Heat shock proteins-multiple roles in inflammation, vaccination and homeostasis
This is a Euroscicon Small Conference, an outline of the day can be found at
This is an exciting meeting focusing on the interface between innate and adaptive immunity and the potential of Heat shock proteins in inflammation resolution. The role of HSPs in health and disease and their potential as immune modulators will be examined and discussed
This event has CPD accreditation and will have a discussion panel session.
On registration you will be able to submit your questions to the panel that will be asked by the chair on the day of the event
Meeting Chair: Dr Lesley Bergmeier, CBiol, MIBiol, PhD, FHEA
Institute of Dentistry, Barts and The London School of Medicine and Dentistry, UK
9:00 – 9:45 Registration
9:45 – 10:00 Introduction by the Chair: Dr Lesley Bergmeier, CBiol, MIBiol, PhD, FHEA.
Institute of Dentistry, Barts and The London School of Medicine and Dentistry, UK
10:00 – 10:30 Specialised functions of the Hsc70 chaperone system
Dr Paul Chapple, William Harvey Research Institute, London, UK
In humans there are 13 different Hsp70 proteins and approximately 50 J proteins. This diversity of cochaperone J proteins allows the recruitment of Hsp70 family members to multiple cellular locales and clients, mediating functions beyond de novo protein folding and quality control. Specialized function of the Hsc70 chaperone system will be illustrated using examples from our recent work that link to human disease. This will include evidence for Hsc70 functioning to promote traffic to the cell surface of melanocortin-4 receptor. Data linking Hsc70 to the regulation of mitochondrial dynamics through the J protein sacsin will also be outlined.
10:30 – 11:00 Function of hspB1 in inflammation
Dr Jonathan Dean, University of Oxford, UK
Heat shock protein B1 (human hsp27, or the murine orthologue hsp25) has long been known to be phosphorylated in cells in response to pro-inflammatory stimuli. Purification of activities responsible for its phosphorylation led to the identification of the p38 mitogen-activated protein kinase pathway, one of the major signalling pathways in inflammation. Despite being a downstream component of the p38 pathway the role of hspB1 in inflammation has remained obscure until recently. I will outline progress in our understanding of the function of hspB1 in inflammation.
11:00 – 11:30 Stimulation of innate anti-HIV immunity and antigen independent memory T cell homeotasis by HSP70
Dr Yufei Wang, Kings Collge, London
HSP70 activates dendritic cells (DC) to produce inflammatory cytokines, chemokines and DC maturation. Evidence is presented that exogenous HSP70 stimulates DC to express membrane-associated IL-15 (maIL-15) molecules. This was further demonstrated that stress-activated DC which induce endogenous intra-cellular and cell surface HSP70 also express maIL-15. maIL-15 on DC interact with the IL-15 receptor complex on CD4(+) T cells, leading to T cell proliferation, production of IFN-γ and expression of CD40L. Induction of endogenouos HSP70 by stress inducing agents can function as adjuvants eliciting antigen specific T and B cell responses and activation of inflammasomes in vivo. Interestingly, alum-mediated adjuvanticity was also shown a function of stress which elicited inflammasomes and HSP70. Treatment with PES (phenylethynesulfonamide), which disrupts inducible HSP70 function, and inhibited both inflammasomes and the adjuvant function of alum. Our studies provided an alternative strategy in developing novel adjuvants.
11:30 – 12:00 Speakers’ photo then mid-morning break and trade show
12:00 – 12:30 Binding immunoglobulin protein (BiP): a powerful anti-inflammatory mediator
Dr Valerie Corrigall, Kings College London, UK
Binding immunoglobulin protein (BiP) is a ubiquitously expressed protein resident of the endoplasmic reticulum. During cellular stress, particularly lack of glucose and oxygen, BiP is upregulated, secreted and, as an extracellular protein, has an immunoregulatory role outwith its vital intracellular role. BiP acts predominantly through a monocyte expressed receptor, as yet unknown, initiating alternative activation of these cells. Although profuse IL-10 production is characteristic of BiP activated monocytes the downstream effects differ from those attributable solely to IL-10. Downregulation of costimulatory molecules, HLA-DR and inhibition of TNFα production are among the most consistent biomarkers of BiP activation. Additionally, monocyte differentiation into either dendritic cells or osteoclasts is inhibited by the presence of BiP. Cell–to-cell contact between BiP-treated dendritic cells and T cells, in the absence of BiP, leads to increased CD152 +regulatory T cell function. In vitro development of human BiP specific T cell clones show a predominantly CD8+ phenotype and a clear TH2 bias. This skewed TH2 response is consistent with the T cell recall antigen responses seen in the murine collagen induced arthritis model where BiP has been successfully used both prophylactically and therapeutically. The overall impression from these studies is that BiP acts to switch the immune response from a pro-inflammatory to an anti-inflammatory profile and therefore aid resolution of inflammation.
