Genetic studies associate Parkinson’s disease with alleles of the major histocompatibility complex1–3. We find that a defined set of peptides derived from α-synuclein, a protein aggregated in Parkinson’s disease4, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.

Evidence from a variety of studies implicates a role for the adaptive immune system in Parkinson's disease (PD). Similar to multiple sclerosis (MS) patients who display a high number of T cells in the brain attacking oligodendrocytes, PD patients show higher numbers of T cells in the ventral midbrain than healthy, age-matched controls. Mouse models of the disease also show the presence of T cells in the brain. The role of these infiltrating T cells in the propagation of disease is controversial; however, recent studies indicate that they may be autoreactive in nature, recognizing disease-altered self-proteins as foreign antigens. T cells of PD patients can generate an autoimmune response to α-synuclein, a protein that is aggregated in PD. α-Synuclein and other proteins are post-translationally modified in an environment in which protein processing is altered, possibly leading to the generation of neo-epitopes, or self-peptides that have not been identified by the host immune system as non-foreign. Infiltrating T cells may also be responding to such modified proteins. Genome-wide association studies (GWAS) have shown associations of PD with haplotypes of major histocompatibility complex (MHC) class II genes, and a polymorphism in a non-coding region that may increase MHC class II in PD patients. We speculate that the inflammation observed in PD may play both pathogenic and protective roles. Future studies on the adaptive immune system in neurodegenerative disorders may elucidate steps in disease pathogenesis and assist with the development of both biomarkers and treatments.

No abstract

No abstract

Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau-derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4 + T cell responses to tau-derived peptides, which were associated with secretion of IFN-g, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease.

In this Letter, owing to an error during the production process, two values in Table 1 were incorrect. The relative frequency for the DQB1* 03:04 allele should have been '4.5' rather than '0' , and the odds ratio for the DQB1* 03:04 allele should have been 'inf. ' rather than '11'. The original Letter has been corrected online.

No abstract

Parkinson's disease (PD) patients possess circulating T cells that recognize specific α-synuclein- (α-syn)-derived epitopes. One epitope, α-syn32-46, interacts strongly with the HLA-DRB1*15:01 allele implicated in multiple autoimmune diseases. Whether this interaction and α-syn-specific T cells play roles in PD pathogenesis remains unknown. We report that α-syn32-46 immunization of a humanized mouse that expresses HLA-DRB1*15:01 triggers intestinal inflammation. This enteric pathology is characterized by activation of innate and adaptive immune responses and type I interferon signaling as well as loss of enteric dopaminergic neurons in the submucosal plexus, and results in constipation and weight loss. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Thus, an interaction between α-syn32-46 and HLA-DRB1*15:01 induces gut inflammation and CD4+ T cell-mediated loss of enteric dopaminergic neurons in the humanized mice. These findings suggest a mechanism for the prodromal enteric features of PD and indicate future directions for disease screening and treatment.