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Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis

Current understanding of Multiple Sclerosis (MS) pathophysiology implicates perturbations in adaptive cellular immune responses, predominantly T cells, in Relapsing-Remitting forms (RRMS). Nevertheless, from a clinical perspective MS is a heterogeneous disease reflecting the heterogeneity of involve...

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Autores principales: Vakrakou, Aigli G., Paschalidis, Nikolaos, Pavlos, Eleftherios, Giannouli, Christina, Karathanasis, Dimitris, Tsipota, Xristina, Velonakis, Georgios, Stadelmann-Nessler, Christine, Evangelopoulos, Maria-Eleftheria, Stefanis, Leonidas, Kilidireas, Constantinos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9905713/
https://www.ncbi.nlm.nih.gov/pubmed/36761741
http://dx.doi.org/10.3389/fimmu.2023.1071623
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author Vakrakou, Aigli G.
Paschalidis, Nikolaos
Pavlos, Eleftherios
Giannouli, Christina
Karathanasis, Dimitris
Tsipota, Xristina
Velonakis, Georgios
Stadelmann-Nessler, Christine
Evangelopoulos, Maria-Eleftheria
Stefanis, Leonidas
Kilidireas, Constantinos
author_facet Vakrakou, Aigli G.
Paschalidis, Nikolaos
Pavlos, Eleftherios
Giannouli, Christina
Karathanasis, Dimitris
Tsipota, Xristina
Velonakis, Georgios
Stadelmann-Nessler, Christine
Evangelopoulos, Maria-Eleftheria
Stefanis, Leonidas
Kilidireas, Constantinos
author_sort Vakrakou, Aigli G.
collection PubMed
description Current understanding of Multiple Sclerosis (MS) pathophysiology implicates perturbations in adaptive cellular immune responses, predominantly T cells, in Relapsing-Remitting forms (RRMS). Nevertheless, from a clinical perspective MS is a heterogeneous disease reflecting the heterogeneity of involved biological systems. This complexity requires advanced analysis tools at the single-cell level to discover biomarkers for better patient-group stratification. We designed a novel 44-parameter mass cytometry panel to interrogate predominantly the role of effector and regulatory subpopulations of peripheral blood myeloid subsets along with B and T-cells (excluding granulocytes) in MS, assessing three different patient cohorts: RRMS, PPMS (Primary Progressive) and Tumefactive MS patients (TMS) (n=10, 8, 14 respectively). We further subgrouped our cohort into inactive or active disease stages to capture the early underlying events in disease pathophysiology. Peripheral blood analysis showed that TMS cases belonged to the spectrum of RRMS, whereas PPMS cases displayed different features. In particular, TMS patients during a relapse stage were characterized by a specific subset of CD11c+CD14+ CD33+, CD192+, CD172+-myeloid cells with an alternative phenotype of monocyte-derived macrophages (high arginase-1, CD38, HLA-DR-low and endogenous TNF-a production). Moreover, TMS patients in relapse displayed a selective CD4 T-cell lymphopenia of cells with a Th2-like polarised phenotype. PPMS patients did not display substantial differences from healthy controls, apart from a trend toward higher expansion of NK cell subsets. Importantly, we found that myeloid cell populations are reshaped under effective disease-modifying therapy predominantly with glatiramer acetate and to a lesser extent with anti-CD20, suggesting that the identified cell signature represents a specific therapeutic target in TMS. The expanded myeloid signature in TMS patients was also confirmed by flow cytometry. Serum neurofilament light-chain levels confirmed the correlation of this myeloid cell signature with indices of axonal injury. More in-depth analysis of myeloid subsets revealed an increase of a subset of highly cytolytic and terminally differentiated NK cells in PPMS patients with leptomeningeal enhancement (active-PPMS), compared to those without (inactive-PPMS). We have identified previously uncharacterized subsets of circulating myeloid cells and shown them to correlate with distinct disease forms of MS as well as with specific disease states (relapse/remission).
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spelling pubmed-99057132023-02-08 Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis Vakrakou, Aigli G. Paschalidis, Nikolaos Pavlos, Eleftherios Giannouli, Christina Karathanasis, Dimitris Tsipota, Xristina Velonakis, Georgios Stadelmann-Nessler, Christine Evangelopoulos, Maria-Eleftheria Stefanis, Leonidas Kilidireas, Constantinos Front Immunol Immunology Current understanding of Multiple Sclerosis (MS) pathophysiology implicates perturbations in adaptive cellular immune responses, predominantly T cells, in Relapsing-Remitting forms (RRMS). Nevertheless, from a clinical perspective MS is a heterogeneous disease reflecting the heterogeneity of involved biological systems. This complexity requires advanced analysis tools at the single-cell level to discover biomarkers for better patient-group stratification. We designed a novel 44-parameter mass cytometry panel to interrogate predominantly the role of effector and regulatory subpopulations of peripheral blood myeloid subsets along with B and T-cells (excluding granulocytes) in MS, assessing three different patient cohorts: RRMS, PPMS (Primary Progressive) and Tumefactive MS patients (TMS) (n=10, 8, 14 respectively). We further subgrouped our cohort into inactive or active disease stages to capture the early underlying events in disease pathophysiology. Peripheral blood analysis showed that TMS cases belonged to the spectrum of RRMS, whereas PPMS cases displayed different features. In particular, TMS patients during a relapse stage were characterized by a specific subset of CD11c+CD14+ CD33+, CD192+, CD172+-myeloid cells with an alternative phenotype of monocyte-derived macrophages (high arginase-1, CD38, HLA-DR-low and endogenous TNF-a production). Moreover, TMS patients in relapse displayed a selective CD4 T-cell lymphopenia of cells with a Th2-like polarised phenotype. PPMS patients did not display substantial differences from healthy controls, apart from a trend toward higher expansion of NK cell subsets. Importantly, we found that myeloid cell populations are reshaped under effective disease-modifying therapy predominantly with glatiramer acetate and to a lesser extent with anti-CD20, suggesting that the identified cell signature represents a specific therapeutic target in TMS. The expanded myeloid signature in TMS patients was also confirmed by flow cytometry. Serum neurofilament light-chain levels confirmed the correlation of this myeloid cell signature with indices of axonal injury. More in-depth analysis of myeloid subsets revealed an increase of a subset of highly cytolytic and terminally differentiated NK cells in PPMS patients with leptomeningeal enhancement (active-PPMS), compared to those without (inactive-PPMS). We have identified previously uncharacterized subsets of circulating myeloid cells and shown them to correlate with distinct disease forms of MS as well as with specific disease states (relapse/remission). Frontiers Media S.A. 2023-01-25 /pmc/articles/PMC9905713/ /pubmed/36761741 http://dx.doi.org/10.3389/fimmu.2023.1071623 Text en Copyright © 2023 Vakrakou, Paschalidis, Pavlos, Giannouli, Karathanasis, Tsipota, Velonakis, Stadelmann-Nessler, Evangelopoulos, Stefanis and Kilidireas https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Vakrakou, Aigli G.
Paschalidis, Nikolaos
Pavlos, Eleftherios
Giannouli, Christina
Karathanasis, Dimitris
Tsipota, Xristina
Velonakis, Georgios
Stadelmann-Nessler, Christine
Evangelopoulos, Maria-Eleftheria
Stefanis, Leonidas
Kilidireas, Constantinos
Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
title Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
title_full Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
title_fullStr Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
title_full_unstemmed Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
title_short Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
title_sort specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9905713/
https://www.ncbi.nlm.nih.gov/pubmed/36761741
http://dx.doi.org/10.3389/fimmu.2023.1071623
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