title: Chaperoned amyloid proteins for immune manipulation: α-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype.
abstract: α-Synuclein (αSyn) is a 140-residue amyloid-forming protein whose aggregation is linked to Parkinson's disease (PD). It has also been found to play a critical role in the immune imbalance that accompanies disease progression, a characteristic that has prompted the search for an effective αSyn-based immunotherapy. In this study, we have simultaneously exploited two important features of certain heat-shock proteins (HSPs): their classical "chaperone" activities and their recently discovered and diverse "immunoactive" properties. In particular, we have explored the immune response elicited by immunization of C57BL/6 mice with an αSyn/Hsp70 protein combination in the absence of added adjuvant. Our results show differential effects for mice immunized with the αSyn/Hsp70 complex, including a restrained αSyn-specific (IgM and IgG) humoral response as well as minimized alterations in the Treg (CD4(+)CD25(+)Foxp3(+)) and Teff (CD4(+)Foxp3(-)) cell populations, as opposed to significant changes in mice immunized with αSyn and Hsp70 alone. Furthermore, in vitro-stimulated splenocytes from immunized mice showed the lowest relative response against αSyn challenge for the "αSyn/Hsp70" experimental group as measured by IFN-γ and IL-17 secretion, and higher IL-10 levels when stimulated with LPS. Finally, serum levels of Th1-cytokine IFN-γ and immunomodulatory IL-10 indicated a unique shift toward an immunomodulatory/immunoprotective phenotype in mice immunized with the αSyn/Hsp70 complex. Overall, we propose the use of functional "HSP-chaperoned amyloid/aggregating proteins" generated with appropriate HSP-substrate protein combinations, such as the αSyn/Hsp70 complex, as a novel strategy for immune-based intervention against synucleinopathies and other amyloid or "misfolding" neurodegenerative disorders.
authors: CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain ; Department of Medical Biochemistry Molecular Biology and Immunology School of Medicine, University of Seville Spain.
authors: Adahir
authors: A
authors: Labrador-Garrido
authors: CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain ; Department of Medical Biochemistry Molecular Biology and Immunology School of Medicine, University of Seville Spain.
authors: Marta
authors: M
authors: Cejudo-Guillén
authors: CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain ; Department of Medical Biochemistry Molecular Biology and Immunology School of Medicine, University of Seville Spain.
authors: Rebecca
authors: R
authors: Klippstein
authors: Department of Chemistry, University of Cambridge UK.
authors: Erwin J
authors: EJ
authors: De Genst
authors: CABD, Andalusian Center for Developmental Biology Seville, Spain.
authors: Laura
authors: L
authors: Tomas-Gallardo
authors: CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain.
authors: María M
authors: MM
authors: Leal
authors: IBiS Institute of Biomedicine of Seville, University Hospital Virgen del Rocío-CSIC-University of Seville Spain ; Department of Medical Physiology and Biophysics School of Medicine, University of Seville Spain ; CIBERNED, Centers for Networked Biomedical Research in Neurodegenerative Diseases Spain.
authors: Javier
authors: J
authors: Villadiego
authors: IBiS Institute of Biomedicine of Seville, University Hospital Virgen del Rocío-CSIC-University of Seville Spain ; Department of Medical Physiology and Biophysics School of Medicine, University of Seville Spain ; CIBERNED, Centers for Networked Biomedical Research in Neurodegenerative Diseases Spain.
authors: Juan J
authors: JJ
authors: Toledo-Aral
authors: Department of Chemistry, University of Cambridge UK.
authors: Christopher M
authors: CM
authors: Dobson
authors: CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain ; Department of Medical Biochemistry Molecular Biology and Immunology School of Medicine, University of Seville Spain.
authors: David
authors: D
authors: Pozo
authors: CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain.
authors: Cintia
authors: C
authors: Roodveldt
keywords: amyloid disease; heat-shock proteins (HSPs); immunization; immunomodulation; α-synuclein