Immunoglobulins from rats that are resistant to adjuvant arthritis suppress the disease in arthritis‐susceptible rats

Ulmansky, Rina; Naparstek, Yaakov

doi:10.1002/eji.1830250415

Cited by 18 publications

(21 citation statements)

References 30 publications

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“…infusion of these Igs derived from resistant strains (25). In this study we have analyzed the fine epitope specificity of the anti-HSP Abs of arthritis-susceptible and -resistant rats.…”

Section: A Djuvant Arthritis (Aa)mentioning

confidence: 99%

Resistance to Adjuvant Arthritis Is Due to Protective Antibodies Against Heat Shock Protein Surface Epitopes and the Induction of IL-10 Secretion

Ulmansky

Cohen

Szafer

et al. 2002

The Journal of Immunology

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115

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Adjuvant arthritis (AA) is an experimental model of autoimmune arthritis that can be induced in susceptible strains of rats such as inbred Lewis upon immunization with CFA. AA cannot be induced in resistant strains like Brown-Norway or in Lewis rats after recovery from arthritis. We have previously shown that resistance to AA is due to the presence of natural as well as acquired anti-heat shock protein (HSP) Abs. In this work we have studied the fine specificity of the protective anti-HSP Abs by analysis of their interaction with a panel of overlapping peptides covering the whole HSP molecule. We found that arthritis-susceptible rats lack Abs to a small number of defined epitopes of the mycobacterial HSP65. These Abs are found naturally in resistant strains and are acquired by Lewis rats after recovery from the disease. Active vaccination of Lewis rats with the protective epitopes as well as passive vaccination with these Abs induced suppression of arthritis. Incubation of murine and human mononuclear cells with the protective Abs induced secretion of IL-10. Analysis of the primary and tertiary structure of the whole Mycobacterium tuberculosis HSP65 molecule indicated that the protective epitopes are B cell epitopes with nonconserved amino acid sequences found on the outer surface of the molecule. We conclude that HSP, the Ag that contains the pathogenic T cell epitopes in AA, also contains protective B cell epitopes exposed on its surface, and that natural and acquired resistance to AA is associated with the ability to respond to these epitopes.

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“…infusion of these Igs derived from resistant strains (25). In this study we have analyzed the fine epitope specificity of the anti-HSP Abs of arthritis-susceptible and -resistant rats.…”

Section: A Djuvant Arthritis (Aa)mentioning

confidence: 99%

Resistance to Adjuvant Arthritis Is Due to Protective Antibodies Against Heat Shock Protein Surface Epitopes and the Induction of IL-10 Secretion

Ulmansky

Cohen

Szafer

et al. 2002

The Journal of Immunology

Self Cite

115

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“…However, it is likely that T cells specific for other regulatory epitopes of Bhsp65 (10) and mammalian self hsp65 (48, 51-54), including those against not yet identified epitopes within these proteins, that might be primed or restimulated following immunization with Mtb (5, 48), might also contribute to natural regression of acute AA. Besides T cells against hsp65, Abs against Bhsp65 may also contribute to protection against AA (5,55). Moreover, other mycobacterial and self hsp (e.g., hsp90, hsp70, hsp10) besides hsp65 may also contribute to regulation of acute AA (56 -59).…”

Section: Discussionmentioning

confidence: 99%

The Regulatory C-Terminal Determinants within Mycobacterial Heat Shock Protein 65 Are Cryptic and Cross-Reactive with the Dominant Self Homologs: Implications for the Pathogenesis of Autoimmune Arthritis

