Chaperoned amyloid proteins for immune manipulation: ?-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype.

ABSTRACT: ?-Synuclein (?Syn) 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 ?Syn-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 ?Syn/Hsp70 protein combination in the absence of added adjuvant. Our results show differential effects for mice immunized with the ?Syn/Hsp70 complex, including a restrained ?Syn-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 ?Syn and Hsp70 alone. Furthermore, in vitro-stimulated splenocytes from immunized mice showed the lowest relative response against ?Syn challenge for the "?Syn/Hsp70" experimental group as measured by IFN-? and IL-17 secretion, and higher IL-10 levels when stimulated with LPS. Finally, serum levels of Th1-cytokine IFN-? and immunomodulatory IL-10 indicated a unique shift toward an immunomodulatory/immunoprotective phenotype in mice immunized with the ?Syn/Hsp70 complex. Overall, we propose the use of functional "HSP-chaperoned amyloid/aggregating proteins" generated with appropriate HSP-substrate protein combinations, such as the ?Syn/Hsp70 complex, as a novel strategy for immune-based intervention against synucleinopathies and other amyloid or "misfolding" neurodegenerative disorders.

SUBMITTER: Labrador-Garrido A 

PROVIDER: S-EPMC4386917 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature