The humoral immune response to heat shock proteins

Humoral immune reactions to heat shock proteins (hsp) from microorganisms are one aspect of microbial infections in humans. The production of antibodies which are specific to epitopes present on procaryotic hsp leads also to the appearance of cross-reactive serum antibodies in the host organism that react with human hsp. This article discusses the consequences of such autoreactive antibodies for the host in context with the development of immune tolerance and autoimmune diseases, especially rheumatoid arthritis (RA), and in experimental animal models for arthritis such as adjuvant arthritis in rats. On the basis of epitope cross-reactivity between hsp and other host proteins, a hypothesis is presented for the development of autoimmune disease following the production of hsp-specific antibodies.     

The cellular immune response to heat shock proteins.

T lymphocytes, which are central to almost every immune response, frequently recognize microbial hsp60. Such cells could provide an early defense mechanism against pathogenic microbes. However, T cells also recognize epitopes of hsp60 shared by microbe and host. Not only conventional alpha/beta T cells respond to hsp60; gamma/delta T cells do so, as well. In fact, certain gamma/delta T cells seem to have a particular preference for this molecule. Recognition of stressed host cells expressing hsp60 could facilitate the scavenger function of the T cell system. On the other hand, such recognition could be involved in autoimmune disease.     

The small heat shock proteins and their clients

Small heat shock proteins are ubiquitous proteins found throughout all kingdoms. One of the most notable features is their large oligomeric structures with conserved structural organization. It is well documented that small heat shock proteins can capture unfolding proteins to form stable complexes and prevent their irreversible aggregation. In addition, small heat shock proteins coaggregate with aggregation-prone proteins for subsequent, efficient disaggregation of the protein aggregates. The release of substrate proteins from the transient reservoirs, i.e. complexes and aggregates with small heat shock proteins, and their refolding require cooperation with ATP-dependent chaperone systems. The amphitropic small heat shock proteins were shown to associate with membranes, although they do not contain transmembrane domains or signal sequences. Recent studies indicate that small heat shock proteins play an important role in membrane quality control and thereby potentially contribute to the maintenance of membrane integrity especially under stress conditions. Received 11 July 2006; received after revision 4 October 2006; accepted 10 November 2006     

The humoral immune response to heat shock proteins.

Humoral immune reactions to heat shock proteins (hsp) from microorganisms are one aspect of microbial infections in humans. The production of antibodies which are specific to epitopes present on procaryotic hsp leads also to the appearance of cross-reactive serum antibodies in the host organism that react with human hsp. This article discusses the consequences of such autoreactive antibodies for the host in context with the development of immune tolerance and autoimmune diseases, especially rheumatoid arthritis (RA), and in experimental animal models for arthritis such as adjuvant arthritis in rats. On the basis of epitope cross-reactivity between hsp and other host proteins, a hypothesis is presented for the development of autoimmune disease following the production of hsp-specific antibodies.     

Heat shock response inDrosophila

Major alterations in genetic activity have been observed in every organism after exposure to abnormally high temperatures. This phenomenon, called the heat shock response, was discovered in the fruit flyDrosophila. Studies with this organism led to the discovery of the heat shock proteins, whose genes were among the first eukaryotic genes to be cloned. Several of the most important aspects of the regulation of the heat shock response and of the functions of the heat shock proteins have been unraveled inDrosophila.     

Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?

Heat shock proteins (hsp) are highly conserved from bacteria to man. Bacterial hsp, with approximate molecular weights of 60 kDa (hsp60), are immunodominant antigens that are immunologically cross-reactive with their mammalian counterparts. Hsp molecules are therefore useful in studies of fundamental questions concerning immune responses to foreign as opposed to self antigens. The finding that immune responses to hsp are associated with both experimentally-induced and spontaneous autoimmune diseases in animals has prompted intensive research to assess the role of bacterial hsp as the etiological agents involved in the development of autoimmune diseases. Recent evidence from animal models of autoimmune disease has clearly demonstrated the involvement of hsp in both the pathogenesis and the immunoregulation of autoimmune diseases. Studies with arthritogenic and diabetogenic T cell clones have identified immunogenic epitopes of hsp. These have been shown to ameliorate adjuvant arthritis in Lewis rats, and insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. Such studies may have important therapeutic implications for the future treatment of human autoimmune disease.Dedicated to Professor Hermann A. Moser on the occasion of his 71st birthday.     

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 andnot to the HSP. Thus the HSP acts as a carrier for the antigenic peptide. The role of HSP in recognition by γδ 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.     

