HSP-derived Peptides Inducing Uveitis and IgG and IgA Antibodies

doi:10.1006/exer.1998.0574

Experimental Eye Research

Volume 67, Issue 6, December 1998, Pages 719-727

https://doi.org/10.1006/exer.1998.0574 Get rights and content

Abstract

Heat shock protein (HSP) 65 kD-derived peptides, which specifically stimulate T cells from patients with Behçet's disease (BD), are capable of inducing uveitis in rats. Mycobacterial HSP 65 kD and BD-specific peptides were injected into Lewis rats and the development of uveitis was monitored clinically and histologically, and IgG and IgA antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Rats immunized with HSP peptides that developed uveitis showed significantly higher serum IgG antibody levels to peptide 311–326 (P<0.05) and the corresponding homologous human peptide 336–351 (P<0.01) than rats without uveitis. Significant increases in serum IgA antibodies in rats with uveitis were also observed in those immunized with peptides 111–125, 311–326 and 336–351 (P<0.05). Rats injected with HSP 65 kD showed a rise in IgG antibody levels to peptides 111–125, 154–172 and 311–326 and to a lesser extent, a rise in IgA antibody level to peptide 311–326. HSP showed almost complete inhibition of binding of IgG antibodies to HSP 65 kD, but peptides 111–125, 154–172, 311–326 and 336–351 showed inhibition to a lesser extent in a competitive assay. These results suggest that increases in IgG and IgA antibody levels to specific peptides within HSP, develop in rats with uveitis. The T and B cell epitopes responsible for the development of ocular disease in rats immunized with HSP-derived peptides, appear to be similar or identical to those found in patients with the ocular type of BD.

References (31)

M.G. Danieli et al.
Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis (scleroderma)
J. Autoimmun.
(1992)
A. Hasan et al.
Role of γδ T cells in pathogenesis and diagnosis of Behçet's disease
Lancet
(1996)
J. Holoshitz et al.
T lymphocytes of rheumatoid arthritis patients show augmented reactivity to a fraction of mycobacteria cross-reactive with cartilage
Lancet
(1986)
E. Kasp et al.
Improved method for the purification of S-antigen using selective hydrophobic adsorption chromatography
J. Immunol. Methods
(1987)
D.B. Young et al.
The 65 kD antigen ofMycobacteria
Immunol. Today
(1987)
M.E.J. Billingham et al.
A mycobacterial 65 kD heat shock protein induces antigen specific suppression of adjuvant arthritis but is not itself arthrogenic
J. Exp. Med.
(1990)
W. Born et al.
Recognition of a peptide antigen by heat shock-reactive γδ
Science
(1990)
H. Direskeneli et al.
Recognition of B-cell epitopes of the 65 kDa HSP in Behçet's disease
Scand. J. Immunol.
(1996)
D. Elias et al.
Induction and therapy of autoimmune diabetes in non-obese diabetic (NOD/U) mouse by 65-kDa heat shock protein
Proc. Natl. Acad. Sci. U.S.A.
(1990)
D. Elias et al.
Vaccination against autoimmune mouse diabetes using a T-cell epitope of the human 65-kDa heat shock protein
Proc. Natl. Acad. Sci. USA
(1991)

A. Elsaghier et al.

Disease association of antibodies to human and mycobacterial hsp70 and hsp60 stress proteins

Clin. Exp. Immunol.

(1992)

I Gery et al.

Retinal specific antigens and immunopathogenic process they provoke

Progress in retinal research

(1986)

Holoshitz, J., Maitiabu, A. and Cohen, I. R. (1984). Arthritis induced in rats by cloned T lymphocytes responsive to...

W.N. Jarjour et al.

Autoantibodies to human stress proteins

Arthritis Rheum.

(1991)

F. Kaneko et al.

Immunological studies on aphthous ulcer and erythema nodosum-like eruptions in Behçet's disease

Br. J. Dermatol.

