Immune response in Parkinson’s disease driven by HLA display of α-synuclein peptides

Abstract

Abstract Abnormal processing of self-proteins can produce epitopes presented by major histocompatibility (MHC) proteins to be recognized by specific T cells that escaped central tolerance during thymic selection. Such actions by the acquired immune system are widely held to produce autoimmune disorders such as Type-1 diabetes. While not considered to possess autoimmune features, neurodegenerative diseases are characterized by the altered processing of specific proteins. One of the major pathological features of Parkinson’s disease are the presence of intraneuronal aggregrates known as Lewy bodies and neurites composed of α-synuclein. Genetic studies associate Parkinson’s disease with DRB5*01 and DRB1*15:01 MHC alleles. To address the hypothesis that Parkinson’s disease is associated with T cell recognition of epitopes derived from α-synuclein and presented by specific MHC alleles, we recruited 67 Parkinson’s disease patients and 36 age-matched non-Parkinson’s healthy controls. We found that a defined set of peptides derived from α-synuclein, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. We identified two antigenic regions in α-synuclein, the first near the N terminus (aa31-46), which was bound by DRB1*15:01 and DRB5*01:01, and the second near the C terminus, which required phosphorylation of an amino acid residue (S129). These α-synuclein epitopes were shown to arise from natural processing of both extracellular native α-synuclein and the fibrilized form associated with Parkinson’s disease pathogenesis. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.