Durai

Kim

Moudgil

2004

The Journal of Immunology

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The 65-kDa mycobacterial heat shock protein (Bhsp65) has been invoked in the pathogenesis of both adjuvant arthritis (AA) in the Lewis rat (RT.1l) and human rheumatoid arthritis. Arthritic Lewis rats in the late phase of AA show diversification of the T cell response to Bhsp65 C-terminal determinants (BCTD), and pretreatment of naive Lewis rats with a mixture of peptides representing these neoepitopes affords protection against AA. However, the fine specificity and physiologic significance of the BCTD-directed T cell repertoire, and the role of homologous self (rat) hsp65 (Rhsp65), if any, in spreading of the T cell response to Bhsp65 have not yet been examined. We observed that T cells primed by peptides comprising BCTD can adoptively transfer protection against AA to the recipient Lewis rats. However, these T cells can be activated by preprocessed (peptide) form of BCTD, but not native Bhsp65, showing that BCTD are cryptic epitopes. The BCTD-reactive T cells can be activated by the naturally generated (dominant) C-terminal epitopes of both exogenous and endogenous Rhsp65 and vice versa. Furthermore, certain individual peptides constituting BCTD and their self homologs can also induce protection against AA. These results support a model for the diversification of T cell response to Bhsp65 during the course of AA involving up-regulation of the display of cryptic BCTD coupled with spontaneous induction of T cell response to the cross-reactive dominant C-terminal epitopes of Rhsp65. The identification of disease-regulating cryptic determinants in Ags implicated in arthritis provides a novel approach for immunotherapy of rheumatoid arthritis.

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“…Increasing evidence suggests that antibodies to certain disease-related antigens might be regulatory in nature (7,8,130,131). We and others have shown that arthritic Lewis (LEW) rats develop antibodies to Bhsp65 during the peak and recovery phase of AA (7,8).…”

Section: B Cell Tolerance and The Protective Effect Of Antibodies In mentioning

confidence: 92%

Antigen-Specific Tolerogenic and Immunomodulatory Strategies for the Treatment of Autoimmune Arthritis

Satpute

Durai

Moudgil

2008

Seminars in Arthritis and Rheumatism

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Objectives-To review various antigen-specific tolerogenic and immunomodulatory approaches for arthritis in animal models and patients in regard to their efficacy, mechanisms of action and limitations.Methods-We reviewed the published literature in Medline (PubMed) on the induction of antigenspecific tolerance and its effect on autoimmune arthritis, as well as the recent work on B cell-mediated tolerance from our laboratory. The prominent key words used in different combinations included arthritis, autoimmunity, immunotherapy, innate immunity, tolerance, treatment, and rheumatoid arthritis (RA). Although this search spanned the years 1975 to 2007, the majority of the short-listed articles belonged to the period 1990 to 2007. The relevant primary as well as cross-referenced articles were then collected from links within PubMed and reviewed.Results-Antigen-specific tolerance has been successful in the prevention and/or treatment of arthritis in animal models. The administration of soluble native antigen or an altered peptide ligand intravenously, orally, or nasally, and the delivery of the DNA encoding a particular antigen by gene therapy have been the mainstay of immunomodulation. Recently, the methods for in vitro-expansion of CD4+CD25+ regulatory T cells have been optimized. Furthermore, interleukin-17 has emerged as a promising new therapeutic target in arthritis. However, in RA patients, non-antigen-specific therapeutic approaches have been much more successful than antigen-specific tolerogenic regimens.Conclusion-An antigen-specific treatment against autoimmune arthritis is still elusive. However, insights into newly emerging mechanisms of disease pathogenesis provide hope for the development of effective and safe immunotherapeutic strategies in the near future.

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Immunoglobulins from rats that are resistant to adjuvant arthritis suppress the disease in arthritis‐susceptible rats

Cited by 18 publications

References 30 publications

Resistance to Adjuvant Arthritis Is Due to Protective Antibodies Against Heat Shock Protein Surface Epitopes and the Induction of IL-10 Secretion

Resistance to Adjuvant Arthritis Is Due to Protective Antibodies Against Heat Shock Protein Surface Epitopes and the Induction of IL-10 Secretion

The Regulatory C-Terminal Determinants within Mycobacterial Heat Shock Protein 65 Are Cryptic and Cross-Reactive with the Dominant Self Homologs: Implications for the Pathogenesis of Autoimmune Arthritis

Antigen-Specific Tolerogenic and Immunomodulatory Strategies for the Treatment of Autoimmune Arthritis

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