Roles for the adaptive immune system in Parkinson’s and Alzheimer’s diseases
Graphical abstract
Introduction
Inflammation is pervasive in neurodegenerative diseases, including Parkinson’s (PD) and Alzheimer’s (AD). Here, we focus on evidence, mostly accumulated during the last decade, for a role of the adaptive immune response by T cells in PD and AD. Recent studies from our group have identified α-synuclein (α-syn)-derived T cell epitopes that are preferentially recognized by PD patients, as well as T cells in regions attacked in PD, suggesting an autoimmune component to PD [1••]. T cells also localize to the areas of degeneration in AD and recognize amyloid; but studies of their epitope and patient specificity are preliminary. We propose a model for development of neurodegenerative disease-specific T cell responses to assist ongoing research. Understanding the function of the adaptive immune system in neurodegenerative pathogenesis promises novel diagnostic markers and treatments.
Section snippets
The case for an inflammatory and immunological component in neurodegenerative diseases
The neurodegenerative diseases of older age, including AD and PD, are major burdens to society, families, and individuals, particularly as the average life expectancy has increased. AD and PD, as well as many other neurodegenerative disorders, exhibit the loss of neurons in the central nervous system (CNS), but the means by which this occurs remains unknown [2]. These disorders also exhibit the abnormal accumulation of high levels of specific aggregated proteins [3].
In the case of PD, while
Roles for T cells in AD
AD pathological studies have long shown evidence for changes in a broad range of immune cells [13], particularly including a high presence of microglia [14]. More recently, genetic and pathological studies indicate a role associated with neurotropic virus, particularly herpes simplex [15,16]. It has been suggested that a function of Aβ peptide is to provide a protective mechanism against infection by herpes virus [17].
T cells in both the periphery and CNS are also implicated in AD, although
Roles for T cells in PD
In addition to many long-standing reports of sustained microglial activation, particularly in the SN of PD patients, more recent lines of evidence suggest a role for T cells in PD [1••]. Both early and more recent pathology studies found that CD8+ and CD4+ T cells were present at higher levels in the SN of PD brains [29, 30, 31], although the antigenic targets were not defined. In a mouse model using viral α-syn overexpression, MHC class II-/- mice were protected from SN neuronal death [32],
Human T cells recognize α-synuclein derived peptides in PD patients
To address whether PD is associated with α-syn-specific recognition by T cells, peripheral blood mononuclear cells (PBMCs) from 67 PD and 36 healthy, age-matched controls were screened with potential α-syn peptides [1••]. These peptides included both overlapping 15-mers spanning α-syn and 9–10-mers predicted to bind common HLA class I alleles. This study identified several T cell epitopes, with the majority of α-syn-specific responses directed against two main antigenic regions; one centered
A working model for the role of T cells in neurodegenerative disorders
On the basis of these results, we have suggested a model in which α-syn-specific T cells drive neuronal death in neurodegenerative diseases associated with specific misfolded proteins. CD4+ T cell recognition of antigens presented by APC such as microglia, and by CD8+ T cells on neurons, could mediate both direct and indirect neuronal damage. Substantia nigra and locus coeruleus neurons express HLA class I [9••], but there has been no description of HLA class II expression. Importantly,
Outlook for further investigations
The current data implicating α-syn and Aβ epitopes may represent the proverbial tip of the iceberg for characterizing the role of the immune response in neurodegenerative disease. Clearly, much remains to be done. Analysis of reactivity against other additional autoantigens associated with PD, as well as investigation of the potential for T cell autoimmunity in other neurodegenerative diseases such as AD and ALS, is of clear interest. Future research should analyze the relationship between
Conclusions
Our data establish a crucial link between T cell recognition and susceptibility to PD, a common neurodegenerative disease. Understanding the role of adaptive immune responses in neurodegenerative diseases may provide novel diagnostic and/or therapeutic strategies. Our current research efforts are aimed at expanding these lines of investigation to other antigens and other neurodegenerative diseases, and to dissecting the role of T cell reactivity in the prodromal phase and disease pathogenesis.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the National Institutes of Health [grant numbers R01NS095435, U19 AI118626], the Michael J. Fox Foundation, JPB Foundation and Parkinson Foundation and UCSD-LJI Program in Immunology funding.
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