Abstract
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.
Highlights
PARKINSON’S DISEASE AND INFLAMMATIONMultiple studies have highlighted an association between sustained inflammation and a number of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotropic lateral sclerosis (ALS), and frontal temporal dementia (FTD) [1]
Numerous independent studies suggest that a heightened and sustained immune response observed in PD patients may be a driver, rather than a consequence, of neuronal death. αSyn pathology may begin in the periphery, where the enteric nervous system is compromised up to 20 years prior to diagnosis
Circulating T cells of PD patients have been shown to respond to α-syn stimulation in vitro
Summary
Multiple studies have highlighted an association between sustained inflammation and a number of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotropic lateral sclerosis (ALS), and frontal temporal dementia (FTD) [1]. Human α-syn overexpression triggers microglial activation, BBB leakage, and recruitment of T and B cells into the SN prior to neurodegeneration in mice [92] These findings support the concept that immune cell recruitment and local inflammatory features play roles in neurodegeneration, rather than that they are consequences downstream from neuronal death. Association of HLA alleles to late-onset PD and a positive correlation between levels of MHC-II expression and disease severity in humans, in conjunction with the necessity for MHC-II expression in PD mouse models, suggests that antigen presentation and adaptive immune signaling may be involved in dopaminergic neuron death. Deficits in microglial restraint exacerbate dopaminergic neurodegeneration in 6-OHDA rats [128] Taken together, these studies show that microglial activation is critical for immune cell recruitment and neuronal death in PD. Peripheral α-syn-specific T cells may migrate to the brain and be further activated by α-syn-presenting microglia that have internalized aggregates
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