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The unusual immunogenicity of heat shock proteins (also known as stress proteins) was discovered in studies of the immune response to microbial infection, in which a large proportion of the humoral and cellular immune response to diverse microbial pathogens was found to be specific for pathogen-derived heat shock protein . These studies demonstrated that immune recognition of pathogen-derived heat shock proteins occurs in natural and experimental settings in animals and man. This is discussed in detail in Chapter 16. Immune responses elicited to mycobacterial heat shock proteins have been particularly well studied. In man, recognition of mycobacterial heat shock protein by CD4+ T cells occurs in the context of numerous human leukocyte antigen (HLA) alleles, and epitopes have been identified that are presented by multiple HLA molecules . The promiscuous recognition of mycobacterial heat shock proteins supports their utility as ‘universal’ immunogens for the genetically diverse human population. The immunogenic properties of microbial heat shock proteins have accordingly led to their application in a variety of immunisation formats as prophylactic and therapeutic agents in models of infectious disease and cancer . In these studies, heat shock proteins have been delivered as subunit vaccines, carrier proteins in chemical conjugates, recombinant fusion proteins and DNA expression vectors for induction of humoral and cellular immunity.
To explain the disproportionate focus of the immune response on a small subset of pathogen antigens, heat shock proteins were proposed to act as ‘red flags’ – alerting the immune system to the presence of a foreign invader .
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