Our studies with this cusp ligand have also provided a mechanistic basis for the long-observed association between RA, cigarette smoking and carriage of SE-coding alleles (117), by demonstrating that in the presence of aryl hydrocarbon receptor (AhR) agonists - environmental pollutants found in cigarette smoke - the activation potency of the SE-mediated pathway is amplified synergistically with resultant augmented inflammatory response and bone erosive damage that lead to more severe experimental arthritis in mice (21). Here, AHR is linked to arthritic joint disease.