12:30 – 13:00 Heat shock (stress) proteins in biological fluids and the immunoregulatory properties of gp96
Professor Graham Pockley, University of Sheffield, UK
Although yet to be fully accepted by the wider scientific community, it is clear that heat shock (stress) proteins can be released from a number of different cell types via mechanisms that do not involve overt cell death. The literature relating to the presence of these proteins in biological fluids has increased dramatically over the last few years and this talk will summarise elements of this that relate to the presence of heat shock proteins in biological fluids and their association with disease processes. It is also clear that certain heat shock proteins can elicit a range of inflammatory and anti-inflammatory effects, and that these, to some extent at least, depend on the context in which they are encountered by the immune system. Although originally described as being a potent inflammatory molecule, glucose regulated protein 94 (also known as stress-inducible tumor rejection antigen GP96, tumor rejection antigen gp96, TRA1 [tumor rejection antigen 1], CaBP4 [calcium binding protein 4], Endoplasmin, GRP94 [glucose-regulated protein 94 kDa], ERp99, and TfBP [transferrin binding protein]) has been reported to have a range of anti-inflammatory effects. Data relating to the capacity of gp96 (HSPC4) to delay the rejection of cardiac transplants in an experimental system will therefore also be presented.
Although much progress has been made, we need to better structure our studies in order to provide more informative insights into the functions of these proteins. It is likely that heat shock protein profiling and assessing the functions of these in a broader physiological context will provide more insight into the significance of these multifunctional proteins, the sequence conservation of which illustrates their importance to organismal regulation and homeostasis
13:00 – 14:00 Lunch and trade show
14:00 – 14:30 Question and Answer Session
Delegates will be asked to submit questions to a panel of experts. Questions can be submitted before the event or on the day
14:30 - 14:45 Mycobacterial heat shock proteins in the etiopathogenesis of sarcoidosis.
Anna Dubaniewicz, Medical University of Gdansk, Poland
we suggest the participation of Mtb-hsp in SA etiopathogenesis. In genetically different individuals, the same antigens (e.g., Mtb-hsp) may induce different immune response develop SA or TB. In light of the direct, indirect and circumstantial evidences, which are necessary to establish that a human disease is autoimmune in origin, presence NRAMP1 polymorphism, serum anty-Mtb-hsp antibodies, decreased CD8+γδ+IL-4+T, IL-4, nitrate/nitrite concentration and increased IL-10 or resistant monocytes to stimulated apoptosis may suggest autoimmunological factor in SA etiopathogenesis
14:45– 15:15 Afternoon Tea/Coffee and trade show
15:15 – 15:45 Heat Shock Protein 70 induces cytotoxicity of T-helper cells and augmented the immunosuppressive capacity of FoxP3+ T regulatory cells
Professor Britta Eiz-Vesper, Institut für Transfusionsmedizin, Medizinische Hochschule Hannover, Germany
Heat shock proteins (HSPs) play a regulatory role for maturation of antigen-presenting cells (APCs) and gained plenty of attention because of its potent adjuvant capability to induce antigen-specific CD8+ cytotoxic T-lymphocyte and CD4+ T-helper cell responses, but the mechanism how HSP70 affects the immunosuppressive function of Tregs is still unknown. Our data pro-vide novel insights into the role of extracellular HSP70 and Calreticulin on antigen presentation, maturation of APCs as well as T-cell immune response.
15:45– 16:15 Bacterial molecular chaperones: moonlighting proteins involved in bacterial virulence
Professor Brian Henderson, Eastman Dental Institute, London, UK
Protein moonlighting describes the phenomenon of proteins having more than one unique biological function. It turns out that a number of bacterial pathogens use well known proteins in their virulence behaviour. A major group of such proteins are the molecular chaperones with major pathogens such as Mycobacterium tuberculosis, Helicobacter pylori and Chlamydia pneumoniae using such proteins to aid in the infectious process. A detailed description of the use of molecular chaperones in bacterial virulence will be provided.
