Differential recognition of heat‐shock protein dnaJ–derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis

Massa, Margherita; Passalia, Maristella; Magni‐Manzoni, Silvia; Campanelli, Rita; Ciardelli, Laura; Yung, Gisella Puga; Kamphuis, Sylvia; Pistorio, Angela; Meli, Valentina; Sette, Alessandro; Prakken, Berent J.; Martini, Alberto; Albani, Salvatore

doi:10.1002/art.22567

Cited by 68 publications

(48 citation statements)

References 26 publications

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“…The results from the present study show that the phenomenon of disease-and inflammation-specific recognition of HSP-derived epitopic peptides, which we first described in patients with RA using DnaJ P1, is, in reality, more complex and involves peptides that are functionally similar to DnaJ P1 (proinflammatory) as well as others that are quite different (50). Thus, our study contributes to a better understanding of the mechanism that can be manipulated for therapeutic purposes.…”

Section: Discussionsupporting

confidence: 56%

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Jong¹,

Lafeber²,

Jager³

et al. 2009

Arthritis & Rheumatism

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Objective. Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan-DR-binding Hsp60-derived epitopes as possible modulators of autoimmune inflammation in RA.Methods. Lymphocyte proliferation assays (using 3 H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls. Results. A disease (RA)-specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4؉ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5-10-fold higher IL-10:TNF␣ ratio, compared with that of the microbial peptides.Conclusion. These results suggest a diseasespecific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan-DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy.

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Section: Discussionsupporting

confidence: 56%

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Jong¹,

Lafeber²,

Jager³

et al. 2009

Arthritis & Rheumatism

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“…Previously, Hsp60-or Hsp60 peptide-specific T-cell responses have been associated with disease remission and a favorable disease outcome in patients with juvenile idiopathic arthritis or rheumatoid arthritis (de GraeffMeeder et al 1995;Kamphuis et al 2005). Recently, the immunomodulatory effects of T-cell epitopes from DNAJ proteins of both human and Escherichia coli origin have been studied in juvenile idiopathic patients (Massa et al 2007). In that study, T-cell responses to bacterial peptides were shown to be pro-inflammatory.…”

Section: Discussionmentioning

confidence: 99%

Hsp70 expression and induction as a readout for detection of immune modulatory components in food

Wieten

Zee

Goedemans

et al. 2010

Cell Stress and Chaperones

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Stress proteins such as heat shock proteins (Hsps) are up-regulated in cells in response to various forms of stress, like thermal and oxidative stress and inflammation. Hsps prevent cellular damage and increase immunoregulation by the activation of anti-inflammatory Tcells. Decreased capacity for stress-induced Hsp expression is associated with immune disorders. Thus, therapeutic boosting Hsp expression might restore or enhance cellular stress resistance and immunoregulation. Especially food-or herb-derived phytonutrients may be attractive compounds to restore optimal Hsp expression in response to stress. In the present study, we explored three readout systems to monitor Hsp70 expression in a manner relevant for the immune system and evaluated novel Hsp co-inducers. First, intracellular staining and analysis by flow cytometry was used to detect stress and/or dietary compound induced Hsp70 expression in multiple rodent cell types efficiently. This system was used to screen a panel of food-derived extracts with potent anti-oxidant capacity. This strategy yielded the identity of several new enhancers of stressinduced Hsp70 expression, among them carvacrol, found in thyme and oregano. Second, CD4+ T-cell hybridomas were generated that specifically recognized an immunodominant Hsp70 peptide. These hybridomas were used to show that carvacrol enhanced Hsp70 levels increased T-cell activation. Third, we generated a DNAJB1-luc-O23 reporter cell line to show that carvacrol increased the transcriptional activation of a heat shock promoter in the presence of arsenite. These assay systems are generally applicable to identify compounds that affect the Hsp level in cells of the immune system.