(1985)

Cited by (23)

The possible role of HSPs on Behçet's disease: A bioinformatic approach
2012, Computers in Biology and Medicine
Citation Excerpt :
B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with the T-cell epitopes and both IgG and IgA antibodies have been identified. Among the four immunodominant T- and B-cell epitopes, peptide 336–351 of the 60 kDa HSP is significantly associated with BD [29–36]. Patients with Behçet's disease have been shown to have antibodies against HSP60s, but the results of the ELISA antibody titer assay shows that, although the various HSP60s share a common basic antigenicity, they differ in reactivity to the anti-HSP60 antibodies in the sera of the BD patients [20,37].
Current evidence lends increasing support to immunoinflammatory mechanisms as one of the prime pathogenic processes involved in the development and progression of Behçet's disease (BD). It has been observed that most human beings have cellular and humoral reactions against microbial heat shock proteins (HSPs). The observation that eukaryotic and prokaryotic HSPs have high sequence similarity promoted the hypothesis that HSPs might be potential candidates for molecular mimicry and could act as potentially dangerous autoantigens. In this study, using bioinformatics tools, we examined the hypothesis that HSPs (evolutionarily conserved proteins), which are present in pathogenic and commensal organisms and their hosts, provide the stimulus that initiates BD in susceptible individuals. In this regards, the nucleotide and amino acid sequences of the human HSP 60 kDa and bacterial HSP 60 kDa deposited in the NCBI and PDB databases were subjected to analysis using bioinformatics tools, including The CLC Sequence Viewer and MEGA softwares. These data showed that the sequence homology between bacterial and self HSPs (leading to cross-reactivity and molecular mimicry phenomenon) may be associated with the development of the disease; and suggesting that microbial HSPs, which cross-react with host tissues and elicit significant immune responses are possible pathogenetic agents involved in the development and progression of BD.
New insights into the pathogenesis of Behçet's disease
2012, Autoimmunity Reviews
Citation Excerpt :
It is widely assumed that cross-reactivity between the human and bacterial HSP may induce proliferation of autoreactive T cells specific to human HSP60 as a clue for autoimmune disorders. Subcutaneous, oral or nasal administration of HSP peptide to experimental mice has been shown to induce uveitis [129,130]. Antigenic homology between HSP60 and retinal antigen has been shown [131].
Behçet's disease (BD) is a recurrent systemic inflammatory disorder of unknown origin characterized by oral and genital mucous ulcer, uveitis, and skin lesions. Involvement of large vessels, central nervous system (CNS), gastrointestinal tract and thrombotic events are less frequent but can be life threatening. The aim of this review is to provide new insights into the pathogenesis of BD. Over the past year substantial advances have been done in the understanding of the genetic [1,2] and immunology [3] of BD. BD is at the crossroad between autoimmune and autoinflammatory syndromes. In common with autoimmune diseases BD shares class I MHC association. However, in contrast to autoimmune disorders, BD has clinical features that seem to be mostly autoinflammatory. The pathogenesis of BD is still unknown, but major determinants of the genetic and immune system abnormalities have been reported recently. Triggering infectious factors are supposed to participate in the outbreak of BD in genetically predisposed patients. Two recent large genome-wide association study (GWAS) conducted in Turkey and Japan reported association between single nucleotide polymorphism (SNP) of interleukin (IL)-10 and IL-23R/IL-12RB2 genes and BD. New insights into the perturbations of T cell homeostasis of BD recently emerged. We have recently demonstrated the promotion of Th17 responses and the suppression of regulatory T cells (Tregs) that were driven by interleukin (IL)-21 production and that correlates with BD activity. Inflammatory cells within BD inflammatory lesions included mostly neutrophils, Th1 and Th17 cells, and cytotoxic CD8+ and γδ T cells. Altogether, the recent progresses in the knowledge of BD pathogenesis pave the way for innovative therapy.
Behet's syndrome and micro-organisms
2011, Best Practice and Research: Clinical Rheumatology
Citation Excerpt :
Mycobacterial and four homologous human HSP T-cell-peptide determinants were administered to Lewis rats and it was observed that uveitis developed in these rats [104]. Moreover, the rats which developed uveitis following immunisation with HSP peptides showed significantly higher serum IgG and IgA levels to specific peptides when compared to the rats without uveitis [105]. γδ T cells are important in oral mucosal immunity.