16:15 Chairman’s summing up
About the Chair
Lesley Bergmeier is Senior Lecturer in Applied Mucosal Immunology in the Institute of Dentistry at Queen Mary, University of London. Her career has focused on mucosal immunity research with early work on the development of a vaccine against dental caries. She then went on to investigate mucosal vaccine candidates for HIV/SIV and the use of heat shock proteins as adjuvants. She has contributed to studies on the immune modulation of HSPs in both Behçet’s disease and Crohn’s disease and continues to work in the Behçet’s field where her interest now focuses on the induction of the pro-inflammatory cytokine nature of this autoimmune/auto inflammatory disease.
About the Speakers
Jonathan Dean studied for his PhD at the University of Sheffield before taking up a post-doctoral fellowship at the Kennedy Institute of Rheumatology Division, Imperial College London. In 2003 he became Lecturer in Cell Signalling at the Kennedy which recently joined the University of Oxford. His research focuses pro-inflammatory signalling downstream of p38, including post-transcriptional regulation by the RNA-binding protein, TTP and the small heat shock protein.
Brian Henderson is Professor of Biochemistry at UCL's Eastman Dental Institute and is one of the early discoverers that bacteria secrete molecular chaperones which signal to host cells. This has led on to the thesis that bacteria use their molecular chaperones as secreted moonlighting proteins which aid in the process of bacterial virulence.
Valerie Corrigall is non-clinical senior lecturer in the Department of Academic Rheumatology on the Guy’s Hospital Campus of King’s College London School of Medicine at Guy’s, King’s College and St Thomas’ Hospitals. Having graduated from Edinburgh University with a degree in Bacteriology where she developed an interest in Immunology her PhD was studied at Guy’s Hospital with Prof Gabriel Panayi. She has a specific interest in T cells and monocytes in inflammation biology and in particular their role in rheumatoid arthritis. Recently, she isolated and identified BiP, a stress protein, as a novel autoantigen in rheumatoid arthritis. Subsequent work has generated data showing BiP has powerful anti-inflammatory properties which are predominantly associated with the resolution of inflammation. BiP, therefore, may provide a novel biologic treatment for inflammatory and/or autoimmune diseases and will enter clinical trial 2012.
Graham Pockley was the first to report the presence of Hsp60 and Hsp70 in the peripheral circulation and this has led to a burgeoning literature in this and associated areas. His career has focussed on immunoregulatory mechanisms in human pregnancy, ocular mucosal immunity, transplantation and latterly the role of the tumour microenvironment in the orchestration or protective anti-tumour immunity. He has recently moved from the Department of Oncology at the University of Sheffield to become the Associate Director of the John van Geest Cancer Research Centre in Nottingham. He will continue to pursue his interests in regulatory T cells, NK cells and the immunoregulatory properties of cancer cell-derived factors and integrate these into the Centre’s ongoing translational oncology research programme
Paul Chapple was awarded a PhD by UCL in 1997. His PhD studied the role of molecular chaperones in environmental adaptation. The majority of my postdoctoral research was undertaken in the laboratory of Mike Cheetham at the Institute of Ophthalmology UCL, where he researched the cell biology of chaperones with links to neurodegenerative disease. He also spent a year working with Jean-Marc Gallo at the MRC Centre for Neurodegeneration Research KCL. He moved to Barts and the London Medical School QMUL as a lecturer in 2005 and was promoted to reader in 2010. His current research investigates specialized chaperone systems..
Keywords: HSP, imunnemodulation, adjuvant, regulatory, signalling,hspB1, hsp27, inflammation, inflammatory gene expression, HSP70, Calreticulin, dendritic cells, regulatory T cell, Bacterial diseases, protein moonlighting, virulence factors, molecular chaperones, Hsc70, J protein, neurodegeneration, sacsin, trafficking, Heat stress; rat’s liver, GRP94, TRA1, gp96, CaBP4, ERp99, ERp99, HSPC4, HSp60, gp96, extracellular fluids, immunoregulation
Registration Web Site: www.regonline.co.uk/chap2012
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THE SINALING ACTIVITY OF EXTRACELLULAR HSP&) MIGHT BE REGULATED
Institute of Cytology RAS, Department of Cell Signalling and Transport, Tikhoretsky avenue 4
194064St Petersburg, Russia. firstname.lastname@example.org
Heat-inducible Hsp72 is the founding member of the Hsp70 (heat shock proteins of 70 kDa) family of molecular chaperones. It is localized primarily in cytoplasm and nucleus but is also found extracellularly. The source of e-Hsp70 (extracellular Hsp72) is not precisely identified and may not be the same in every situation. A number of studies demonstrated that e-Hsp70 plays an important role in cell survival, tumour rejection and immune response. However, currently little is known about regulation of e-Hsp70 function. In cells, Hsp72 is controlled by co-chaperones. An abundant co-chaperone, HspBP1 (Hsp72-binding protein 1) was found extracellularly in the serum. In the present study we analysed the secretion and function of e-HspBP1 (extracellular HspBP1).
