1. Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons
- Author
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Livia Guadalupi, Antonietta Gentile, Fabio Buttari, Alessandra Musella, Francesca Romana Rizzo, Diego Fresegna, F. De Vito, M Stampanoni Bassi, Georgia Mandolesi, Silvia Bullitta, Valentina Vanni, Alessandro Leuti, Diego Centonze, Valerio Chiurchiù, and Girolama Alessandra Marfia
- Subjects
Adult ,Male ,0301 basic medicine ,Histology ,T-Lymphocytes ,striatum ,T cells ,Excitotoxicity ,Glutamic Acid ,multiple sclerosis ,Settore MED/26 ,medicine.disease_cause ,glutamate-excitotoxicity ,Pathology and Forensic Medicine ,03 medical and health sciences ,Glutamatergic ,tumour necrosis factor ,0302 clinical medicine ,Physiology (medical) ,medicine ,Animals ,Humans ,synaptic transmission ,Patch clamp ,Neurons ,Microglia ,Chemistry ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Glutamate receptor ,Brain ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Synapses ,Cancer research ,Female ,Tumor necrosis factor alpha ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2019