Heat shock proteins refine the danger theory.

Abstract

Deficiencies of the self–non-self paradigm in explaining immune phenomena, such as the existence and breaking of immune tolerance, have lead the likes of Janeway1 and Matzinger2 to suggest additional levels of control of antigen-specific immune responses. In simple terms, the immune system is thought to be turned on by ‘danger’ associated with certain molecules of infectious organisms, or cell products released during tissue damage or stress. Antigen-presenting cells (APC) possess pattern-recognition receptors that can recognize such molecules. This recognition is thought to cause upregulation of costimulatory molecules on local APC, which is the second signal [in addition to antigenic peptide with major histocompatibility complex (MHC)] that is required to initiate an antigen-specific immune response. Candidate danger signals from infectious organisms include lipopolysaccharide, mannans, glycans and CpG DNA motifs, whilst those from mammalian cells include heat shock proteins (hsp; inducible and constitutive), mitochondria, mannose, RNA and DNA. With respect to hsp, recent evidence now suggests that their role in signalling danger may be wide ranging and, not surprisingly for immunology, more complicated than first thought.