Presence of Human 65 kD Heat Shock Protein (hsp) in Inflamed Joints and Subcutaneous Nodules of RA Patients

Karlsson‐Parra, Alex; Söderström, Kalle; Ferm, Mats; Iványi, J; Kiessling, Rolf; Klareskog, Lars

doi:10.1111/j.1365-3083.1990.tb02770.x

Cited by 131 publications

(55 citation statements)

References 19 publications

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“…We further suggest that the APC in the arthritic joints might also have increased expression of self hsp65, and that processing of self hsp65 in vivo could reveal T cell epitopes (e.g., RCTD equivalents) that might be relevant to the regulation of autoimmune arthritis. In fact, an increased level of expression of mRNA of Rhsp60 in ankle joint synovial membrane of arthritic Lewis rats (50), and the expression of self hsp60 in the inflamed pannus of arthritic joints of mice (51) and that of patients with RA and juvenile chronic arthritis (JCA) (52,53) has been observed by other investigators. Moreover, an interesting correlation between the proliferative T cell response to self hsp60 (Hhsp60) and clinical outcome in patients with juvenile RA has been observed (54).…”

Section: Discussionmentioning

confidence: 98%

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

Durai

Gupta

Moudgil

2004

The Journal of Immunology

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Immunization of Lewis rats with heat-killed Mycobacterium tuberculosis H37Ra leads to development of polyarthritis (adjuvant-induced arthritis; AA) that shares several features with human rheumatoid arthritis (RA). Immune response to the 65-kDa mycobacterial heat-shock protein (Bhsp65) is believed to be involved in induction of AA as well as in experimental modulation of this disease. However, the understanding of several critical aspects of the pathogenesis of AA in the Lewis rat has severely been hampered by the lack of information both regarding the level as well as epitope specificity of tolerance to the mammalian self (rat) homologue of Bhsp65, 65-kDa rat heat-shock protein (Rhsp65), and about the functional attributes of the T cell repertoire specific for this self protein. In this study, we established that tolerance to Rhsp65 in the Lewis rat is incomplete, and that the residual T cells primed upon challenge with this self hsp65 are disease regulating in nature. We also have defined the T cell epitopes in the C-terminal region within Rhsp65 that contribute predominantly to the immune reactivity as well as the AA-protective effect of this self protein. Furthermore, the T cells primed by peptides comprising these C-terminal determinants can be efficiently restimulated by the naturally generated epitopes from endogenous Rhsp65, suggesting that self hsp65 might also be involved in natural remission from acute AA. These novel first experimental insights into the self hsp65-directed regulatory T cell repertoire in AA would help develop better immunotherapeutic approaches for autoimmune arthritis.

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Section: Discussionmentioning

confidence: 98%

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

Durai

Gupta

Moudgil

2004

The Journal of Immunology

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“…This strong sequence conservation is not restricted to hsp; however, hsp are unique in their up-regulated expression in response to various stress stimuli (13), and elevated expression of hsp60 has been found in inflamed synovia of arthritis patients and arthritic rats (14,15). Thus, bacterial hsp-primed T cells, crossreactive with self hsp60, might play an important role in the regulation of pathogenic autoimmune responses.…”

mentioning

confidence: 99%

“…Total RNA was isolated from cell pellets by extraction with RNAzol (Life Technologies). The isolated RNA and 0.5 g oligo(dT) [12][13][14][15][16][17][18] were heated at 55°C for 10 min and cooled to room temperature. First-strand synthesis was performed by incubating 1 g of RNA in a reaction mixture (total volume, 20 l) containing 5 mM Tris-HCl, pH 8.3, at 42°C, 50 mM KCl, 10 mM MgCl 2 , 2 mM DTT, 25 U reverse transcriptase, and 1 mM each of dATP, dCTP, dGTP, and dTTP.…”

Section: Cytokine Pcr Analysismentioning

confidence: 99%

Highly Autoproliferative T Cells Specific for 60-kDa Heat Shock Protein Produce IL-4/IL-10 and IFN-γ and Are Protective in Adjuvant Arthritis

Paul

Kooten

Eden

et al. 2000

The Journal of Immunology

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Previously we have shown that T cell responses to the mycobacterial 60-kDa heat shock protein (hsp60) peptide M256–270 mediated protection against adjuvant arthritis in Lewis rats. We have demonstrated now that M256–270-primed T cells become highly reactive to naive syngeneic APC upon repetitive restimulation in vitro with peptide M256–265, comprising the conserved core of peptide M256–270. These autoproliferative responses in the absence of added Ag were MHC class II restricted and resulted in the production of IL-4/IL-10 and IFN-γ. Enhanced autoproliferation and expression of the cell surface molecule B7.2 by these T cells were observed in response to syngeneic heat-shocked APC, which indicated that the autoproliferation and expression of B7.2 resulted from the recognition of endogenously expressed and processed hsp. Despite their strong autoreactivity, upon transfer such T cells were found to induce a significant disease reduction in adjuvant arthritis. In contrast, T cells both primed and restimulated with peptide M256–270 became unresponsive toward syngeneic APC as well as toward the conserved core peptide M256–265, and they were devoid of protective capacity. This study demonstrates that the loss of self-tolerance toward hsp60 does not necessarily lead to autoimmune disease, but that hsp60-specific self-reactive and autoproliferative T cells may mediate T cell regulation in arthritis.

