Do heat shock proteins control the balance of T-cell regulation in inlammatory diseases?

Eden, Willem van; Zee, Ruurd van der; Paul, Alberta; Prakken, Berent J.; Wendling, Uwe; Anderton, Stephen M.; Wauben, Marca H. M.

doi:10.1016/s0167-5699(98)01283-3

Cited by 153 publications

(88 citation statements)

References 34 publications

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“…23 In several experimental models, T cells responding to Hsps play an important role in the regulation of peripheral tolerance and suppressing pathogenic immune response. 24 HspBP1 (Hsp70 binding protein 1) has an inhibitory effect in Hsp70-assisted refolding reactions in the cytosol, 25,26 suggesting that HspBP1 plays an important role in regulating immune responses. HspBP1 duplication may alter immune responses in the s-JIA patient.…”

Section: Discussionmentioning

confidence: 99%

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

et al. 2011

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Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed singlenucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA.

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Section: Discussionmentioning

confidence: 99%

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

et al. 2011

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“…Besides the above described immune-activating effects, Hsp70 exerts immune regulatory and antiinflammatory functions as well [63,76,81]. It was shown that low-affinity T cells are reactive against autologous heat shock proteins [57], which might lead to the generation of Th2 (IL-4-and IL-10-producing), Th3 (transforming growth factor-β-producing), or Tr1 (IL-10-producing) regulatory T cell responses (and release of these regulatory cytokines) [63,76,81].…”

Section: Immuno−modulatory Effects Of Hsp70mentioning

confidence: 99%

“…Consequently, the potential effects of salivary Hsp70 on lymphocytes such as NK cells [51,53], cytotoxic T cells [7,51,75,84], or regulatory T cells [63,76,81] may play a less important role in the mucosal and periodontal defense mechanisms.…”

Section: The Possible Defense Functions Of Salivary Hsp70 In Mucosal mentioning

confidence: 99%

Potential immunological functions of salivary Hsp70 in mucosal and periodontal defense mechanisms

Fábían

Fejérdy

Nguyen

et al. 2007

Arch. Immunol. Ther. Exp.

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Molecular chaperones were considered to be intracellular, but there is increasing evidence demonstrating their cytoprotective and immune modulator properties outside the cell. The major extracellular chaperone (Hsp70) was also found in saliva, indicating a possible effect of Hsp70 on mucosal surfaces. Here we summarize the immune-modulatory role of the 70-kDa stress protein family, with special attention on the potential impact of salivary Hsp70 on oral defense mechanisms. There are three major facets of Hsp70-induced immune activation: 1) the appearance of Hsp70 on the surface of certain tumor cells or virally infected cells, leading to their phagocytosis and subsequent lysis; 2) the role of extracellular uncomplexed Hsp70 as a danger signal, leading to the secretion of proinflammatory cytokines from antigen-presenting cells and T lymphocytes and of nitric oxide from macrophages as well as to complement activation; 3) receptor-mediated uptake of peptide-loaded Hsp70 to antigen-presenting cells and cross-presentation of the Hsp70-peptide complex as an antigen to cytotoxic T cells and natural killer lymphocytes. The immune-activating effect of salivary Hsp70 may also be highly important in oral defense, especially in areas where molecular and cellular participants of the immune response appear on the surface of the oral cavity (i.e. several lesions of the mucosa and the periodontal tissues).

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“…In RA, T cells stimulated with human Hsp60 display a marked suppressive phenotype, compared with T cells stimulated with homologous mycobacterial Hsp65 (26). Thus, Hsp60 self-reactive T cells may play a role in modulating chronic arthritis (adjuvant-induced arthritis, RA, and JIA), underscoring their potential as candidate antigens to modulate the immune response in chronic arthritis (24,30).…”

mentioning

confidence: 99%

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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Do heat shock proteins control the balance of T-cell regulation in inlammatory diseases?

Cited by 153 publications

References 34 publications

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

Potential immunological functions of salivary Hsp70 in mucosal and periodontal defense mechanisms

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

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