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“…6, there were many human housekeeping proteins such as Hsp40 homologs, ␣ adrenergic receptors, adenylate cyclase, protein ariadne-2, collagen ␣-3 chain receptor, acetyl-CoA carboxylases, HLA class IIDQ4, DQ-DRW9, tyrosine-protein kinase JAK2, and many other proteins, and the number of such molecules was at least more than 317. In case of Hsp40 homologs among these 317 molecules, recent studies suggested that these protein-derived peptides efficiently activated CD4 ϩ CD25 ϩ regulatory T cells (37)(38)(39). Therefore, one explanation for these data is that successful induction of immunosuppressive regulatory T cells might be attributable to Hsp40-derived peptides that could bind to Hsp70 with high affinity.…”

Section: Discussionmentioning

confidence: 99%

Biological Heterogeneity of the Peptide-binding Motif of the 70-kDa Heat Shock Protein by Surface Plasmon Resonance Analysis

Maeda

Sahara

Mori

et al. 2007

Journal of Biological Chemistry

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70-kDa heat shock protein family is a molecular chaperone that binds to a variety of client proteins and peptides in the cytoplasm. Several studies have revealed binding motifs between 70-kDa heat shock protein family and cytoplasmic proteins by conventional techniques such as phage display library screening. However, little is known about the binding motif based on kinetic parameters determined by surface plasmon resonance analysis. We investigated the major inducible cytosolic 70-kDa heat shock protein (Hsp70)-binding motif with the human leukocyte antigen B*2702-derived peptide Bw4 (RENL-RIALRY) by using a Biacore system based on surface plasmon resonance analysis. The K D value of Hsp70-Bw4 interaction was 1.8 ؋ 10 ؊6 M. Analyses with truncated Bw4 variant peptides showed the binding motif of Hsp70 to be seven residues, LRI-ALRY. To further study the characteristics of this motif, 126 peptides derived from Bw4, each with single amino acid substitution, were synthesized and analyzed for Hsp70 binding affinity. Interestingly, the Hsp70 binding affinity was abrogated when the residues were substituted for by acidic (Asp and Glu) ones at any position. In contrast, if the substitute residue was aromatic (Trp, Tyr, and Phe) or an Arg residue at any position, Hsp70 binding affinity was maintained. Thus, this study presents a new binding motif between Hsp70 and peptides derived from the natural protein human leukocyte antigen B*2702 and may also elucidate some characteristics of the Hsp70 binding characteristic, enhancing our understanding of Hsp70-binding determinants that may influence diverse cellular and physiological processes.Molecular chaperones of the 70-kDa heat shock protein family perform numerous functions in the quality control of cells that mediate protein folding, translocation, assembly/disassembly, and repair of unfolded proteins damaged by environmental stress (1). Chaperone activity of this protein family is necessary to recognize binding sites of a target native protein, referred to as the binding motif. It has been reported that the endoplasmic reticulum 70-kDa heat shock protein Bip (Grp78) binds to a peptide containing at least seven residues with maximal affinity in the presence of ATPase activity (2, 3). It was also suggested that peptide-binding sites of Bip show a preference for sequences rich in aliphatic residues. Subsequently, from a study employing a phage display library, the binding motif for Bip was revealed to be a heptapeptide with high contents of aromatic and hydrophobic residues (4).On the other hand, the bacterial cytoplasmic 70-kDa heat shock protein homolog DnaK has a substrate-binding region in the C terminus, and repeated binding/release to substrates is dependent on the ATPase cycle at an ATPase domain of the N terminus (5, 6). Zhu et al. (7) reported a crystal structure of the C-terminal substrate-binding domain of DnaK, which was located in a hydrophobic substrate-binding cleft with a central pocket placed between a ␤ sheet and two ␣ helices. The consensus motif recogni...

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Differential recognition of heat‐shock protein dnaJ–derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis

Cited by 68 publications

References 26 publications

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Hsp70 expression and induction as a readout for detection of immune modulatory components in food

Biological Heterogeneity of the Peptide-binding Motif of the 70-kDa Heat Shock Protein by Surface Plasmon Resonance Analysis

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