The heat shock protein(hsp), one of the most conserved and ubiquitous proteins in a wide range of species from bacteria to mammals, is strongly immunogenic. High conservation and potent immunogenicity, taken along with the fact that hsp is the target molecule of some gamma/delta T cells place it at the interface between immunity and tolerance. The role of hsp on autoimmune and inflammatory disorders has been vigorously investigated. There are accumulated lines of evidence suggestive of the possible involvement of hsp in clinical disorders but they still remain circumstantial. Two questions must be addressed before the exact role of hsp in these settings is established: 1) Why a conserved protein such as hsp is so immunogenic? 2) Why a ubiquitous protein can be a target of an organ-specific autoimmunity? Our data indicated that antibodies against highly conserved hsp60 in the sera from patients with autoimmune diseases, highlighted by rheumatoid arthritis, were directed mainly against epitopes specific for bacteria such as E. coli. The role of intestinal flora on the pathogenesis of rheumatoid arthritis has long been pursued and our data might support these lines.