Heat-shock proteins as immunogenic bacterial antigens with the potential to induce and regulate autoimmune arthritis.

Heat-shock proteins are ubiquitous and surprisingly immunogenic bacterial proteins. Due to their extensive evolutionary conservation, development of immune reactivity directed at hsp is expected to jeopardize the maintenance of tolerance for "self". The experimental model of adjuvant arthritis in rats has been illustrative in this respect. In this model disease is induced by immunization to mycobacteria, and by T-cell cloning it appeared that T cells with specificity for the 180-188 sequence of the mycobacterial hsp65 were capable of both inducing the disease or inducing resistance to the disease. Although the exact molecular mimicry relationship of this 180-186 epitope with the proteoglycan moiety of cartilage remains to be elucidated, the crucial significance of hsp65 immunity has been substantiated further, not only in adjuvant arthritis, but also in other models of experimentally induced arthritis. Development of disease is seen to coincide with development of hsp65 reactivity, and in AA to the 180-186 epitope in particular. There is now experimental evidence that responses to hsp65 are subject to regulatory T-cell control, and that such regulatory control may explain the observations that preimmunization with hsp65 induces protection against subsequent development of arthritis. In human arthritis, responses to hsp65 have been seen to occur at the level of synovial fluid-derived T lymphocytes. Especially, in children with juvenile chronic arthritis such responsiveness was seen to be directed at the endogenous "self" hsp60, as it was also found to be expressed at a raised level in the synovial lining cells. Altogether, both from the experimental models and from the human disease, evidence is being collected for hsp65 as a critical antigen which has, in the experimental models, the potential of inducing protective regulatory T-cell control. AA has now offered us some initial possibilities for exploiting this feature of hsp65 in inducing remission of disease. We may hope that, ultimately, such specific immunological intervention in disease will also become a reality in the management of human autoimmune arthritis. The exploitation of the regulatory control mechanisms that normally contain the dangerously autoimmune reactive elements in the system seems to be most attractive for such a purpose. We should not try to modify the outside non-self; however, we should use our understanding of the mechanisms involved in order to stimulate the immune system of the unfortunate to resume control over the management of responses directed at the endogenous "self". It is possible that further analysis of the role of hsp65 in arthritis will lead to such necessary understanding.