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“…Expressed on macrophages and monocytes, TLR4 is critical for the recognition of lipopolysaccharide (LPS) from Gram-negative bacteria. Recent studies have demonstrated that endogenous TLR4 ligands are highly expressed at sites of chronic inflammation, characterized by the accumulation of macrophages, such as the joints of patients with rheumatoid arthritis (2)(3)(4)(5)(6)(7)(8). Resistance to apoptosis may contribute to the persistence of chronic inflammation (9).…”

mentioning

confidence: 99%

NF-κB Protects Macrophages from Lipopolysaccharide-induced Cell Death

Ma¹,

Temkin²,

Liu

et al. 2005

Journal of Biological Chemistry

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Macrophages play a pivotal role in the pathogenesis of a variety of diseases. These studies were performed to characterize the mechanisms by which Toll-like receptor 4 (TLR4)-mediated NF-B activation promotes resistance to cell death in macrophages. When NF-B activation was inhibited by a super-repressor, IB␣, the TLR4 ligand lipopolysaccharide induced the activation of caspase 8, the loss of mitochondrial transmembrane potential (⌬⌿ m ), and apoptotic cell death in macrophages. The inhibition of caspase 8 activation suppressed DNA fragmentation but failed to protect macrophages against the loss of ⌬⌿ m and resulted in necrotic cell death. In contrast, the reduction of receptor-interacting protein 1 suppressed the loss of ⌬⌿ m and inhibited apoptotic cell death. Further, when caspase 8 activation was suppressed, the knock down of receptor-interacting protein inhibited the loss of ⌬⌿ m and necrotic cell death. These observations demonstrate that following TLR4 ligation by lipopolysaccharide, NF-B is a critical determinant of macrophage life or death, whereas caspase 8 determines the pathway employed.Macrophages play a pivotal role in infection, atherosclerosis, and chronic inflammation such as observed in rheumatoid arthritis. The ligation of Toll-like receptors (TLRs) 3 activates intracellular signal transduction pathways, including NF-B (1). Expressed on macrophages and monocytes, TLR4 is critical for the recognition of lipopolysaccharide (LPS) from Gram-negative bacteria. Recent studies have demonstrated that endogenous TLR4 ligands are highly expressed at sites of chronic inflammation, characterized by the accumulation of macrophages, such as the joints of patients with rheumatoid arthritis (2-8). Resistance to apoptosis may contribute to the persistence of chronic inflammation (9). Therefore, microbial and endogenous TLR4 ligands may promote resistance to apoptosis through the activation of NF-B.Apoptosis may be initiated by two different pathways, the death receptor-mediated pathway and the mitochondria-dependent pathway.Death receptors, such as Fas and TNFR1, possess intracellular death domains that may initiate apoptosis through the recruitment of Fasassociated death domain protein (FADD) and the activation of caspase 8. Activated caspase 8 may directly activate caspase 3, which results in apoptotic cell death (reviewed in Ref. 9). In the mitochondria-dependent pathway, apoptotic signals induce the loss of mitochondrial integrity and the release of pro-apoptotic molecules, including cytochrome c. Once in the cytosol, cytochrome c binds to apoptotic protease activating factor-1, resulting in activation of caspases 9 and 3, thus triggering apoptosis (10). These two pathways may be linked by the pro-apoptotic Bcl-2 family member Bid, which may be cleaved by caspase 8, resulting in truncated Bid (tBid), which may trigger the mitochondrial pathway.Although TLR4 ligation induces NF-B activation, which may promote cell survival through the induction of anti-apoptotic genes, recent evidence has demonstrated that ...

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Presence of Human 65 kD Heat Shock Protein (hsp) in Inflamed Joints and Subcutaneous Nodules of RA Patients

Cited by 131 publications

References 19 publications

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

Highly Autoproliferative T Cells Specific for 60-kDa Heat Shock Protein Produce IL-4/IL-10 and IFN-γ and Are Protective in Adjuvant Arthritis

NF-κB Protects Macrophages from Lipopolysaccharide-induced Cell Death

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