Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Martin, Carla A.; Carsons, Steven E.; Kowalewski, Robert; Bernstein, David; Valentino, Michael; Santiago‐Schwarz, Frances

doi:10.4049/jimmunol.171.11.5736

Cited by 79 publications

(62 citation statements)

References 32 publications

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“…Both CRT and HSPs are ER chaperones capable of assisting peptide loading and correct folding of MHC molecules (2,6,35,36). HSPs on the membrane surface of various types of cells (e.g., activated lymphoid cells and tumor cells) exert strong immunobiological functions (37)(38)(39)(40)(41)(42). Similar to CRT, HSP60, HSP70, HSP90, and gp96 are able to directly activate immune cells in vitro (35,36).…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Recombinant Calreticulin Fragment 39–272: Implications for Immunobiological Activities of Calreticulin in Health and Disease

Cheng

Qiu

et al. 2010

The Journal of Immunology

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Although calreticulin (CRT) is a major Ca2+-binding luminal resident protein, it can also appear on the surface of various types of cells and it functions as an immunopotentiating molecule. However, molecular mechanisms underlying the potent immunobiological activity of cell surface CRT are still unclear. In the present study, a recombinant fragment (rCRT/39–272) covering the lectin-like N domain and partial P domain of murine CRT has been expressed in Escherichia coli. The affinity-purified rCRT/39–272 assembles into homodimers and oligomers in solution and exhibits high binding affinity to various glycans, including carrageenan, alginic acids, and hyaluronic acids. Functionally, rCRT/39–272 is capable of driving the activation and maturation of B cells and cytokine production by macrophages in a TLR-4–dependent manner in vitro. It specifically binds recombinant mouse CD14, but not BAFFR and CD40. It is also able to trigger Ig class switching by B cells in the absence of T cell help both in vitro and in vivo. Furthermore, this fragment of CRT exhibits strong adjuvanticity when conjugated to polysaccharides or expressed as part of a fusion protein. Soluble CRT can be detected in the sera of patients with rheumatoid arthritis or systemic lupus erythematosus, but not in healthy subjects. We argue that CRT, either on the membrane surface of cells or in soluble form, is a potent stimulatory molecule to B cells and macrophages via the TLR-4/CD14 pathway and plays important roles in the pathogenisis of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Functional Analysis of Recombinant Calreticulin Fragment 39–272: Implications for Immunobiological Activities of Calreticulin in Health and Disease

Cheng

Qiu

et al. 2010

The Journal of Immunology

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“…For example, several studies suggest that cellular stress results in the increased surface expression and release of stress proteins (164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177). The release of stress proteins into the extracellular environment was first reported in the late 1980s, when Hsp70 release was demonstrated in cultured rat embryo cells following exposure to increased temperature (178).…”

Section: Stress Proteins and Innate Immunitymentioning

confidence: 99%

Heat shock response and acute lung injury☆

Wheeler

Wong

2007

Free Radical Biology and Medicine

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All cells respond to stress through the activation of primitive, evolutionarily conserved genetic programs that maintain homeostasis and assure cell survival. Stress adaptation, which is known in the literature by a myriad of terms, including tolerance, desensitization, conditioning, and reprogramming, is a common paradigm found throughout nature, in which a primary exposure of a cell or organism to a stressful stimulus (e.g., heat) results in an adaptive response by which a second exposure to the same stimulus produces a minimal response. More interesting is the phenomenon of cross-tolerance, by which a primary exposure to a stressful stimulus results in an adaptive response whereby the cell or organism is resistant to a subsequent stress that is different from the initial stress (i.e. exposure to heat stress leading to resistance to oxidant stress). The heat shock response is one of the more commonly described examples of stress adaptation and is characterized by the rapid expression of a unique group of proteins collectively known as heat shock proteins (also commonly referred to as stress proteins). The expression of heat shock proteins is well described in both whole lungs and in specific lung cells from a variety of species and in response to a variety of stressors. More importantly, in vitro data, as well as data from various animal models of acute lung injury, demonstrate that heat shock proteins, especially Hsp27, Hsp32, Hsp60, and Hsp70 have an important cytoprotective role during lung inflammation and injury.

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“…Evidence of a role of TLRs in RA pathogenesis originates from the findings that inducible Hsp70, generally accepted as a TLR-4 ligand, was increased in RA synovial fluid and on DCs isolated from RA synovial fluid (32). Expression of TLR-2 and TLR-4 is increased and regulated by proinflammatory cytokines that are present in the synovial compartment (33,34) and by the identification of the TLR-4 (Asp 299 Gly) functional variant as a marker for RA disease susceptibility (35).…”

mentioning

confidence: 99%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

296

219

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Objective. To evaluate the expression of Toll-like receptors (TLRs) 3 and 7 in synovium and to study potential differences in the maturation and cytokine production mediated by TLR-2, TLR-3, TLR-4, and TLR-7/8 by dendritic cells (DCs) from rheumatoid arthritis (RA) patients and DCs from healthy controls.Methods. Synovial expression of TLR-3 and TLR-7 in RA was studied using immunohistochemistry. Monocyte-derived DCs from RA patients and healthy controls were cultured for 6 days and subsequently stimulated for 48 hours via TLR-mediated pathways (lipoteichoic acid, Pam 3 Cys, and fibroblast-stimulating lipopeptide 1 for TLR-2, poly[I-C] for TLR-3, lipopolysaccharide and extra domain A for TLR-4, and R848 for TLR-7/8). Phenotypic DC maturation was measured using flow cytometry. The secretion of tumor necrosis factor ␣ (TNF␣), interleukin-6 (IL-6), IL-10, and IL-12 was measured using the Bio-Plex system. Cell lines expressing TLR-2 and TLR-4 were used for the detection of TLR-2 and TLR-4 ligands in serum and synovial fluid from RA patients.Results. TLR-3 and TLR-7 were highly expressed in RA synovium. All TLR ligands elicited phenotypic DC maturation equally between DCs from RA patients and those from healthy controls. TLR-2-and TLR-4-mediated stimulation of DCs from RA patients resulted in markedly higher production of inflammatory mediators (TNF␣ and IL-6) compared with DCs from healthy controls. In contrast, upon stimulation of TLR-3 and TLR-7/8, the level of cytokine production was equal between DCs from RA patients and those from healthy controls. Remarkably, both TLR-3 and TLR-7/8 stimulation resulted in a skewed balance toward IL-12. Intriguingly, the combined stimulation of TLR-4 and TLR-3-7/8 resulted in a marked synergy with respect to the production of inflammatory mediators. As a proof of concept, TLR-4 ligands were increased in the serum and synovial fluid of RA patients.Conclusion. TLRs are involved in the regulation of DC activation and cytokine production. We hypothesize that various TLR ligands in the joint trigger multiple TLRs simultaneously, favoring the breakthrough of tolerance in RA.

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Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Cited by 79 publications

References 32 publications

Functional Analysis of Recombinant Calreticulin Fragment 39–272: Implications for Immunobiological Activities of Calreticulin in Health and Disease

Functional Analysis of Recombinant Calreticulin Fragment 39–272: Implications for Immunobiological Activities of Calreticulin in Health and Disease

Heat shock response and acute lung injury☆

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

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