title: Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the α-synuclein-elicited immune response.
abstract: We have investigated the potential role of molecular chaperones as modulators of the immune response by using α-synuclein (αSyn) as an aggregation-prone model protein. We first performed an in vitro immunoscreening with 21 preselected candidate chaperones and selected 2 from this set as displaying immunological activity with differential profiles, Grp94/Gp96 and FKBP4/52. We then immunized mice with both chaperone/α-synuclein combinations using monomeric or oligomeric α-synuclein (MαSyn or OαSyn, respectively), and we characterized the immune response generated in each case. We found that Grp94 promoted αSyn-specific T-helper (Th)1/Th17 and IgG1 antibody responses (up to a 3-fold increase) with MαSyn and OαSyn, respectively, coupled to a Th2-type general phenotype (generating 2.5-fold higher IgG1/IgG2 levels). In addition, we observed that FKBP4 favored a Th1-skewed phenotype with MαSyn but strongly supported a Th2-type phenotype with OαSyn (with a 3-fold higher IL-10/IFN-γ serum levels). Importantly, results from adoptive transfer of splenocytes from immunized animals in a Parkinson's disease mouse model indicates that these effects are robust, stable in time, and physiologically relevant. Taken together, Grp94 and FKBP4 are able to generate differential immune responses to α-synuclein-based immunizations, depending both on the nature of the chaperone and on the aggregation state of α-synuclein. Our work reveals that several chaperones are potential modulators of the immune response and suggests that different chaperones could be exploited to redirect the amyloid-elicited immunity both for basic studies of the immunological processes associated with neurodegeneration and for immunotherapy of pathologies associated with protein misfolding and aggregation.
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Adahir
authors.initials: A
authors.lastname: Labrador-Garrido
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cejudo-Guillén
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Soumya
authors.initials: S
authors.lastname: Daturpalli
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Leal
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klippstein
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Erwin J
authors.initials: EJ
authors.lastname: De Genst
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Villadiego
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Toledo-Aral
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Jackson
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pozo
authors.affiliation: *Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; Department of Medical Biochemistry, Molecular Biology, and Immunology and Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Seville, Spain; and Centers for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Seville, Spain cintia.roodveldt@cabimer.es.
authors.forename: Cintia
authors.initials: C
authors.lastname: Roodveldt
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000502:physiology*; D017510:Protein Folding; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D051844:alpha-Synuclein; C053387:endoplasmin; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4
keywords: Parkinson; heat-shock protein; immunotherapy; misfolding/amyloid disease