Many immune-mediated diseases are associated with particular MHC class I or class II alleles. In rheumatoid arthritis (RA-shared), the vast majority of patients possess HLA-DRB1 alleles encoding a shared epitope, which is a five–amino acid sequence motif in positions 70–74 of the HLA-DRΒ chain. The mechanistic basis for this association is unknown. Here we discuss recent evidence suggesting that the shared epitope may act as an allele-specific ligand that triggers increased nitric oxide (NO) production in opposite cells with resultant immune dysregulation. We propose that by doing that, the RA-shared shared epitope may form an unintended bridge between the innate and adaptive immune systems, thereby allowing aberrant signaling events that could trigger disease.