Behçet’s syndrome (BS) is a multi-systemic vasculitis of unknown aetiology. More than one mechanism seems to be operative in the pathogenesis of Behçet’s syndrome, including genetic and environmental factors, causing different manifestations of the syndrome. There are several clues to the role of environmental factors and especially micro-organisms in the pathogenesis. These include clinical findings such as a decrease in the frequency of a positive pathergy reaction with surgical cleaning of the skin before the procedure, the acne–arthritis association carrying similar features to acne-associated reactive arthritis, a higher rate of tonsillectomy, cold sores, late birth order, higher number of siblings, history of travel to countries with a high incidence of BS and earlier age at first sexual intercourse. Moreover, basic research on both viruses and bacteria suggests that micro-organisms may be playing a role, possibly through heat shock proteins and T-cell hypersensitivity.
Pathophysiology of Behcet's disease
2006, Revue de Medecine Interne
La physiopathologie de la maladie de Behçet (MB) est complexe. De nouvelles données expérimentales permettent de mieux comprendre les mécanismes qui président à l'apparition des lésions organiques.
Ces nouvelles données mettent en exergue le rôle effecteur majeur joué par les polynucléaires neutrophiles et les lymphocytes cytotoxiques. Une susceptibilité génétique, des facteurs environnementaux (infections virales et/ou bactériennes), des anomalies de la réponse inflammatoire (protéines du choc thermique, dysrégulation de la production de NO) et un dysfonctionnement du système immunitaire interviennent également dans la pathogénie de la MB.
Cette meilleure compréhension de la physiopathologie de la MB devrait permettre à terme de développer de nouveaux traitements plus spécifiques.
Pathophysiology of Behçet's disease (BD) is complex. Recent experimental data shed new light on the mechanisms leading to organ lesions.
Neutrophils and cytotoxic lymphocytes are now recognized as key effector cells in BD. Genetic susceptibility, environmental factors (virus and/or bacterial infections), inflammatory response abnormalities (heat shock proteins, dysregulated NO production) and abnormal immune response play also a major role in BD pathogeny.
Better understanding of the BD pathophysiology will allow the development of new therapies more specific of BD.
Infection and Behçet's Syndrome
2004, Infection and Autoimmunity, 2nd edition
Regulation of ocular inflammation - What experimental and human studies have taught us
2001, Progress in Retinal and Eye Research
Study of models of ocular autoimmunity and of autoimmune uveitis in humans has lead to a shift in the perceived nature of immune privilege from one based on anatomical isolation of the eye to a more dynamic, active process of immune tolerance. Using a variety of available models, the basis for this dynamic process of immune regulation is reviewed. The protective role of humoral immunity, the co-stimulatory function of B cells in EAU as well as the influence of cytokines within the inflammatory cascade are outlined. Modulation of the immune response and in particular the possible role of macrophages is explored. Within the current paradyme, a major effector cell is the CD4+ lymphocyte. Its maturation into a Th1 or Th2 phenotype process appears dependent on a number of exogenous factors, which while genetically determined can be manipulated prior to disease onset. Activation of CD4+ cells is dependent on presentation of immunoreactive peptide fragments. These fragments are well characterized in the Lewis rat for S-Ag and interphotoreceptor retinoid binding protein (IRBP). Mapping of the immunoreactivity to S-Ag has been recently completed in uveitis patients. An overlap with certain determinants identified in experimental models has been observed, in at least 2 disease entities. However, the response profile is not fixed in time and is subject to determinant spread. Future studies will be aimed at identifying with more detail immunologic triggers of inflammation in patients, and at better defining the interplay between effector and regulatory pathways both in the eye and in the systemic circulation.

View all citing articles on Scopus

^☆: Osborne, N.Chader, J

^f1: Corresponding author: Eiichi Uchio, Department of Ophthalmology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236, Japan.

View full text

Regular articleHSP-derived Peptides Inducing Uveitis and IgG and IgA Antibodies☆

Abstract

J. Autoimmun.

Lancet

Lancet

J. Immunol. Methods

Immunol. Today

A mycobacterial 65 kD heat shock protein induces antigen specific suppression of adjuvant arthritis but is not itself arthrogenic

J. Exp. Med.

Recognition of a peptide antigen by heat shock-reactive γδ

Science

Recognition of B-cell epitopes of the 65 kDa HSP in Behçet's disease

Scand. J. Immunol.

Induction and therapy of autoimmune diabetes in non-obese diabetic (NOD/U) mouse by 65-kDa heat shock protein

Proc. Natl. Acad. Sci. U.S.A.

Vaccination against autoimmune mouse diabetes using a T-cell epitope of the human 65-kDa heat shock protein

Proc. Natl. Acad. Sci. USA