Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders

Abstract

Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of antigen-specific CD4+ T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal survival. The destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T cells. Temporally, immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the CNS. Immune responses with predominate T cell subtypes may differentially manifest migratory, regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific stimuli. The final result is altered glial and neuronal behaviors that influence the disease course. Thus, discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression.Electronic supplementary materialThe online version of this article (doi:10.1186/2047-9158-3-25) contains supplementary material, which is available to authorized users.

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

“…This CD4+ T-cell phenotype is favoured by exposure to IL-4 and is characterised by the secretion of IL-4, IL-5 and IL-13, cytokines that act as important regulators of microglia and macrophage function (Dardalhon et al 2008;Derecki et al 2010;Shechter et al 2013). Thus, depending on the precise phenotype acquired by autoreactive CD4+ T-cells infiltrating the CNS, these cells can not only induce detrimental exacerbation of the neuroinflammatory process and neuron death associated to neurodegenerative disorders, but they also can exert a beneficial role and even therapeutic (Anderson et al 2014) by attenuating neuroinflammation and brain damage.…”

Porphyromonas gingivalissuppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer’s disease

“…Tregs are regulatory cells that provide immunological tolerance to the individual and actively restrain the immune system from distinguishing self from non-self (35). Tregs control and suppress the activities of specific effector T cells (Teffs) and myeloid lineage cells such as dendritic cells, macrophages, and microglia that contribute to innate immunity (35).…”

ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

“…These responses can either exacerbate neurotoxic responses or enhance neuroprotection (49). The specific destructive or protective mechanisms of these interactions are possibly linked to the relative numerical and functional dominance of Tregs, and their immunomodulatory effects on Teffs and macrophages/microglia populations in vivo.…”