Beneficial Effects of Hsps

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Beneficial effects of hsps based on their chaperone functions have been reported. Evidence for autoprotection of the infected cell by elevated hsp synthesis during infection has been obtained with human cells (62-67). Increased expression and supply of the inducible hsp 72 by astrocytes during scrapie may contribute to neuronal homeostasis by preventing the deposition of neurotoxic amyloid proteins. This could retard damage of the central nervous system, at least in the initial phase of disease (68).

Table 1 Hsps and Infection

Type of pathogen

Viruses HTLV-I HIV

Bacteria

Mycobacterium tuberculosis

Mycobacterium leprae

Chlamydia trachomatis

Borrelia burgdorferi

Coxiella burnetii Treponema pallidum Legionella pneumophila Brucella abortus Bordetella pertussis Helicobacter pylori

Hsp cognate

Disease

Reference

Self-hsp 70 T-cell leukemia 91

Self-hsp 70 AIDS 45

Hsp 70 Tuberculosis 123

Hsp 60 Tuberculosis 123, 124

Small hsps Tuberculosis 125

GroES Tuberculosis 126

Hsp 70 Leprosy 127

Hsp 60 Leprosy 123, 124

Small hsps Leprosy 128

GroES Leprosy 129

Hsp 70 Trachoma 130

Hsp 60 Trachoma 115

Hsp 70 Lyme disease 131

Hsp 60 Lyme disease 132

Hsp 60 Q-fever 133

Hsp 60 Syphilis 134

Hsp 60 Legionnaire's disease 78, 135

Hsp 60 Brucellosis 136

Hsp 60 Pertussis 77

Hsp 60 Gastritis, ulcer 117

Neisseria meningitidis Yersinia enterocolitica

Fungi

Candida albicans Aspergillus fimigatus Histoplasma capsulatum

Protozoa

Plasmodium falciparum

Trypanosoma cruzi

Trypanosoma brucei brucei

Leishmania amazonensis Leishmania brasiliensis Leishmania donovani Leishmania major

Helminths

Schistosoma mansoni

Brugia malayi Onchocerca volvulus

Hsp 60 Hsp 60

Meningitis Yersiniosis

Hsp 90 Candidosis 84, 86

Hsp 90 Aspergillosis 138

Hsp 70 Histoplasmosis 139, 140, 141

Hsp 90 Malaria 142

Hsp 70 Malaria 143, 144

Hsp 90 Chagas' disease 146

Hsp 70 Chagas'disease 147,148

Hsp 90 Trypanosomiasis of cattle 149

Hsp 70 Trypanosomiasis of cattle 150

Hsp 90 Leishmaniasis 151

Hsp 70 Leishmaniasis 148

Hsp 70 Leishmaniasis 152, 153

Hsp 70 Leishmaniasis 154

Hsp 90 Schistosomiasis 155

Hsp 70 Schistosomiasis 156, 157

Small hsps Schistosomiasis 158

Hsp 70 Filariasis 159

Hsp 70 Onchocercosis 160

In these examples, hsps were helpful by preventing protein denaturation. During antigen processing, proteins become denatured and are cleaved into peptides. Consistent with a possible participation of hsps in this process, several reports have been published verifying this concept. A peptide-binding protein (PBP 72/74), which is involved in the intracellular assembly of the anti-gen/MHC class II complex, has been characterized as a member of the hsp 70 family (69). Cytosolic hsp 70 and, similarly, gp 96 in the ER (homologous to p84/86hsp) are associated with tumor-specific peptides (70-72). Antigenic peptides may be transferred to MHC class I directly or through internalization of the hsp/peptide complexes by antigen-presenting cells (72,73). Finally, MHC class I presentation of certain antigenic peptides independent from peptide transporters and dependent on constitutively expressed hsp 73 has been described (74). These latter examples provide first hints as to how chaperones participate in basic immune functions.

Beneficial effects to the host of hsps functioning as immunogen have also been described. Because any kind of microbial pathogen synthesizes hsps (see Table 1), and because hsps are highly conserved among different species, frequent contact with microorganisms of even low virulence could cause a strong immune response to these proteins. Antibody and T-cell responses to hsps have been described using peripheral blood and cord blood cells from healthy individuals (33,50,75,76). High anti-hsp antibody titers were observed in children vaccinated with the trivalent vaccine against tetanus, diphtheria, and pertussis, suggesting immunodominance of hsp antigens (77). Therefore, a more rapid immune response to virulent pathogens displaying hsp cognates may occur in healthy individuals.

Consistent with this idea a purified major cytoplasmic membrane protein (a member of the hsp 60 family) of Legionella pneumophila has been shown to be protective in guinea pigs (78). Adoptive transfer of CD4 a/p T-cell clones with specificity for hsp 60 of Yersinia enterocolitica protects mice from lethal infection with this pathogen (79). A high degree of protection was obtained with a monocytic tumor cell line transfected with the mycobacterial hsp 60 gene as vaccine. Such immunized mice were protected against challenge with Mycobacterium tuberculosis. The responsible T cells were CD8+ and CD4+ (80). Infection with Candida albicans may result in superficial candidosis which is prevented by cell-mediated immunity or systemic candidosis, where humoral immunity against a breakdown product of hsp 90 prevents dissemination beyond the mucosa. In systemic candidosis, low titers of anti-hsp 90 antibodies are fatal to the host (81-85). Studies in a mouse model of systemic candidosis showed that prophylactic administration of anti-hsp 90 antibodies with reactivity to a defined and conserved epitope reduced mortality of mice by about 50% (86). The fungal hsp 90 itself seems to contribute to pathogenesis, and anti-hsp 90

autoantibodies neutralize this unusual effect (87). This reamphasizes the possibility that hsp-specific immunity mediates protection. In another model, hsp was used as carrier of unrelated antigens for vaccination against malaria. This hsp-malaria antigen vaccine showed improved efficacy against malaria plasmodia in mice preimmunized with BCG (36,37).

Self-epitopes of hsps become expressed on the cell surface subsequent to increased hsp production, and thereby the immune system becomes allerted. Stressed cells are detected by CD8+ T lymphocytes cross reactive for bacterial and self hsp 60 in a mouse model, whereby not only heat but also cytokines and even virus induced MHC I presentation of self epitopes which were then recognized by T cells (52,63,88-90). Furthermore, cell surface hsp 60 induced by human immunodeficiency virus (HIV) promoted lysis by antibody-dependent cellular cytotoxicity (ADCC) (45), and HTLV-1-infected cell lines stimulated formation of anti-hsp autoantibodies in rabbits (91). The expression of self-hsp could promote immunosurveillance of virus-infected cells (6,92).

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