Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons

Abstract

2020) Neuropathology and Applied Neurobiology 46, 160-170 Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons Aims: The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients. Methods: A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MS patients.Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. Results: Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. Conclusion: These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.

Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

“…Furthermore, it would be important to use valid experimental models to reveal functions strictly linked to a specific MS pathogenic mechanism. The application of chimeric ex vivo MS models (CSF MS or T-cell MS chimeric models, [ 39 , 104 , 105 ]), consisting in incubation of EVs derived from MS biofluids onto mouse brain slices, together with biochemical, molecular, and electrophysiological analysis, might represent a good tool to study EVs roles in MS pathology.…”

“…The MS brain is also affected by another degenerative but potentially reversible phenomenon, namely inflammatory synaptopathy. Clinical research using transcranial magnetic stimulation (TMS) [ 37 ], pre-clinical studies conducted on an EAE model [ 29 , 38 ], and more recently chimeric ex-vivo models [ 29 , 39 ] have highlighted the presence of an inflammation-dependent decrease in the gamma-aminobutyric acid (GABA) ergic tone and an increase in the glutamatergic transmission in several MS/EAE brain areas. Such a synaptic transmission unbalances results in a diffuse synaptic dysfunction and loss that is mediated by pro-inflammatory molecules released by peripheral immune system cells, microglia, and astroglia [ 29 , 37 ].…”

A Single Nucleotide ADA Genetic Variant Is Associated to Central Inflammation and Clinical Presentation in MS: Implications for Cladribine Treatment

“…TNF is a major proinflammatory cytokine with a crucial pathogenic role in MS [ 3 , 4 , 24 ], extensively investigated in humans and MS animal models. These studies clearly showed that TNF is able to promote synaptic hyperexcitability and excitotoxic neurodegeneration.…”

“…Autoreactive T and B lymphocytes play a crucial role in disease pathogenesis [ 1 , 2 ]. T cells enter CNS and interact with local immune cells, initiating the inflammatory cascade that amplifies the immune response and leads to both excitotoxic synaptopathy and consequent brain damage [ 3 , 4 ]. Both CD4 + and CD8 + autoreactive T lymphocytes have been identified in demyelinating lesions [ 1 ] and have been related to the severity of axonal damage and inflammation [ 3 ].…”

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

“…AMPA and KA receptors are involved in the pathological pathway of excitotoxicity, and an inhibition of these receptors can decrease EAE severity [24]. One reason for increased glutamate receptor activity in EAE could be that T cells either interfere directly with the receptors or enhance glutamate transmission through the release of tumor necrosis factor α (TNF-α) [165]. TNF-α also activates glutamate release from microglia which can further trigger excitotoxicity [166].…”