Chaperones as part of immune networks.

Network theory is increasingly accepted as a basic regulatory mechanism in diverse immunological functions. Heat shock proteins (Hsps) are involved in multiple networks in the immune system. Hsps themselves (foreign or endogenous) activate innate immunity and play important roles to deliver self or nonself materials to antigen presenting cells. However, Hsps are immunodominant antigens during infectious diseases making self Hsps endangered targets of autoimmunity by cross-reactive clones. Therefore, it is not surprising that the mechanism of protection of self Hsps is not clonal deletion in natural self tolerance; rather, self Hsps are protected by active regulating natural autoimmunity. The active regulatory/protective immunity is accomplished by natural autoantibodies and regulatory T cells, both recognizing Hsps. The multiple involvements of Hsps in immune networks make them ideal targets of therapy in autoimmune diseases. Indeed, immunotherapy with Hsps was recently reported to be effective treatment modality against cancer, arthritis or diabetes mellitus.