-DRB1 alleles, the researchers explain. But RA isn’t all down to genes. Environmental factors also influence RA susceptibility. The autoimmune disease is associated with exposure to environmental pollutants such as dioxin-like compounds and tobacco smoke, and RA is more prevalent in urban populations and among people who live near highways, irrespective of whether or not they smoke cigarettes.
Recent evidence also suggests that genes and environment may work together to further increase the risk of RA, such that the likelihood of developing the disease is “significantly amplified in genetically susceptible individuals who have been exposed to various environmental pollutants.” Cigarette smoke, for example, “increases the disease risk of SE-positive individuals in a multiplicative, dose-dependent fashion.” the researchers point out. What scientists haven’t yet uncovered, however, are the mechanisms that underpin the genetic and environmental risks for RA, “let alone the synergism between these two factors.”
Prior research has suggested that aryl hydrocarbon receptor (AhR) may play a role in the link between environmental pollutants and autoimmunity. The AhR is an intracellular ligand-activated transcription factor that mediates the effects of polycyclic aromatic hydrocarbons, including dioxin and the byproducts of cigarette smoking. Interestingly, while SE signaling leads to increased osteoclast differentiation and activity, AhR agonists have similarly been shown to disturb the balance between regulatory T (Treg) cells and Th17 cells, and also to activate osteoclasts. Bone destruction mediated by osteoclasts is a major disease severity factor in RA, the team points out. The AhR pathway has separately been implicated in the pathogenesis of autoimmune disease, they note.
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