Immunological aspects of heat-shock proteins—the optimum stress of life
Introduction
Cellular response to stress is an evolutionary ancient, ubiquitous and essential mechanism for survival. This mechanism protects cells from damage by environmental stress and associated misfolding (denaturation) of intracellular proteins. Molecular resources of this protective mechanism include a family of specialized proteins, molecular chaperones. These proteins are expressed in non-stressed cells at low levels and have essential functions in the cell cycle, as well as in cellular differentiation and growth. They are involved in metabolism, programmed cell death through protein assembly and transport, and influence the activation of enzymes and receptors. Molecular chaperones are often referred to as ‘heat-shock proteins’ (Hsp) or stress proteins, as their expression can be induced by changes in environmental temperature (i.e. heat shock). Non-lethal heat shock (the most widely used experimental stimulus to model environmental stress) causes specific changes in cellular function and gene expression, that is, elicits a cellular stress response. The changes comprise inhibition of DNA synthesis and transcription, as well as of RNA processing and translation; arrest of the cell cycle; denaturation and misaggregation of proteins; enhanced degradation of proteins through both proteasomal and lysosomal pathways; disruption of cytosceletal structures; metabolic alterations that lead to a net reduction in intracellular ATP level; and changes in membrane permeability that lead to the intracellular accumulation of Na+, H+, and Ca2+ (Sonna et al., 2002). In mammalian cells, non-lethal heat-shock alters gene expression and the activity of expressed proteins. Typically, this response enhances thermotolerance (i.e. the ability to survive subsequent, more severe heat stresses) and is temporally associated with the increased expression of Hsps. A cellular stress response can be triggered by other stressors, including exposure to toxins (such as arsenite, bacterial lipopolysaccharide (LPS), etc.—see Table 1), and cellular reactions to a specific stressor often lead to cross-tolerance to others. Increasingly severe exposure to stress activates the apoptotic program, and under extreme conditions, cell necrosis ensues.
Owing to their highly conserved and inducible nature, stress proteins are perfect mediators of cellular stress. Almost all pathogenic microorganisms studied hitherto possess heat inducible genes of stress proteins and respond to thermal (and other) stresses of infection with enhanced Hsp expression. Higher organisms possess (by means of innate immunity) the inherent capability of responding to stress signals. On the other hand, essentially the same molecules can mediate stress of the host organism; making the altered self ‘dangerous’ in case of cell necrosis, for example (Matzinger, 2002). Furthermore, the intrinsic role of Hsps can turn into a nuisance after the advent of adaptive immunity. With the appearance of specific receptors (i.e. antibodies and T-cell receptors), overexpressed and conserved stress proteins become primary targets of autoimmunity, through infection-induced molecular mimicry. Therefore, highly conserved Hsps (present in all mammalian cells) need special protection in the ‘adaptive world’. Owing to the failure of this protection, however, Hsps are indeed implicated in infection-induced autoimmune disorders. This review summarizes the essential features of heat-shock proteins and their recognition by innate immunity to demonstrate their complex role in the pathogenesis of disease, such as infection-induced autoimmunity. In view of the increasing body of evidence on their etiologic significance in certain multifactorial disorders (e.g. inflammatory bowel disease (IBD) and atherosclerosis), current concepts of Hsp-related immunopathological mechanisms underlying these conditions are also discussed.
Section snippets
Essential properties of heat-shock proteins (Hsps)
Hsps are traditionally classified by their molecular weight; the best understood are those with a molecular weight of 110, 90, 70, and 60 kDa (Table 2). These ‘major’ Hsps are expressed at 37 °C in the absence of heat stress. The second group comprises ‘minor’ Hsps that are induced by glucose deprivation and include glucose regulated proteins (grp) with molecular weights of 34, 47, 56, 75, 78, 94, and 174 kDa. A third group consists of low (about 20 kDa) molecular mass Hsps. Being proteins; Hsps
Innate immune recognition
The most appropriate stimulus for innate immunity is exposure to a foreign molecule in a “dangerous” milieu. In this context, “danger” is signaled by certain conserved molecules of invading pathogens (pathogen-associated molecular pattern (PAMP)). The essential decision of responding to or ignoring a particular antigen is made by innate immune recognition receptors upon activation by PAMP molecules, such as lipopolysaccharide (LPS) or bacterial CpG DNA (Janeway and Medzhitov, 2002). Receptors
Immunological protection of heat-shock proteins
As mentioned above, Hsps are highly conserved molecules present from Eubacteria to humans; conservativeness characterizes their molecular structure, biochemical properties and (partially) even their immunological (epitope) structure. It is not surprising therefore, that several autoantigens identified in various autoimmune disorders (Jones et al., 1993) and Hsps share several of their epitopes. These findings indeed support the age-old observation that infections can induce autoimmune
Heat-shock proteins as negotiators between danger and control mechanisms of autoimmunity
The best-studied conditions in this field are adjuvant arthritis (Prakken et al., 2003) and autoimmune Type I diabetes mellitus (Cohen, 2002). In adjuvant arthritis, the role of T-cell reactivity to a non-conserved epitope of Hsp65 (AA180-188) has been shown to be of pathogenetic importance (Van Eden et al., 1988). Subsequent studies confirmed that the self-antigen recognized by this T-cell clone is not Hsp60, but cartilage proteoglycan. Furthermore, Hsp65 can be used effectively to prevent
Several etiologic and pathophysiologic aspects of inflammatory bowel disease
All clinical forms of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by chronic inflammation and mucosal damage in various segments of the gastrointestinal tract. Although its etiology remains unclear, IBD is recognized as multifactorial disease arising from hereditary, environmental and immunological factors (Podolsky et al., 2002). The essential pathogenic triad of IBD comprises hereditary susceptibility to the disease, immune
Immunodeficiency burden and the pathogenesis of atherosclerosis
Atherosclerosis is a multifactorial disease. Over the past decades major risk factors, contributing to the formation of atherosclerotic plaques have been identified. The aggregate effect of concomitant risk factors (‘risk status’) has been shown as the ultimate determinant of disease incidence and prevalence in different populations. Efforts to accomplish risk reduction on population level, along with the improvement of coronary care of patients with acute myocardial infarction or unstable
Conclusion
The aggregate effect of genetic variability, including direct and indirect relationships, determines the level of immunodeficiency burden in any given individual. As illustrated by the examples of inflammatory bowel disease and atherosclerosis, subjects carrying mutations even with minor biological impact, might suffer from multifactorial diseases resulting from the aggregate effect of polymorphisms. Hsps, as guides and targets of the immune response, have complex roles in the
Acknowledgements
This work was supported by the ATHERNET (QLG1-CT-2002-90397) grant of the Fifth FP of EC (www.athernet.hu), Ministry of Education (FKFP 0138/01), and Ministry of Welfare (ETT 248/2001) of Hungary.
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