Shared Epitope - Smoking Pathogenic Link Clarified Save

Proceedings of the National Academy of Sciences (PNAS) has published new research on the mechanistic link between the rheumatoid arthritis (RA) "shared epitope" (SE) risk alleles and environmental triggers such as cigarette smoke that leads to joint inflammation and bony destruction. (Citation source: http://bit.ly/2HhyybG)

A majority of RA patients poses restricted HLA-DRB1 alleles that encode a five-amino acid sequence motif called the shared epitope (SE) in hypervariable region of the HLA-DRβ chain. The SE is the strongest genetic risk factor for severe RA. Moreover, smokers who also carry the SE HLA genes are more likely to get RA and to manifest more severe disease.

Michigan Medicine researchers have studied the interaction between SE and environmental pollutants. Environmental toxins are believed to act via the aryl hydrocarbon receptor (AhR) that bound by polycyclic aromatic hydrocarbons, such as dioxin and tobacco. The AhR pathway has previously been implicated in the pathogenesis of autoimmune diseases, like multiple sclerosis.

Fu and colleagues found that AhR pathway agonists given to transgenic mice carrying human SE-coding alleles resulted in increased arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and lymph nodes of arthritic mice.

Thus, the SE ligand and AhR agonists synergize to increase osteoclast and Th17 cell differentiation to exacerbate disease severity and bone destruction. The cross-talk between these two pathways is mediated by nuclear factor kappa B.

They have shown that environmental toxins interact with the shared epitopes in a manner that activates and worsens rheumatoid inflammatory events. They postulate that new treatments may target this interaction, if only to limit the articular damage seen in RA.