Heat shock proteins and the immune response

Summary: Immune regulation by parasites is a global concept that includes suppression, diversion, and conversion of the host immune response to the benefit of the pathogen. While many microparasites escape immune attack by antigenic variation or sequestration in specialized niches, helminths appear to thrive in exposed extracellular locations, such as the lymphatics, bloodstream, or gastrointestinal tract. We review here the multiple layers of immunoregulation that have now been discovered in helminth infection and discuss both the cellular and the molecular interactions involved. Key events among the host cell population are dominance of the T-helper 2 cell (Th2) phenotype and the selective loss of effector activity, against a background of regulatory T cells, alternatively activated macrophages, and Th2-inducing dendritic cells. Increasingly, there is evidence of important effects on other innate cell types, particularly mast cells and eosinophils. The sum effect of these changes to host reactivity is to create an anti-inflammatory environment, which is most favorable to parasite survival. We hypothesize therefore that parasites have evolved specific molecular strategies to induce this conducive landscape, and we review the foremost candidate immunomodulators released by helminths, including cytokine homologs, protease inhibitors, and an intriguing set of novel products implicated in immune suppression.

Helminth parasites – masters of regulation

Follicular Helper T Cells: Lineage and Location

The egg the exoskeleton growth and moulting the epidermis musculature the nervous system the pseudocoelom the secretory-excretory system the digestive system the reproductive system nematode pathology.

The Structure of Nematodes

Increased synthesis of heat shock proteins (hsp) occurs in prokaryotic and eukaryotic cells when they are exposed to stress. By increasing their hsp content, cells protect themselves from lethal assaults, primarily because hsp interfere with the uncontrolled protein unfolding that occurs under stress. However, hsp are not produced only by stressed cells; some hsp are synthesized constitutively and perform important housekeeping functions. Accordingly, hsp are involved in the assembly of molecules which play important roles in the immune system. It is not surprising that due to their wide distribution and their homology among different species, hsp represent target antigens of the immune response. Frequent confrontation of the immune system with conserved regions of hsp which are shared by various microbial pathogens can potentiate antimicrobial immunity. However, long-term confrontation of the immune system with hsp antigens which are similar in the host and invaders may convert the immune response against these host antigens and promote autoimmune disease. This review provides an overview of the role of hsp in immunity with a focus on infectious and autoimmune diseases.

https://cmr.asm.org/content/cmr/12/1/19.full.pdf

Role of Heat Shock Proteins in Protection from and Pathogenesis of Infectious Diseases

Trichinella spiralis is a highly successful parasite in that it can establish, develop, and reproduce in a wide range of vertebrate hosts. This low host specificity implies that the organism has the ability to adapt to a variety of environmental conditions and hence is relatively unaffected by many of those aspects of natural immunity that impose a more rigid specificity on other species. However, in common with all metazoan parasites, T. spiralis presents the host with a complex antigenic stimulus and thus evokes a powerful immune response. The complexity of the stimulus arises not only from the diversity of antigens present at any one time, but also from the fact that antigens may show stage specificity, changing qualitatively and quantitatively throughout development, and may be released in different tissues of the body. Many components of the immunological response probably have little or no effect on either host or parasite, though they may prove useful in diagnosis; some are deleterious to the parasite and provide protective resistance against infection, yet others are actually or potentially harmful to the host, either from their involvement in immunopathological reactions or through their modulation of unrelated immune responses. This chapter will concentrate on those responses that confer resistance on the host; immune responses in the contexts of diagnosis and pathology are dealt

The Immune Response

Anti-parasitic drugs may achieve their therapeutic effect either by direct activity against the pathogenic organism, or by altering host factors which lead to parasite killing. In this review, we discuss the evidence for an indirect mode of action for one major anti-filarial drug, diethylcarbamazine (DEC). The interpretation most consistent with existing data is that DEC alters arachidonic acid metabolism in microfilariae and in host endothelial cells. These changes may result in vasoconstriction and amplified endothelial adhesion leading to immobilization of microfilarial parasites, enhanced adherence and cytotoxic activity by host platelets and granulocytes. These events would represent activation of the innate, non-specific immune system, independent of the adaptive, antigen-specific, immune response. This model explains the paradox between rapid clearance in vivo and the lack of an in vitro effect, as well as the efficacy of DEC in non-immune animals. It may also account for the inconsistencies in the effects of DEC against different filariae in different host species. In addition, we discuss the significant side-effects often associated with treatment of heavily infected patients, and the longer-term changes in T-cell reactivity and the host-parasite relationship which follow successful treatment with DEC.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0031182000075351

Diethylcarbamazine (DEC): immunopharmacological interactions of an anti-filarial drug.

