Protective autoimmunity against the enemy within: fighting glutamate toxicity

Schwartz, Michal; Shaked, Iftach; Fisher, Jasmin; Mizrahi, Tal; Schori, Hadas

doi:10.1016/s0166-2236(03)00126-7

Cited by 125 publications

(71 citation statements)

References 75 publications

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“…We suggest that an alternative approach to the problem necessitates modulation of microglial phenotype, thereby not only minimizing the risk of malfunctioning microglia, but also exploiting microglial assistance in withstanding Ab and other toxic agents associated with degeneration such as glutamate and oxidative stress. The phenotype acquired by microglia exposed to activated T cells is not destructive as it does not produce inflammatory processes [21]. Thus, locally activated T cells, irrespective of the identity of the antigen(s) residing in the damaged site, can transform adjacent microglia from an enemy into a friend.…”

Section: Discussionmentioning

confidence: 99%

“…It was previously proposed by our group that one way in which autoimmune T cells help to fight off destructive self compounds is by controlling the activity of microglia [21]. Using organotypic hippocampal slice cultures (OHSC), our group showed that after rat microglia are pretreated with Ab 1-40 , they become cytotoxic to neural tissue and their ability to express MHC-II is suppressed (Butovsky et al, unpublished observations).…”

Section: T Cells Prevent Microglia From Developing An Inflammatory Cymentioning

confidence: 95%

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Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells

et al. 2004

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Neurodegenerative diseases differ in etiology but are propagated similarly. We show that neuronal loss caused by intraocular injection of aggregated b-amyloid was significantly greater in immunodeficient mice than in normal mice. The neurodegeneration was attenuated or augmented by elimination or addition, respectively, of naturally occurring CD4 + CD25 + regulatory T cells (Treg). Vaccination with retina-derived antigens or with the synthetic copolymer glatiramer acetate (Copolymer-1, Cop-1), but not with b-amyloid, reduced the ocular neuronal loss. In mouse hippocampal slices, microglia encountering activated T cells overcame the cytotoxicity of aggregated b-amyloid. These findings support the concept of "protective autoimmunity", show that a given T cell-based vaccination is protective at a particular site irrespective of toxicity type, and suggest that locally activated T cells induce a microglial phenotype that helps neurons withstand the insult. Alzheimer's and other neurodegenerative diseases might be arrested or retarded by vaccination with Cop-1 or related compounds or by treatment with compounds that weaken Treg suppression.

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Section: Discussionmentioning

confidence: 99%

Section: T Cells Prevent Microglia From Developing An Inflammatory Cymentioning

confidence: 95%

Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells

et al. 2004

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“…For instance, in nerve transection models of glutamate injury, microglial activity is central to the healing response [65]. By contrast, IFN-primed microglia then treated with LPS will adopt a phenotype adapted for defensive immunity, and hence cytotoxicity.…”

Section: Regulation Of Microglia-mediated Neuroprotectionmentioning

confidence: 99%

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Ashton

Glass²

2007

278

249

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Endocannabinoids are released following brain injury and may protect against excitotoxic damage during the acute stage of injury. Brain injury also activates microglia in a secondary inflammatory phase of more widespread damage. Most drugs targeting the acute stage are not effective if administered more than 6 hours after injury. Therefore, drugs targeting microglia later in the neurodegenerative cascade are desirable. We have found that cannabinoid CB2 receptors are upregulated during the activation of microglia following brain injury. Specifically, CB2-positive cells appear in the rat brain following both hypoxia-ischemia (HI) and middle cerebral artery occlusion (MCAO). This may regulate post-injury microglial activation and inflammatory functions. In this paper we review in vivo and in vitro studies of CB2 receptors in microglia, including our results on CB2 expression post-injury. Taken together, studies show that CB2 is upregulated during a process in which microglia become primed to proliferate, and then become fully reactive. In addition, CB2 activation appears to prevent or decrease microglial activation. In a rodent model of Alzheimer's disease microglial activation was completely prevented by administration of a selective CB2 agonist. The presence of CB2 receptors in microglia in the human Alzheimer's diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies. We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation. CB2 specific compounds have considerable therapeutic appeal over CB1 compounds, as the exclusive expression of CB2 on immune cells within the brain provides a highly specialised target, without the psychoactivity that plagues CB1 directed therapies.

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“…These observations of beneficial effects of autoreactive T cells led to the introduction of the term "protective autoimmunity" implying that the recognition of an exposed self antigen by T cells can result in protection, repair and maintenance of the functional integrity of a tissue rather than the initiation of an autoimmune process. (Schwartz et al, 2003;Schwartz & Shechter, 2010). Regulatory T cells (CD4 + CD25 + Foxp3 + ) that suppress autoimmune activity seem to play a central role in protective autoimmunity.…”

Section: Adaptive Immunitymentioning

confidence: 99%

Traumatic Brain Injury and Inflammation: Emerging Role of Innate and Adaptive Immunity

Dardiotis¹,

Karanikas²,

Paterakis³

et al. 2012

Brain Injury - Pathogenesis, Monitoring, Recovery and Management

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Protective autoimmunity against the enemy within: fighting glutamate toxicity

Cited by 125 publications

References 75 publications

Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells

Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Traumatic Brain Injury and Inflammation: Emerging Role of Innate and Adaptive Immunity

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Protective autoimmunity against the enemy within: fighting glutamate toxicity

Cited by 125 publications

References 75 publications

Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells

Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Traumatic Brain Injury and Inflammation: Emerging Role of Innate and Adaptive Immunity

Contact Info

Product

Resources

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Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells

Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells