%0 Journal Article
%T Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis.
%A Sanna K
%A Bruno A
%A Balletta S
%A Caioli S
%A Nencini M
%A Fresegna D
%A Guadalupi L
%A Dolcetti E
%A Azzolini F
%A Buttari F
%A Fantozzi R
%A Borrelli A
%A Stampanoni Bassi M
%A Gilio L
%A Lauritano G
%A Vanni V
%A De Vito F
%A Tartacca A
%A Mariani F
%A Rovella V
%A Musella A
%A Centonze D
%A Mandolesi G
%J Front Immunol
%V 15
%N 0
%D 2024
%M 38911847
%F 8.786
%R 10.3389/fimmu.2024.1416133
%X UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.