A431 human squamous carcinoma cells accumulated Hsp72 and HspBP1 in chromogranin A-positive granules following heat stress or in the presence of U73122, an inhibitor of phospholipase C. Following these treatments, A431 cells also increased the secretion of both proteins into the culture medium. The secreted e-Hsp70 and e-HspBP1 were co-immunoprecipitated from the conditioned medium. Purified recombinant HspBP1 augmented e-Hsp70-mediated phosphorylation of EGFR (epidermal growth factor receptor) and its down-stream targets, ERK1 (extracellular signal-regulated kinase 1) and ERK2 in a concentration-dependent manner. Finally, a HspBP1 N-terminal domain deletion mutant and boiled recombinant HspBP1 did not affect the e-Hsp72-mediated activity.
Heat stress and PLC (phospholipase C) inhibition result in the enhanced secretion of both Hsp70 and HspBP1. In an extracellular environment, the two chaperones interact both physically and functionally, leading to the activation of th EGFR-ERK1/2 signalling pathway. However, the magnitude of EGFR activation depends on the e-HspBP1/e-Hsp70 ratio in the medium. Extracellular chaperone-mediated activation of EGFR can provide a survival advantage to cells under heat shock and other stresses
EFFECTS OF HEAT STRESS ON RAT’S LIVER
Yadav.S1, Bhattacharya. S1, Jha. C.B2
1, 2 Department of Human Anatomy. B.P.K.I.H.S (Dharan)
Background- Exposure to excessive heat adversely affects on health and known as heat stress. Heat stress is synonymous with "heat load," which carries the connotation that adverse health effects will occur only if the heat stress exceeds the person's heat tolerance capacity. Heat stroke is caused by severe hyperthermia, and rectal temperatures of typical patients are higher than 40°C. Many organs such as liver, kidney and central nervous system (CNS) are damaged by severe hyperthermia. Thrombus, infarct, and death from heat stroke may be caused by injury of these organs. Cellular and intracellular membrane damage and denaturation of enzymes might be important in the pathogenesis of heat injury. Heat stress produced hepatic damage including sinusoidal congestion, monocyte infiltration, hepatocellular vacuolization and widespread necrosis. Aims and Objective:- To Observe alterations on histological architecture of rat’s liver and to evaluate pathological changes due to chronic heat stress on rat’s liver. Materials and Methods:- A total 60 rats were included in this study. Out of which control group consisted of thirty rats (Group-A) and experimental group consisted of another thirty rats (Group-B).Control and Experimental group were included adult albino wistar male and female rats (n = 60) weighing 150-250g. The control group of rats were maintained under controlled room temperature (26 ± 5°C) and light and dark (24:24 hr) conditions and were given mixed diet to be fed ad libitum with equal amount of water and light supply. The experimental group of rats were maintained under increased room temperature (38±2°C) and light conditions and were given mixed diet to be fed ad libitium with equal amount of water. On day 15, experimental and control group of rats were sacrificed by cervical dislocation. Liver was removed and preserved in the formalin. Further, it was processed for section cutting and staining by Haematoxyllin and Eosin method and each rat’s liver weight were also taken by weighing machine .Results:- Large sized hepatocyte cells were seen and swollen. Sinusoids were not densely packed. Hepatic venules were dilated. Nuclei of hepatocyte cells were enlarged. Length and breadth of hepatocyte cells were larger than the control group of rat’s liver. There was whitish-grey color of masses is seen in experimental group of rat’s liver where as control group of rat’s liver haven’t seen such type of changes. Conclusion:- This study provides evidences in support of necrosis, inflammatory changes, irregular cell membrane, enlarged nucleus, binucleated cell, dilated hepatic venules and dilated sinusoids of experimental group of rat’s liver. However, control group of rat’ Despite showing good heat stress effects.
