In addition to the "nonspecific" adjuvant and regulatory effects of natural hsp 60 autoimmunity, it is clear that certain autoimmune diseases can be caused by "specific" hsp 60 autoimmunity. The development of type I diabetes in the NOD mouse seems to fulfill the criteria for assigning such a causal relationship: anti-hsp 60 T cells can transfer diabetes (12), active immunization to the p277 epitope of hsp 60 can induce diabetes, even in mice that are not prone to dia betes (15), and the p277 peptide can be used to downregulate hsp 60 autoimmunity and cure diabetes (13). Another example of the causal relationship between hsp 60 autoimmunity and a specific disease seems to be a form of uveitis (19). The relationship between hsp 60 autoimmunity and arthritis is less clear (30); mimicry between an epitope of a bacterial specific hsp 60 sequence and a cartilage proteoglycan may be involved (31). Thus, adjuvant arthritis may combine bacteria-hsp 60 mimicry of a joint-specific molecule, along with a "nonspecific adjuvant" effect of true hsp 60 autoimmunity.
In any case, the role of hsp 60 autoimmunity in initiating an autoimmune disease would seem to require fulfillment of at least two conditions. The target organ would have to express hsp 60 in a way different from that of other tissues to allow the anti-hsp 60 T cells (or antibodies) to recognize hsp 60 target epitopes in the absence of stress. This seems to be true for insulin-producing p cells that express hsp 60 in their secretory granules unrelated to stress (32). A second condition for a specific disease would be a lapse or failure of the natural regulatory mechanisms that turn off the inflammatory process (27,28). A prolonged failure in regulation should lead to a chronic disease, such as is the insulitis in untreated NOD mice. Reinstatement of regulation would terminate the inflammation, causing the disease to remit "spontaneously." The diabetes actively induced by hsp 60 autoimmunity is indeed self-limited (15), like experimental autoimmune encephalomyelitis (EAE) and other induced autoimmune diseases (33).
A form of chronic autoimmune disease could conceivably be caused by unregulated hsp 60 autoimmunity that follows the induction of damage to the target tissue by some other primary cause. For example, we have reported that hsp 60 autoimmunity and diabetes can be induced in mice of the C57BL/ksj strain by a low dose of the p-cell toxin streptozotocine (14). Here the toxic insult initiates an inflammatory response that seems to be perpetuated by hsp 60 autoimmunity. Indeed, downregulating the hsp 60 autoimmunity after the toxic insult can cure the diabetes (34). Thus, the existence of natural autoimmunity to hsp 60, its membership in the homunculus set of self-antigens, can account for the many of the paradoxical associations of hsp 60 autoimmunity with various types of inflammation. The fundamental questions, however, have yet to be answered.
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