Innate and adaptive immunity for the pathobiology of Parkinson's disease

Abstract

Innate and adaptive immunity affect the pathogenesis of Parkinson's disease (PD). In particular, activation of microglia influences degeneration of dopaminergic neurons. Cell-to-cell interactions and immune regulation critical for neuronal homeostasis also influence immune responses. The links between T cell immunity and nigrostriatal degeneration are supported by laboratory, animal model, and human pathologic investigations. Immune-associated biomarkers in spinal fluids and brain tissue of patients with idiopathic or familial forms of PD provide means to improve diagnosis and therapeutic monitoring. Relationships between oxidative stress, inflammation, and immune-mediated cell death pathways are examined in this review as they are linked to PD pathogenesis. Harnessing the immune system by drugs or by vaccination remain promising future therapeutic options.

FIG. 1.

Oxidative Stress and PD pathobiology. Free radicals can arise as a result of glial cell activation, mitochondrial dysfunction, or protein aggregation. Increased microglial activation is attributable to increased neuronal cell death and cell debris including aggregated proteins. Microglial-derived NO and superoxide (•O⁻₂) species react in extracellular spaces to form peroxynitrite (ONOO⁻). Peroxynitrite readily crosses cell membranes where it contributes to lipid peroxidation, DNA damage, and nitrotyrosine formation in α-syn and other cellular proteins. Damaged proteins are targeted to cellular proteosomes for degradation via the ubiquitin pathway. Excessive protein damage caused by oxidants and disruptions in the ubiquitin pathways may overload or inhibit protein degradation quality control measures leading to the accumulation of damaged proteins in cells. When reactive species exceed antioxidant defenses, oxidative stress is generated, destroying molecular structures, such as proteins, lipids, and DNA, causing irreversible and detrimental damage, neuronal cell injury and death. Adapted from Gao et al. (47). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Nitrated-α-syn-mediated PD immunopathology. A hallmark feature of PD is the presence of Lewy body neuronal inclusions consisting of nitrated-α-syn (N-α-syn). As the neurons die, the inclusions are released into the extracellular environment where the protein aggregates (most notably N-α-syn) interact with adjacent microglia and initiate an activation cascade. Recent evidence from our own laboratories suggests that N-α-syn in the brain can also drain to cervical lymph nodes where the protein can initiate an adaptive immune response. Antigen presenting cells would present synuclein as a neo-epitope to T cells present in lymphoid tissues. The ongoing inflammatory processes facilitate infiltration of autoreactive T cells into the brain, exacerbating microglial activation and accelerating neuronal death.

FIG. 3.

Tregs and neuroimmunity. Tregs are proposed to have several mechanisms of action to suppress immune reactivity depending on the target effector cells. Albeit in vitro, Treg-mediated suppression of effector T cell responses is primarily through cell-to-cell contact; several mechanisms of action are postulated for Treg-mediated suppression of effector T cells in vivo. These mechanisms include cytokine-mediated inhibition of activation (A), induction of apoptosis either through a granzyme/perforin-dependant mechanism (B), or through disruption of metabolic function or IL-2 competition (C), or indirectly by inducing tolerance through modulation of dendritic cell activation (D). Recent evidence supports a role for Tregs in modulating mononuclear phagocyte activation through both cytokine dependent and independent mechanisms (E). Moreover, Tregs are proposed to influence astrocytes to promote neurotrophin expression and glutamate clearance (F). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

Therapeutic Strategies for PD. Several targeted approaches are currently available or proposed for the treatment of PD. The first of these targets the aggregated or misfolded proteins themselves in an effort to prevent oligomerization induce neuronal damage and microglial activation. Vaccine-induced antibodies or intracellular-produced single chain antibodies directed against misfolded proteins, or drugs (e.g., rapamycin) that stimulate phagocytosis by mononuclear phagocytes, and lysosomal degradation has been proposed for the clearance of extracellular and intracellular aggregated proteins. Alternatively, drugs that affect inflammatory responses, directly inhibit neurotoxicity (by inhibiting apoptotic pathways or excitotoxcity), or promote neuroprotection (e.g., glial derived neurotrophic factor, GDNF) have shown to be effective in animal models for human disease. Finally, efforts are being made to modulate the immune response to aggregated proteins through either immune modifiers or antioxidants that attenuate microglial activation, with the observation that disease can either be exacerbated by effector T cells specific for neo-epitopes or ameliorated by regulatory T cells. Therefore, therapeutic intervention by immunomodulators or adjuvants to induce or upregulate regulatory T cell responses can inhibit ongoing adaptive and innate immune responses and prevent further neurodegeneration.