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

Abstract

J. Neurochem. (2010) 114, 1261–1276. 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.

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

“…Although the cause of PD remains unknown, aberrant innate and adaptive immune responses direct the tempo of nigral neuronal loss [1][2][3]. Associated immune activation is propagated through the accumulation and extracellular release of α-synuclein (α-syn), an endogenous self-protein [4].…”

“…Recent works from our own laboratories have served to highlight the role of effector T cells (Teffs) and regulatory T cells (Tregs) in attenuating such neuroinflammatory response cascades [12,13]. The balance between effector T cells and Treg activities leads to respective degenerative or protective effects in the brain, depending on defined T-cell polarity and cell phenotype [2,12,[14][15][16][17]. Immune profiles performed in patients with PD support a functional balance between the cells as circulating immunocyte profiles demonstrate increased proinflammatory profiles and decreased Treg function [18].…”

Inflammation and Adaptive Immunity in Parkinson's Disease

“…Currently, no curative treatments or treatments that interdict disease progression exist. Although the etiology of PD remains unknown, abundant evidence implicates immune system abnormalities and central nervous system (CNS) inflammation in disease pathobiology (McGeer et al 1988a;Stone et al 2009;Kosloski et al 2010). Harnessing inflammatory responses through targeted modulation of innate and adaptive immune responses has gained increasing interest in recent years as a potential therapeutic strategy.…”

Activated Immune Cells in Parkinson's Disease

“…However, the accumulation of misfolded protein aggregates in neurons might override intracellular clearance mechanisms and thus caused the disintegration of neurons. Subsequently, the released modified proteins might impose persistent stimulation on the peripheral immune system, which might in turn shift microglia toward a more proinflammatory state (Kosloski et al 2010). Indeed, CD4+ CD25-derived Teff exacerbated N-α-Syn-induced microglial inflammation and elicited a neurotoxic microglial response in vitro (Reynolds et al 2009a).…”