Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis.

Autor:	Sanna K; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy., Bruno A; Ph.D. Program in Neuroscience, Department of Systems Medicine, Tor Vergata University, Rome, Italy.; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Balletta S; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Caioli S; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Nencini M; Synaptic Immunopathology Lab, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Roma, Rome, Italy., Fresegna D; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.; Synaptic Immunopathology Lab, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Roma, Rome, Italy., Guadalupi L; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.; Synaptic Immunopathology Lab, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Roma, Rome, Italy., Dolcetti E; Ph.D. Program in Neuroscience, Department of Systems Medicine, Tor Vergata University, Rome, Italy.; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Azzolini F; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Buttari F; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Fantozzi R; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Borrelli A; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Stampanoni Bassi M; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Gilio L; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Lauritano G; Ph.D. Program in Neuroscience, Department of Systems Medicine, Tor Vergata University, Rome, Italy.; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Vanni V; Synaptic Immunopathology Lab, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Roma, Rome, Italy., De Vito F; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Tartacca A; Ph.D. Program in Neuroscience, Department of Systems Medicine, Tor Vergata University, Rome, Italy., Mariani F; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy., Rovella V; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy., Musella A; Synaptic Immunopathology Lab, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Roma, Rome, Italy.; Department of Human Sciences and Quality of Life Promotion, University of Rome San Raffaele, Rome, Italy., Centonze D; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.; Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, IS, Italy., Mandolesi G; Synaptic Immunopathology Lab, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Roma, Rome, Italy.; Department of Human Sciences and Quality of Life Promotion, University of Rome San Raffaele, Rome, Italy.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jun 07; Vol. 15, pp. 1416133. Date of Electronic Publication: 2024 Jun 07 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1416133
Abstrakt:	Background: Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients. Methods: Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery. Results: SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod's protective effects. Conclusion: Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target. Competing Interests: DC is the recipient of an Institutional grant from Novartis Pharma. No personal compensation was received. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Sanna, Bruno, Balletta, Caioli, Nencini, Fresegna, Guadalupi, Dolcetti, Azzolini, Buttari, Fantozzi, Borrelli, Stampanoni Bassi, Gilio, Lauritano, Vanni, De Vito, Tartacca, Mariani, Rovella, Musella, Centonze and Mandolesi.)
Databáze:	MEDLINE
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