Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories.

Autor: Gross CC; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Schulte-Mecklenbeck A; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Steinberg OV; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Wirth T; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Lauks S; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Bittner S; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Schindler P; Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.; Neuroscience Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.; Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany., Baranzini SE; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Groppa S; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Bellmann-Strobl J; Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.; Neuroscience Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany., Bünger N; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Chien C; Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.; NeuroCure Clinical Research Center, Charité - Univeritäsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany., Dawin E; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Eveslage M; Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany., Fleischer V; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Gonzalez-Escamilla G; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Gisevius B; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany., Haas J; Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany., Kerschensteiner M; Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center (BMC), Faculty of Medicine, Ludwig Maximilians University of Munich, 81377 Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany., Kirstein L; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Korsukewitz C; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Lohmann L; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Lünemann JD; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Luessi F; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Meyer Zu Hörste G; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Motte J; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany., Ruck T; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany., Ruprecht K; Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany., Schwab N; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Steffen F; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Meuth SG; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany., Paul F; Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.; Neuroscience Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.; Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany., Wildemann B; Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany., Kümpfel T; Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center (BMC), Faculty of Medicine, Ludwig Maximilians University of Munich, 81377 Munich, Germany., Gold R; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany., Hahn T; Institute for Translational Psychiatry, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Zipp F; Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Klotz L; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany., Wiendl H; Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, University of Münster, 48149 Münster, Germany.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Mar 27; Vol. 16 (740), pp. eade8560. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1126/scitranslmed.ade8560
Abstrakt: One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis ( n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-β on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient's blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.
Databáze: MEDLINE