Glutamate, T cells and multiple sclerosis

Glutamate is the major excitatory neurotransmitter in the nervous system, where it induces multiple beneficial and essential effects. Yet, excess glutamate, evident in a kaleidoscope of acute and chronic pathologies, is absolutely catastrophic, since it induces excitotoxicity and massive loss of brain function. Both the beneficial and the detrimental effects of glutamate are mediated by a large family of glutamate receptors (GluRs): the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs), expressed by most/all cells of the nervous system, and also by many non-neural cells in various peripheral organs and tissues. T cells express on their cell surface several types of functional GluRs, and so do few other immune cells. Furthermore, glutamate by itself activates resting normal human T cells, and induces/elevates key T cell functions, among them: T cell adhesion, chemotactic migration, cytokine secretion, gene expression and more. Glutamate has also potent effects on antigen/mitogen/cytokine-activated T cells. Furthermore, T cells can even produce and release glutamate, and affect other cells and themselves via their own glutamate. Multiple sclerosis (MS) and its animal model Experimental Autoimmune Encephalomyelitis (EAE) are mediated by autoimmune T cells. In MS and EAE, there are excess glutamate levels, and multiple abnormalities in glutamate degrading enzymes, glutamate transporters, glutamate receptors and glutamate signaling. Some GluR antagonists block EAE. Enhancer of mGluR4 protects from EAE via regulatory T cells (Tregs), while mGluR4 deficiency exacerbates EAE. The protective effect of mGluR4 on EAE calls for testing GluR4 enhancers in MS patients. Oral MS therapeutics, namely Fingolimod, dimethyl fumarate and their respective metabolites Fingolimod-phosphate and monomethyl fumarate, can protect neurons against acute glutamatergic excitotoxic damage. Furthermore, Fingolimod reduce glutamate-mediated intracortical excitability in relapsing–remitting MS. Glatiramer acetate -COPAXONE®, an immunomodulator drug for MS, reverses TNF-α-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents in EAE-afflicted mice. With regard to T cells of MS patients: (1) The cell surface expression of a specific GluR: the AMPA GluR3 is elevated in T cells of MS patients during relapse and with active disease, (2) Glutamate and AMPA (a selective agonist for glutamate/AMPA iGluRs) augment chemotactic migrat