Heat shock proteins in immune response to cancer: the Fourth Paradigm

The involvement of heat shock proteins in immune response is categorized into four distinct paradigms. In the First Paradigm, HSP derived from foreign organisms act as classical foreign antigens, and they elicit immune response to the non-conserved HSP epitopes. The Second Paradigm refers to instances where the host responds to self HSP to which there is no central or peripheral tolerance. The Third Paradigm involves molecular mimicry, where cross-reactivity between an HSP and another protein leads to an immune response to the latter under conditions which elicit an immune response to the former, such as infection with a bacterium whose immunodominant antigen is an HSP. The Fourth Paradigm refers to situations where an HSP-antigen complex elicits an effective response to the antigen and not to the HSP. Thus the HSP acts as a carrier for the antigenic peptide. The role of HSP in recognition by gamma delta T cells may also fall into this paradigm. In this article, the Fourth Paradigm is considered as a crucial element in the development of vaccines against cancers and infectious diseases, and is analyzed through the prism of the observed association of hsp70 species with antigenic peptides.