Protective autoimmunity against the enemy within: fighting glutamate toxicity

doi:10.1016/S0166-2236(03)00126-7

Trends in Neurosciences

Volume 26, Issue 6, June 2003, Pages 297-302

https://doi.org/10.1016/S0166-2236(03)00126-7 Get rights and content

Abstract

Glutamate, a key neurotransmitter, is pivotal to CNS function. Alterations in its concentration can be dangerous, as seen for example in acute injuries of the CNS, chronic neurodegenerative disorders and mental disorders. Its homeostasis is attributed to the efficient removal of glutamate from the extracellular milieu by reuptake via local transport mechanisms. Our recent studies suggest that glutamate, either directly or indirectly, elicits a purposeful systemic T-cell-mediated immune response directed against immunodominant self-antigens that reside at the site of glutamate-induced damage. We suggest that the harnessed autoimmunity (which we have termed ‘protective autoimmunity’) helps the resident microglia in their dual function as antigen-presenting cells (serving the immune system) and as cells that clear the damaged site of potentially harmful material (serving the nervous system). The interplay between glutamate and an adaptive immune response illustrates the bidirectional dialog between the immune and nervous systems, under both physiological and pathological conditions. These results point to the possible development of a therapeutic vaccination with self-antigens, or with antigens cross-reactive with self-antigens, as a way to augment autoimmunity without inducing an autoimmune disease, thus providing a safe method of limiting degeneration. This approach, which boosts a physiological mechanism for the regulation of glutamate, and possibly also that of other self-compounds, might prove to be a feasible strategy for therapeutic protection against glutamate-associated neurodegenerative or mental disorders.

Section snippets

Protective autoimmunity – a physiological response to CNS insult

Early studies in rats, using a partial crush injury of the optic nerve as a model, showed that systemic injection of T cells that were specific to myelin-associated peptides reduced the post-injury loss of neurons and fibers. Thus, significantly more retinal ganglion cells (RGCs) survive injury in rats treated with myelin-specific T cells than in rats treated with T cells specific to an irrelevant antigen or not treated at all [34]. Similar findings were obtained for recovery of motor activity

T-cell-dependent protection against glutamate toxicity

Both an excess and a deficiency of glutamate can lead to neuronal death (review in Ref. [48]). An excess of glutamate has been documented in several animal models of CNS insults, including head trauma, spinal cord injury and optic nerve injury 49, 50, 51. Glutamate intoxication of RGCs is a useful animal model for evaluating the role of T cells in the ability of an animal to withstand such toxicity [52]. Glutamate injected into the vitreous humor of mice is significantly more toxic if the mice

Glutamate toxicity evokes a specific autoimmune response directed against immunodominant antigens residing at the damaged site

Myelin proteins and peptides failed to boost the T-cell-dependent protection against glutamate toxicity in the eye 37, 52, whereas vaccination with antigens that are immunodominant in the eye led to significant protection 37, 59, 60. It therefore appeared that a peptide that boosts beneficial autoimmunity resides at the site of stress and is derived from a protein that is also potentially capable of inducing an autoimmune disease at the same site. Antigen specificity is needed for homing of the

Regulation of protective autoimmunity

As summarized in the preceding section, it seems that the T cells that protect against CNS insults have the same phenotype as those implicated in the pathogenesis of autoimmune disease [43]. The difference in their effects apparently lies in their regulation [44]. Evidently, however, Th1 cells specific to a cryptic epitope 34, 61 or to a modified pathogenic epitope [63] are protective, whereas Th1 cells specific to a pathogenic epitope within the same immunodominant protein can be both

Mode of action of protective autoimmunity

After a CNS insult, the site of injury is depleted of astrocytes (the usual buffering cells) [65] and repopulated by macrophages, microglia, or both 66, 67. Thus, under stressful conditions, microglia can migrate to the damaged site and act both as antigen-presenting cells and as cells that remove potentially harmful materials (e.g. by uptake of glutamate – a nerve-related activity). Their ability to express glutamate transporters has recently been described [21] and their potential for acting

A therapeutic vaccine for glutamate-associated neurodegenerative diseases

Deviation of glutamate from physiological concentrations is common to numerous diseases. This fact, coupled with the finding that glutamate concentrations can be controlled by harnessing of the systemic adaptive immunity against antigens residing in the site of damage, encouraged us to seek a way to boost this adaptive immune response without causing an autoimmune disease to develop.

Our experiments in rats and mice have shown that vaccination with the synthetic polymer Cop-1 activates a wide

Concluding remarks

Our findings show for the first time that glutamate is controlled, not only locally but also systemically, by the adaptive arm of the immune response directed against antigens residing at the site of glutamate stress. They provide the first direct evidence that glutamate-induced immune responses mediate an ongoing dialog between T cells and CNS tissue. As glutamate is a key player in brain activity, and lack of its proper regulation is a key factor in cognitive, neural, psychogenic and

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Trends in Neurosciences

Protective autoimmunity against the enemy within: fighting glutamate toxicity

Abstract

Section snippets

Protective autoimmunity – a physiological response to CNS insult

T-cell-dependent protection against glutamate toxicity

Glutamate toxicity evokes a specific autoimmune response directed against immunodominant antigens residing at the damaged site

Regulation of protective autoimmunity

Mode of action of protective autoimmunity

A therapeutic vaccine for glutamate-associated neurodegenerative diseases

Concluding remarks

Prog. Neurobiol.

Neuron

J. Biol. Chem.

J. Neuroimmunol.

Neurosci. Lett.

FEBS Lett.

J. Neurol. Sci.

J. Neuroimmunol.

Neurosci. Lett.

Lancet

J. Neuroimmunol.

Exp. Neurol.

Trends Pharmacol. Sci.

Trends Neurosci.

Exp. Neurol.

Pain

J. Neuroimmunol.

Trends Immunol.

Exp. Eye Res.

Trends Neurosci.

Neuroscience

Trends Mol. Med.

Glutamate: a neurotransmitter in mammalian brain

J. Neurochem.

Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences

Curr. Opin. Neurol.

Axonal loss in normal-appearing white matter in a patient with acute MS

Neurology

Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability

Arch. Neurol.

Multiple sclerosis as a by-product of the failure to sustain protective autoimmunity: a paradigm shift

Neuroscientist

Multiple sclerosis: a two-stage disease

Nat. Immun.

Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function

J. Neurochem.

Expression of excitatory amino acid transporter-2 (EAAT-2) and glutamine synthetase (GS) in brain macrophages and microglia of SIVmac251-infected macaques

Neuropathol. Appl. Neurobiol.

Long-term activation of the glutamatergic system associated with n-methyl-d-aspartate receptors after postischemic hypothermia in gerbils

Neurosurgery

A novel neuronal messenger molecule in brain: the free radical, nitric oxide

Ann. Neurol.

NMDA receptors activate the arachidonic acid cascade system in striatal neurons

Nature

Glutamate induces oxidative stress not mediated by glutamate receptors or cystine transporters: protective effect of melatonin and other antioxidants

J. Pineal Res.

Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson's disease

J. Neurochem.

Oxygen-derived free radicals in postischemic tissue injury

N. Engl. J. Med.

Involvement of the cystine transport system xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons

J. Immunol.

CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity

Nat. Neurosci.

Na+-dependent high-affinity glutamate transport in macrophages

J. Immunol.

Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat

Glia