MYCOBACTERIAL HEAT SHOCK PROTEINS IN THE ETIOPATHOGENESIS OF SARCOIDOSIS.
Department of Pneumonology, Medical University of Gdansk, Poland
Sarcoidosis (SA) is a granulomatous disorder of unknown etiology. Infectious organisms (e.g., Mycobacterium tuberculosis heat shock proteins-Mtb-hsp), genetic factors and autoimmunity have been explored as potential causes. Hsp as target of T cell- and humoral-mediated immune responses to infections may provide a link between infection and autoimmunity caused by cross-reactivity between Mtb-hsp and human hsp.
HSP70/peptide complexes: potent mediators for the generation of antiviral T cells particularly with regard to low precursor frequencies
S. Tischera,b, M. Basilaa, C. Bunsea, M. Kramera, B. Maecker-Kolhoffb,c, C. Figueiredoa,b, S. Immenschuha, M. Oelked, R. Blasczyka,b, and B. Eiz-Vespera,b
aInstitute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
bIntegrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover Germany
cDepartment of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
dDepartment of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Background. Viral infections resulting from reactivation of latent viruses (e.g. CMV, ADV, EBV) are associated with high morbidity and mortality after transplantation. Low precursor frequencies often hamper the application of virus-specific T cells. In this study the ability of HSP70/peptide complexes (HSP70/PCs) to elicit antiviral T cells even with low precursor frequencies through cross-presentation was evaluated.
Methods. We examined the role of HSP70-chaperoned viral peptides (CMVpp65: A*02:01, ADVhexon: A*01:01, A*24:02, B*07:02) in HLA class I-restricted cross-presentation for ex vivo expansion of antiviral CTLs. T cells generated from PBMCs of healthy donors by HSP70/PCs were analyzed in phenotypical and functional assays.
Results. About 90% of T cells generated with HSP70/CMV-PC were CMV-specific as compared to about 69% stimulated alone with the CMVpp65 peptide. In response to HSP70/ADV-PCs an up to 210fold increase of ADV-specific T cells was achieved as compared to the corresponding peptides. HSP70/PCs-induced T cells exhibited a significantly higher IFN-g secretion and cytotoxic activity compared to those stimulated with the viral peptides. The enhancement of antiviral T-cell responses by HSP70-chaperoned peptides was most significant in donors with low memory precursor frequencies. Blockage of CD91 by a2-macroglobulin substantially reduced the T-cell proliferation suggesting a major role of this receptor in the HSP70/PC uptake.
Conclusions. This study demonstrates that HSP70/PCs are stronger mediators for inducing antiviral T cells than soluble peptides, thus offering new approaches to generate relevant quantities of antiviral CTLs. HSP70-mediated cross-presentation may dispense with the need of dendritic cells or enriching CD8+ T cells. In particular, HSP70/PCs may even be able to overcome limitations related to low precursor frequencies and broaden the application of antigen-specific T cells to much more targets than currently possible.
Human keratinocytes take up Heat Shock Protein 70 and associated peptides
M Wittmann, B Eiz-Vesper, R Dressel , D Wang, T Werfel
Leeds Institute of Molecular Medicine, University of Leeds, Chapel Allerton Hospital,, Leeds, LS7 4SA, UK
The stress inducible chaperone heat shock protein (HSP) 70 has been proposed to play a role in the pathogenesis of skin diseases such as psoriasis and lupus erythematosus. We aimed to investigate if HSP70 and HSP70 associated peptides could be processed by human primary keratinocytes. Uptake of labelled HSP70 or labelled peptide by human primary keratinocytes or macrophages was analysed by flow cytometry and fluorescent microscopy. We found that keratinocytes bind and internalise HSP70/HSP70-peptide complexes and that CD91 is involved in HSP70 binding. TNFa, IL-27 as well as HMGB-1 enhanced the uptake of HSP70. No difference with regard to HSP70 release or uptake was observable between keratinocytes from healthy donors or cutaneous lupus erythematosus patients. Keratinocytes pulsed with HSP70-peptide complexes significantly increased IFNg production by autologous T cells. Production and uptake of inducible HSP70 by keratinocytes may critically influence the chronic course of inflammatory skin diseases.
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