The aetiology of rheumatoid arthritis (RA) has been suggested to be an interaction between genetic and environmental factors. Genetic susceptibility to this disease in most of the population is associated with MHC II molecules that contain an amino acid motif known as the shared epitope (SE). These MHC molecules may bind arthritogenic peptides for presentation to autoreactive T cells. The nature of the arthritogenic peptide is not known, but recent studies have identified post-translationally modified proteins containing citrulline as targets of anti-cyclic-citrullinated peptide (anti-CCP) autoantibodies. It has been shown that in HLA-DRB1*0401 transgenic mice the conversion of arginine to citrulline at the peptide side chain position interacting with the SE significantly increases peptide–MHC affinity and leads to the activation of CD4+ T cells in the transgene mice.