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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalNeuropathology and Applied Neurobiology
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Multiple Sclerosis
T-Lymphocytes
Neurons
Autoimmune Experimental Encephalomyelitis
Healthy Volunteers
Tumor Necrosis Factor-alpha
Glutamic Acid
Brain
Corpus Striatum
Relapsing-Remitting Multiple Sclerosis
Tumor Necrosis Factor Receptors
Microglia
Patch-Clamp Techniques
Flow Cytometry
Staining and Labeling

Keywords

  • glutamate-excitotoxicity
  • multiple sclerosis
  • striatum
  • synaptic transmission
  • T cells
  • tumour necrosis factor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Neurology
  • Clinical Neurology
  • Physiology (medical)

Cite this

@article{2a46b88122844b1083f75d931b8a9b11,
title = "Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons",
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.",
keywords = "glutamate-excitotoxicity, multiple sclerosis, striatum, synaptic transmission, T cells, tumour necrosis factor",
author = "A. Gentile and {De Vito}, F. and D. Fresegna and Rizzo, {F. R.} and S. Bullitta and L. Guadalupi and V. Vanni and F. Buttari and {Stampanoni Bassi}, M. and A. Leuti and V. Chiurchi{\`u} and Marfia, {G. A.} and G. Mandolesi and D. Centonze and A. Musella",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/nan.12569",
language = "English",
journal = "Neuropathology and Applied Neurobiology",
issn = "0305-1846",
publisher = "Wiley Blackwell",

}

TY - JOUR

T1 - Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons

AU - Gentile, A.

AU - De Vito, F.

AU - Fresegna, D.

AU - Rizzo, F. R.

AU - Bullitta, S.

AU - Guadalupi, L.

AU - Vanni, V.

AU - Buttari, F.

AU - Stampanoni Bassi, M.

AU - Leuti, A.

AU - Chiurchiù, V.

AU - Marfia, G. A.

AU - Mandolesi, G.

AU - Centonze, D.

AU - Musella, A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - glutamate-excitotoxicity

KW - multiple sclerosis

KW - striatum

KW - synaptic transmission

KW - T cells

KW - tumour necrosis factor

UR - http://www.scopus.com/inward/record.url?scp=85067460209&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067460209&partnerID=8YFLogxK

U2 - 10.1111/nan.12569

DO - 10.1111/nan.12569

M3 - Article

C2 - 31125471

AN - SCOPUS:85067460209

JO - Neuropathology and Applied Neurobiology

JF - Neuropathology and Applied Neurobiology

SN - 0305-1846

ER -