Small heat shock proteins: molecular structure and chaperone function

Small heat shock proteins (sHSPs) associate with nuclei, cytoskeleton and membranes, and as molecular chaperones they bind partially denatured proteins, thereby preventing irreversible protein aggregation during stress. sHSP monomers consist of a conserved α-crystallin domain of approximately 90 amino acid residues, bordered by variable amino- and carboxy-terminal extensions. The sHSPs undergo dynamic assembly into mono- and poly-disperse oligomers where the rate of disassembly affects chaperoning. The α-crystallin domain contains several β-strands organized into two β-sheets responsible for dimer formation, the basic building block of most sHSPS. The amino-terminal extension modulates oligomerization, subunit dynamics and substrate binding, whereas the flexible carboxy-terminal extension promotes solubility, chaperoning and oligomerization, the latter by inter-subunit linkage. Crystallization studies have revealed sHSP structure and function. Additionally, site-directed mutagenesis, biophysical investigations, functional studies and the discovery of relationships between mutated sHSPs and diseases have illuminated the role of sHSP within cells. Received 8 May 2005; received after revision 24 June 2005; accepted 19 July 2005     

Heat shock protein gene expression during Xenopus development

Stress-induced heat shock protein gene expression is developmentally regulated during early embryogen esis of the frog, Xenopus laevis. For example, a number of heat shock protein genes, such as hsp70, hsp90, and ubiquitin are not heat-inducible until after the midblastula stage of embryogenesis. Furthermore, the family of small heat shock protein genes, hsp30, are differentially expressed after the midblastula stage as well as being regulated at the level of mRNA stability. Many of these stress proteins are also synthesized constitutively during oogenesis and embryogenesis during which they may act as molecular chaperones as well as being involved in sequestering proteins in an inactive state until required by the developing embryo. Furthermore the induction of these stress protein genes has been correlated with enhanced thermoresistance. During stressful conditions heat shock proteins probably prevent aggregation or misfolding of damaged protei ns within the embryo.     

Heat shock proteins in three relatedDrosophila species belonging to theobscura group

The effect of heat shock on protein synthesis in three relatedDrosophila species belonging to theobscura group was analyzed on SDS-acrylamide gels. Four major heat shock proteins (hsps) were found in these species, in which synthesis reaches a maximum at 34°C. Although the higher molecular weight proteins are conserved, differences in size were found for the small hsps in these species. By means of in situ hybridization usingD. melanogaster probes for the small hsp genes, it was inferred that the small hsp genes of theobscura group species are clustered at the 27A locus in all three species.     

Molecular mimicry in neurological disease: what is the evidence?

Autoimmune diseases are a leading cause of disability and are increasing in incidence in industrialized countries. How people develop autoimmune diseases is not completely understood, but is related to an interaction between genetic background, environmental agents, autoantigens and the immune response. Molecular mimicry continues to be an important hypothesis that explains how an infection with an environmental agent results in autoimmune disease of the nervous system and other target organs. Although molecular mimicry has yet to be unequivocally proven, in the past several years there has been a sharpening of its definition with better experimental data implicating it as a cause of neurological disease in humans. Received 9 July 2007; received after revision 15 November 2007; accepted 27 November 2007     

Developmental control of heat shock and chaperone gene expression Hsp70 genes and heat shock factors during preimplantation phase of mouse development

Heat shock genes are found in all organisms, and synthesis of heat shock proteins is induced by various stressors in nearly all the cells forming these organisms. However, a particular situation is noticed for hsp70 genes in mouse embryos at the beginning of their development. First, spontaneous expression of hsp70 is observed at the onset of zygotic genome activity. Second, inducible expression is delayed until morula or early blastocyst stages. A better understanding of both these points depends on a more careful analysis of hsp70 expression in relation to their major regulators, the heat shock factors. In this review, we will see how the development of the preimplanta tion embryo highlights the complexity of heat shock gene regulation involving trans-cis interactions and the cellular and nuclear environment.     

Synthesis of a ubiquitously present new HSP60 family protein is enhanced by heat shock only in the Malpighian tubules ofDrosophila

A homologue of the chaperonin protein of the HSP60 family has not been shown so far inDrosophila. Using an antibody specific to HSP60 family protein in Western blotting and immunocytochemistry, we showed that a 64-kDa polypeptide, homologous to the HSP60, is constitutively present in all tissues ofDrosophila melanogaster throughout the life cycle from the freshly laid egg to all embryonic, larval and adult stages. A 64-kDa polypeptide reacting with the same antibody in Western blots is present in all species ofDrosophila examined. Using Western blotting in conjunction with³⁵S-methionine labeling of newly synthesized proteins and immuno-precipitation of the labeled proteins with HSP60-specific antibody, it was shown that synthesis of the 64-kDa homologue of HSP60 is appreciably increased by heat shock only in the Malpighian tubules, which are already known to lack the common HSPs.     

Heat stress induced enhancement of heat shock protein gene activity in the honey bee (Apis mellifera)

Summary We employed in vitro translation of mRNA and product separation using SDS-PAGE to examine the heat-shock response of the worker honey bee. Increases in the levels of 6 translatable RNA populations were observed following heat stress. The greatest response was observed among bees aged 9 days. Slight levels of induction of 70 and 82 kDa heat shock proteins were evident among bees taken directly from the colony.     

Divergent effects of hyperosmolality on stress-response (heat shock) protein expression in cultured human tumor cells: an immunocytochemical study

Exposing cells to adverse conditions usually elicits expression of stress-response (heat shock) proteins (srp). Here we show that hyperosmolar growth conditions do not uniformly affect srp expression in MCF-7 and HeLa S3 cells, derived from carcinoma of the breast and cervix, respectively. Thus, whereas srp 27 expression was increased in MCF-7, but not in HeLa S3, the opposite was the case with srp 72. On the other hand, hyperosmolality did not induce B-crystallin or ubiquitin in either cell line. These findings show that srp expression by the human tumor cells studied is non-coordinate, suggesting that each srp is independently modulated.