Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases

Abstract

Neurodegenerative diseases, notably Alzheimer's and Parkinson's diseases, are amongst the most devastating disorders afflicting the elderly. Currently, no curative treatments or treatments that interdict disease progression exist. Over the past decade, immunization strategies have been proposed to combat disease progression. Such strategies induce humoral immune responses against misfolded protein aggregates to facilitate their clearance. Robust adaptive immunity against misfolded proteins, however, accelerates disease progression, precipitated by induced effector T cell responses that lead to encephalitis and neuronal death. Since then, mechanisms that attenuate such adaptive neurotoxic immune responses have been sought. We propose that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. This review summarizes advances in immune regulation to achieve a homeostatic glial response for therapeutic gain. Promising new ways to optimize immunization schemes and measure their clinical efficacy are also discussed.

Figure 1

In the pathogenesis of PD, injured and apoptotic dopaminergic neurons release aggregated N-α-synuclein (N-α-syn), either as unconjugated species or as conglomerates from Lewy bodies. Extraneuronal N-α-syn crosses the BBB to the CSF and the draining lymph nodes where it is processed by antigen presenting cells, and presented in the context of MHC class II molecules to naïve T cells. This stimulates naïve T cell differentiation to effector T cells (Teff) and Teff expansion, which then migrate to inflammatory foci in the brain. Upon recognition of N-α-syn by antigen-presenting microglia, Th1 or Th17 Teffs produce and secrete proinflammatory cytokines, such as TNF-α, IFN-γ, and Th17. Teffs can drive the innate immune response from a homeostatic state to a classically-activated state that serves to thwart invasion of pathogenic organisms, yet is also neurotoxic; a state that also acutely induced by agents such as aggregated N-α-syn, Aβ, MPP+, or lipopolysaccharide (LPS). Alternatively, microglia can be activated in a less robust manner by release of lower levels of inflammatory cytokines or by weaker stimuli from injured or dying neurons and other microglia. Prolonged stimulation leads to a chronically-activated microglia, which may further progress to a phenotype resembling classically-activated microglia, which is hyper-inflammatory and can lead to more rapid progression of disease. The inflammatory microglia phenotypes (reactive, chronic, and acute) themselves can contribute to further neuronal damage and death by the release of pro-inflammatory cytokines, reactive oxygen species (ROS), reactive nitrogen species (RNS), peroxynitrite (OONO-), glutamate, and arachidonic acid metabolites. Reactive and chronically-activated microglia may exhibit a mixed phenotype which in response to toxic stimuli, is inflammatory in nature, but can convert to an anti-inflammatory phenotype to direct repair and resolution of inflammation after attempted clearance of aggregated proteins and dead neurons. However in neurodegenerative disease with the limited regenerative properties of neurons, the capacity of chronically- and classically-activated microglia to further injure neurons, promote protein misfolding and aggregation through increased oxidative stress, coupled with their inability to completely clear aggregated proteins, restrict complete recovery and thus warrants therapeutic approaches to drive the microglia phenotype toward a more homeostatic state. Predominant microglia phenotypes are represented pictorially by increased size.

Figure 2

A PD immunization strategy is proposed to clear aggregated N-α-syn while attenuating the immune response to prevent dopaminergic neuronal death. As N-α-syn is presented to the immune system, antibodies against N-α-syn are produced to assist in aggregate clearance via microglia. Formulated with the vaccine is an adjuvant, such as vasoactive intestinal peptide (VIP), which stimulates induction of regulatory T cell (Treg) expansion and/or activity. Tregs migrate to areas of neuroinflammation and traverse the BBB, release IL-10, TGF-β, and FasL to drive activated microglia toward restoration of a homeostatic state or induce their apoptosis, thus inhibiting the production and secretion of pro-inflammatory cytokines, ROS, RNS, peroxynitrite (OONO-), and glutamate; diminishing accumulation of misfolded α-syn; attenuating neuroinflammation, ameliorating further neuronal injury and apoptosis; and interdicting PD progression. An efficacious antigen-specific vaccination strategy against aggregated, misfolded proteins would preclude the necessity for global immunosuppression, yet provide Treg-mediated control to drive classically- and chronically-activated microglia toward a predominant neurotrophic microglial phenotype (represented by larger microglia) that permits increased phagocytosis and proteasome function, as well as release of neurotrophic factors that support repair or clearance of injured neurons. Combined with the production of specific antibodies for cognate misfolded protein species, T cell regulated control over neuroinflammation would allow enhanced clearance of aggregated proteins, diminished neuronal injury or death, and ultimately interdiction of PD progression. Such an immunization strategy can be applied to develop vaccines for other neurodegenerative conditions, such as AD.