Summary A set of cross-reactive antigens is described which are present in somatic extracts and in-vitro secretions of the filarial nematodes Brugia pahangi and B malayi A monoclonal antibody reactive with a repeating epitope on these molecules readily detects circulating antigen in the serum of animals infected with lymphatic filariae, using either an immunoradiometric assay or enzyme-linked immunosorbent assay (ELISA) This epitope has the immunological reactivity and chemical characteristics of the phosphorylcholine (PC) hapten The anti-PC monoclonal has been used to define the antigens bearing this epitope, and in chromatographic studies on material from extracts of Brugia adult worms, a heterogeneous profile of PC-positive molecules are found In sera from Brugia-infected jirds, an antigen with a native molecular weight of approximately 500000 is observed, which displays limited sensitivity to protease degradation However, denatured samples on Western blots show a major parasite circulating antigen of Mr 90000 The detection of this antigen in the presence of excess host antibody is also demonstrated, taking advantage of the stability of the target epitope to a range of treatments designed to dissociate and eliminate immune complexes

Phosphorylcholine‐bearing antigens in filarial nematode parasites: analysis of somatic extracts, in‐vitro secretions and infection sera from Brugia malayi and B. pahangi

Surface antigens of three stages of three species of the filarial nematode genus Brugia have been analysed by radio-iodination and immunoprecipitation. These surface antigens have been shown to be characteristic for each stage by polyacrylamide gel electrophoresis. For example, infective larvae and adult worms have relatively complex patterns while microfilariae have few bands which are not found when other stages are radio-isotope labelled by the same technique. The surface antigens of Brugia malayi, B. timori and B. pahangi adult worms are all closely homologous, as are the surface antigens of infective larvae of the same three species, and of microfilariae of B. malayi and B. pahangi. Immunoprecipitation revealed that antibody raised in mice against one stage or species reacted with surface antigens from other stages and species. For example, sera raised against B. pahangi male adults reacted strongly with surface antigens from all three species. This cross-reactivity was dominant despite the apparent stage-specificity of the surface pattern seen on SDS-PAGE analysis. Moreover, in cross-immunization experiments, infective larvae were able to stimulate a secondary antibody response in mice previously primed with microfilarial surface antigens. The major microfilarial surface antigens (of mol. wt 65−70000 Daltons) were recognized by serum antibody from microfilariae-, infective larvae- or adult-infected animals. Thus, although the dominant antigens from each stage are of different molecular weight, cross-reactions with stage-specific antisera suggest that there must be shared epitopes on Brugia surface antigens from each stage. Such shared antigenic determinants dominate the immune response, although other evidence, including the differences in molecular weight, indicates the existence of stage-and species-specific components.

Cross-reactive surface antigens on three stages of Brugia malayi, B. pahangi and B. timori

Seven microfilaraemic and five amicrofilaraemic cats which had been repeatedly infected with Brugia pahangi were challenged along with normal cats 28, 14 and 1 day before autopsy. The lymphatics of the amicrofilaraemic cats contained no female adult worms originating from the repeat infections and only two adult males (both from the same cat). Only 5.2% of the worms in the control cats were recovered from the amicrofilaraemic cats. Most of the challenge worms were killed in the first 24 h. The microfilaraemic cats all contained fertile adult male and female worms derived from the repeated infection but in such low numbers as to indicate considerable resistance to infection. Compared to their controls 26.4% of the challenge worms were recovered. Analysis of the life-cycle stages recovered showed that in both groups there was attrition of all stages and that although a number of worms reached L5 these were all killed later in the amicrofilaraemic cats.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0031182000057127

D. A. Denham

Papers

The Immune Response

Diethylcarbamazine (DEC): immunopharmacological interactions of an anti-filarial drug.

Phosphorylcholine‐bearing antigens in filarial nematode parasites: analysis of somatic extracts, in‐vitro secretions and infection sera from Brugia malayi and B. pahangi

Cross-reactive surface antigens on three stages of Brugia malayi, B. pahangi and B. timori

The resistance to re-infection of cats repeatedly inoculated with infective larvae of Brugia pahangi