Hsps Are Unique Targets Of Autoimmune Responses

Autoimmunity, generally considered unfavorable for the host, at its root means recognition of self and hence has to be viewed in an unbiased form (3,6,38). The outcome of self-recognition depends on the context: Elimination of aberrant cells via recognition of self-epitopes indicating an abnormally altered state may be to the benefit of the host. When such an autoimmune reaction, however, becomes chronic or exacerbated owing to permanent stimulation by the ongoing inflammation, autoimmune disease may arise. The y/8 T cells have been proposed to play a unique role in recognizing certain antigens indicative for stress such as hsps (20-24,39). Hsp epitopes which are expressed after "stress" (e.g., after viral infection) become detectable for the specific immune system and thus can serve as an indicator for abnormality. The structures visible to the immune system are MHC/peptide complexes and perhaps also hsps on the cell surface (6). Either kind of recognition would promote immune surveillance.

The possibility that hsps proper are expressed on the cell surface remains a matter of controversy. Several experimental systems have provided circumstantial evidence to support this notion principally based on the identification of hsps by specific monoclonal antibodies (MAbs) (40-43). Immune precipitation and SDS-PAGE analyses revealed that proteins, which were specifically recognized by such MAbs, have the expected size of 60 kDa (22,24). Final proof, however, for the identity of these proteins requires amino acid sequencing. Passive cotranslocation of hsps together with typical membrane-bound proteins is possible, since coprecipitation of hsp 60 with a 70-kDa molecule and of hsp-like proteins with MHC class I molecules has been described (24,44). The immune system neglects, whether this protein is an hsp proper, or alternatively has a similar image to allow for cross recognition by hsp-specific antibodies (45,46).

Not only antibodies but possibly also y/8 T lymphocytes may recognize such surface-expressed proteins directly. Several studies have provided evidence for recognition of hsps by y/8 T cells (22,24,39). Particularly, the intraepithelial y/5 lymphocytes in the intestine, which are entrapped between epithelial cells and hence are unable to recirculate, fail to contact a great variety of antigens (16, 39,47,48). Therefore, they must be biased to a restricted number of markers of alterations, such as hsps. It appears an interesting possibility for y/8 T cells to focus on only few antigens instead of expressing a broad spectrum of specificity to any kind of antigen (6,49).

a/p T cells will recognize conventional MHC/peptide complexes, and T cells with specificity for cross-reactive regions of hsps shared between microbe and host have been identified (50-52). CD4 T cells recognizing such epitopes have been frequently observed, indicating the existence of self-reactive lymphocytes in the periphery. Although hsp-reactive CD8 T cells appear to be less frequent, such T-cell lines have been established and shown to recognize stressed host cells (52). Similarly, conventional recognition of antigenic peptides including those derived from hsps in the context of MHC gene products by some y/S T cells has been described (21,23,53).

Recent progress in peptide elution and sequencing have made it possible to isolate and identify peptides from MHC-encoded proteins (11,54-57). Frequently, epitopes derived from hsps have been identified. When compared with a protein sequence database, several hsp peptides were found identical with or highly similar to sequences from hsps of parasites, and furthermore to hsps of some common nutrients. Such peptides may concern T cells cross-reactive to self-hsp. Since self-reactive T cells can evade thymic deletion, peripheral silencing mechanisms must exist. One such mechanism is tolerization by oral immunization. This could mean that the route by which hsps contact the immune system influences the kind of immune response that develops: either activation of immunity with the potential risk of autoimmune disease by highly similar epitopes from microbial pathogens or, alternatively, by induction of oral tolerance of cross-reactive food-derived epitopes through the intestine (6,58).

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