The last four decades of the 20th century saw the discovery of the heat shock or cell stress response and the identification of the proteins produced by cells in response to adverse environmental conditions. In 1987, the term ‘molecular chaperone’ was coined to describe several unrelated protein families which had the ability to assist the correct folding and assembly/disassembly of other proteins. The past 20 years have seen the elucidation of the structural mechanisms of protein chaperoning by several key molecules including chaperonin (Hsp) 60 and Hsp70 and the realisation that not all molecular chaperones are cell stress proteins and vice versa. The genesis of molecular chaperones was contemporaneous with the identification of these highly conserved proteins as paradoxical immunodominant antigens that appeared to be important in microbial infection and autoimmunity. Indeed, the administration of molecular chaperones such as Hsp60 and Hsp70 was found to inhibit experimental autoimmune disease. By the 1990s, it was realised that correct protein folding was the key to cellular homeostasis and the paradigm that developed was that molecular chaperones were intracellular proteins whose function was to assist in protein folding. The paradoxical immunogenicity and immunomodulatory effects of molecular chaperones remained unexplained.
Another strand of the molecular chaperone story began to develop in the late 1980s and early 1990s with reports of the appearance of certain molecular chaperones on the surface of cells. Later, reports began to appear that molecular chaperones when applied exogenously to cells in culture had effects similar to those of pro-inflammatory cytokines.