Unbiased Approach to Identify Antigen-Specific Immune Response in PD

Many lines of evidence suggest that the immune system plays a key role in Parkinson's disease (PD) initiation and progression, but the actual mechanistic dysfunction of the immune system in this neurodegenerative disease remains unknown. Genetic studies and pathology hint that the immune system's ability to mount a controlled antigen-specific response has been lost in PD with detrimental consequences. We will take a comprehensive approach using cutting-edge tools to explore this hypothesis in PD. Combining human immunology, peptidomics, and single-cell transcriptomics, we will dissect antigen-specific immune responses occurring in the brains of individuals with PD. Post-mortem pathology of individuals with PD reveals an infiltration of T cells in the substantia nigra, a region expected to be immune privileged, leading to speculation that PD might have an autoimmune or infectious etiology. However, most of the immune processes that are potentially involved in PD are poorly understood: the antigen specificity and phenotype of the infiltrating T cells, and the antigen-presenting role of microglia. Our pilot proposal seeks to answer these key questions in the context of human sporadic PD, which will lead to a greater understanding of how the genetic risk alleles modify the immune system's behavior and cellular crosstalk in the central nervous system. This basic science proposal will leverage human brain autopsies from PD patients to lay the groundwork for therapeutic approaches.