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The work of CMD and EJDG was supported by the Cambridge Center for Misfolding Diseases. CR holds a senior Servet II","award":["CPII16\/58"],"award-info":[{"award-number":["CPII16\/58"]}]},{"name":"Spanish Ministry of Economy (Instituto de Salud Carlos III) cofounded by FEDER"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Glia"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded \u03b1\u2010synuclein (\u03b1Syn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat\u2010shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of \u03b1Syn and Grp94 (HSPC4 or Gp96) chaperone and a murine PD model. We used two different procedures, first, the adoptive transfer of splenocytes from \u03b1Syn\/Grp94\u2010immunized mice to recipient animals, and second, direct immunization with \u03b1Syn\/Grp94, to study the effects in a chronic mouse MPTP\u2010model of parkinsonism. We found that both approaches promoted a distinct profile in the peripheral system\u2014supported by humoral and cellular immunity\u2014consisting of a Th1\u2010shifted \u03b1Syn\u2010specific response accompanied by an immune\u2010regulatory\/Th2\u2010skewed general phenotype. Remarkably, this mixed profile sustained by \u03b1Syn\/Grp94 immunization led to strong suppression of microglial activation in the <jats:italic>substantia nigra<\/jats:italic> and <jats:italic>striatum<\/jats:italic>, pointing to a newly described positive effect of anti\u2010\u03b1Syn Th1\u2010responses in the context of PD. This strategy is the first to target \u03b1Syn and report the suppression of PD\u2010associated microgliosis. Overall, we show that the \u03b1Syn\/Grp94 combination supports a distinct and long\u2010lasting immune profile in the peripheral system, which has an impact at the CNS level by suppressing chronic microglial activation in an MPTP model of PD. Furthermore, our study demonstrates that reshaping peripheral immunity by vaccination with appropriate misfolding protein\/HSP combinations could be highly beneficial as a treatment for neurodegenerative misfolding diseases.<\/jats:p>","DOI":"10.1002\/glia.23237","type":"journal-article","created":{"date-parts":[[2017,10,11]],"date-time":"2017-10-11T08:38:50Z","timestamp":1507711130000},"page":"191-205","source":"Crossref","is-referenced-by-count":28,"title":["Immunization with \u03b1\u2010synuclein\/Grp94 reshapes peripheral immunity and suppresses microgliosis in a chronic Parkinsonism model"],"prefix":"10.1002","volume":"66","author":[{"given":"Javier","family":"Villadiego","sequence":"first","affiliation":[{"name":"Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio\u2010CSIC\u2010Universidad de Sevilla Seville Spain"},{"name":"Departamento de Fisiolog\u00eda M\u00e9dica y Biof\u00edsica Universidad de Sevilla Seville Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adahir","family":"Labrador\u2010Garrido","sequence":"additional","affiliation":[{"name":"Andalusian Center for Molecular Biology and Regenerative Medicine\u2010CABIMER. Universidad de Sevilla\u2010CSIC\u2010Universidad Pablo de Olavide Seville Spain"},{"name":"Departamento de Bioqu\u00edmica M\u00e9dica Biolog\u00eda Molecular e Inmunolog\u00eda. Universidad de Sevilla Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime M.","family":"Franco","sequence":"additional","affiliation":[{"name":"Andalusian Center for Molecular Biology and Regenerative Medicine\u2010CABIMER. Universidad de Sevilla\u2010CSIC\u2010Universidad Pablo de Olavide Seville Spain"},{"name":"Departamento de Bioqu\u00edmica M\u00e9dica Biolog\u00eda Molecular e Inmunolog\u00eda. Universidad de Sevilla Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Leal\u2010Lasarte","sequence":"additional","affiliation":[{"name":"Andalusian Center for Molecular Biology and Regenerative Medicine\u2010CABIMER. Universidad de Sevilla\u2010CSIC\u2010Universidad Pablo de Olavide Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin J.","family":"De Genst","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cambridge Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Dobson","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cambridge Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pozo","sequence":"additional","affiliation":[{"name":"Andalusian Center for Molecular Biology and Regenerative Medicine\u2010CABIMER. Universidad de Sevilla\u2010CSIC\u2010Universidad Pablo de Olavide Seville Spain"},{"name":"Departamento de Bioqu\u00edmica M\u00e9dica Biolog\u00eda Molecular e Inmunolog\u00eda. Universidad de Sevilla Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan J.","family":"Toledo\u2010Aral","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio\u2010CSIC\u2010Universidad de Sevilla Seville Spain"},{"name":"Departamento de Fisiolog\u00eda M\u00e9dica y Biof\u00edsica Universidad de Sevilla Seville Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4124-8769","authenticated-orcid":false,"given":"Cintia","family":"Roodveldt","sequence":"additional","affiliation":[{"name":"Andalusian Center for Molecular Biology and Regenerative Medicine\u2010CABIMER. 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