Rellevància etiopatogènica de les cèl·lules t cd8+ en la malaltia de parkinson

• Autores: Jordi Galiano Landeira
• Directores de la Tesis: Jordi Bové Badell (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
• Idioma: catalán
• Tribunal Calificador de la Tesis: Ana María Planas Obradors (presid.), Carlos Barcia González (secret.), Ellen Gelpi Mantius (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Autónoma de Barcelona
• Materias:
  • Ciencia política
    • Opinión publica
      • Información
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Mounting evidence has pointed out that the adaptive immune system has an important role in Parkinson’s disease (PD) etiopathogenesis. T cell infiltration has been described in both PD experimental animal models and post-mortem human tissue. Some authors have proposed α-synuclein posttranslational modifications as the antigen eliciting this adaptive immune response. Thus, the main goal of this thesis was to determine whether T cells participate in the onset and progression of the disease. Moreover, we wanted to know whether α-synuclein behaved as a neoantigen. In order to overcome this, we analyzed and phenotypically characterized substantia nigra pars compacta (SNpc) infiltrating T cells in post-mortem human tissue at distinct disease stages. PD and incidental Lewy Body disease (iLBD) cases, which are considered to be an early pre-motor stage of the disorder, were analyzed. We studied the relationship between T cell infiltration with dopaminergic cell loss and synucleinopathy, two hallmarks of the disorder. We found a biphasic SNpc CD8+ cytotoxic T lymphocyte (CTL) infiltration. Strikingly, the first and highest peak was found when synucleinopathy and dopaminergic cell loss were not established. SNpc CTL infiltration subsided when synucleinopathy and dopaminergic cell loss started. SNpc CTL infiltration again increased in PD cases where CD8+ T cell densities correlated with neuronal death. Similar results were also obtained in another PD brain affected area such as locus coeruleus (LC). The fact that SNpc CTLs made contact with dopaminergic neurons and correlated with dopaminergic cell loss, suggests a likely role in dopaminergic cell death. To delve further into this concept, we found that SNpc CTLs expressed cytotoxic machinery i.e. granzymes and interferon-g. Infiltrating SNpc granzyme+ CTLs were found increased in iLBD cases indicating an acute adaptive immune response in early stages of the disease. A high percentage of SNpc CTLs were tissue resident memory T cells identified by CD103 expression. Antigen presentation by means of MHC class-II+ microglia was reduced in early stages of the disease. Low densities of ameboid/activated MHC class-II+ microglial cells correlated with higher dopaminergic cell loss, suggesting a positive role of MHC class-II+ microglia in the disease. To determine the best rodent model to assess the T cell role in PD, we characterized the immune response in MPTP injected mice and rats overexpressing α-synuclein. We found a transient CD4+ and CD8+ T cell infiltration preceding dopaminergic cell death in the subacute MPTP injected mice which correlated with striatal damage. Nonetheless, breaking immune tolerance through systemic Treg depletion did not increase nigrostriatal damage. Finally, we also observed CD4+ and CD8+ T cell SNpc infiltration in rats overexpressing α-synuclein. However, these rats did show neither behavioural motor changes nor nigrostriatal damage. To conclude, human PD-specific brain adaptive immune response reported in our study is different to the one observed in PD experimental animal models. In SNpc human tissue CD4+ T cells were not elevated, and CTL infiltration preceded synucleinopathy. These results point out the fact that α-synuclein seems not to be the antigen for the cytotoxic attack elicited by CD8+ T cells. Overall, this thesis demonstrated that CTL infiltration is an early event of the disease preceding both α-synuclein deposition and dopaminergic cell loss. Thus, targeting the adaptive immune response in both early and late stages of the disease may have beneficial effects. Nevertheless, there is a need to establish new PD experimental animal models which recapitulate the human adaptive immune response.