Browsing by Subject "Heat shock proteins"

Now showing 1 - 4 of 4
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    Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children
    (Thieme, 2014-03) Standage, Stephen W.; Lahni, Patrick M.; Ma, William; Kernie, Steven G.; Wong, Hector R.; Wheeler, Derek S.; Pediatrics, School of Medicine
    Extracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes.
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    Heat shock protein 90, a potential biomarker for type I diabetes: mechanisms of release from pancreatic beta cells
    (2016-05-23) Ocaña, Gail Jean; Blum, Janice Sherry, 1957-; Kaplan, Mark H.; Serezani, C. Henrique; Sun, Jie
    Heat shock protein (HSP) 90 is a molecular chaperone that regulates diverse cellular processes by facilitating activities of various protein clients. Recent studies have shown serum levels of the alpha cytoplasmic HSP90 isoform are elevated in newly diagnosed type I diabetic patients, thus distinguishing this protein as a potential biomarker for pre-clinical type I diabetes mellitus (TIDM). This phase of disease is known to be associated with various forms of beta cell stress, including endoplasmic reticulum stress, insulitis, and hyperglycemia. Therefore, to test the hypothesis that HSP90 is released by these cells in response to stress, human pancreatic beta cells were subjected to various forms of stress in vitro. Beta cells released HSP90 in response to stimulation with a combination of cytokines that included IL-1β, TNF-α, and IFN-γ, as well as an agonist of toll-like receptor 3. HSP90 release was not found to result from cellular increases in HSP90AA1 gene or HSP90 protein expression levels. Rather, cell stress and ensuing cytotoxicity mediated by c-Jun N-terminal kinase (JNK) appeared to play a role in HSP90 release. Beta cell HSP90 release was attenuated by pre-treatment with tauroursodeoxycholic acid (TUDCA), which has been shown previously to protect beta cells against JNK-mediated, cytokine-induced apoptosis. Experiments here confirmed TUDCA reduced beta cell JNK phosphorylation in response to cytokine stress. Furthermore pharmacological inhibition and siRNA-mediated knockdown of JNK in beta cells also attenuated HSP90 release in response to cytokine stress. Pharmacological inhibition of HSP90 chaperone function exacerbated islet cell stress during the development of TIDM in vivo; however, it did not affect the overall incidence of disease. Together, these data suggest extracellular HSP90 could serve as a biomarker for preclinical TIDM. This knowledge may be clinically relevant in optimizing treatments aimed at restoring beta cell mass. The goal of such treatments would be to halt the progression of at-risk patients to insulin dependence and lifelong TIDM.
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    THE ROLE OF HSPs IN MHC CLASS II PRESENTATION OF SELECT ANTIGENS
    (2010-01-26T20:06:19Z) Houlihan, Josetta Lynn; Blum, Janice Sherry, 1957-; Brutkiewicz, Randy R.; Klemsz, Michael J.; Thurmond, Debbie C.
    The function of major histocompatability complex (MHC) class II molecules is to present antigenic peptides to CD4+ T cells. Typically, MHC class II molecules present peptides derived from exogenous sources. Yet, certain endogenous antigens (Ags) have been found to be presented by class II molecules. Studies suggest that specific heat shock protein family members may play a role in Ag processing and subsequent class II presentation. The studies presented here using B lymphoblasts demonstrate the importance of HSP90α, HSP90β, and possibly HSP70 in selectively regulating MHC class II presentation. Inactivation of HSP90 function using pharmacological inhibitors inhibited class II presentation of exogenous and endogenous GAD, but did not perturb the presentation of several other intra- and extracellular Ags. Individual knockdown of HSP90 isoforms using isoform specific siRNA selectively inhibited GAD Ag presentation. These results demonstrate a requirement for HSP90α and HSP90β in regulating MHC class II presentation of select Ags. Studies to explore mechanistically the roles of HSP90α and HSP90β in regulating GAD Ag presentation were pursued. The pathways of exogenous and endogenous MHC class II presentation of GAD Ag are distinct yet converge with shared terminal processing of GAD within endosomal/lysosomal vesicles. The effect of HSP90 manipulation on various shared components of the MHC class II pathway was examined. The studies presented here suggest that HSP90α and HSP90β regulate MHC class II presentation of GAD Ag at discrete steps most likely involving HSP90 binding to GAD Ag rather than perturbing overall MHC class II function. vi Studying the role of HSP90 in MHC class II presentation in B cells revealed the potential requirement for HSP70 in the presentation of select Ags. The studies presented here demonstrate a possible role for HSP70 in the presentation of Ags such as SMA or Ig kappa by MHC class II molecules. Also included in this work is a study of a rare case of diabetes caused by type B insulin resistance due to development of insulin receptor autoantibodies during the treatment of hepatitis C with interferon alpha and ribavirin. Clinical and laboratory findings in the case are presented.
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    Targeting Neuroinflammation to Treat Alzheimer's Disease
    (Springer, 2017-12) Ardura-Fabregat, A.; Boddeke, E. W. G. M.; Boza-Serrano, A.; Brioschi, S.; Castro-Gomez, S.; Ceyzériat, K.; Dansokho, C.; Dierkes, T.; Gelders, G.; Heneka, Michael T.; Hoeijmakers, L.; Hoffmann, A.; Iaccarino, L.; Jahnert, S.; Kuhbandner, K.; Landreth, G.; Lonnemann, N.; Löschmann, P. A.; McManus, R. M.; Paulus, A.; Reemst, K.; Sanchez-Caro, J. M.; Tiberi, A.; Perren, A. van der; Vautheny, A.; Venegas, C.; Webers, A.; Weydt, P.; Wijasa, T. S.; Xiang, X.; Yang, Y.; Neurology, School of Medicine
    Over the past few decades, research on Alzheimer's disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that-upon engagement of pattern recognition receptors-induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.