Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 1; p. e2209944120
• Main Authors: Janoschka, Claudia, Lindner, Maren, Koppers, Nils, Starost, Laura, Liebmann, Marie, Eschborn, Melanie, Schneider-Hohendorf, Tilman, Windener, Farina, Schafflick, David, Fleck, Ann-Katrin, Koch, Kathrin, Deffner, Marie, Schwarze, Anna-Sophie, Schulte-Mecklenbeck, Andreas, Metz, Imke, Meuth, Sven G., Gross, Catharina C., Meyer zu Hörste, Gerd, Schwab, Nicholas, Kuhlmann, Tanja, Wiendl, Heinz, Stoll, Monika, Klotz, Luisa
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.01.2023
• Subjects: Animals; Apoptosis; Biological Sciences; Brain; Brain damage; CCR6 protein; Cerebrospinal fluid; Helper cells; Histology; Inflammation; Interleukin 17; Lymphocytes T; Mice; Multiple sclerosis; Multiple Sclerosis - cerebrospinal fluid; Multiple Sclerosis - drug therapy; Natalizumab - pharmacology; Natalizumab - therapeutic use; Pathogenicity; Pathogens; Pathophysiology; Patients; Peripheral blood; Risk assessment; Th17 Cells; Virulence; pathogenicity; disease rebound; multiple sclerosis; natalizumab; Th17 cells
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2209944120

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, brain endothelial barrier impairment, and oligodendrocyte damage via induction of apoptotic pathways. This is accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT-treated patients. Notably, Th17 cells derived from NAT-treated patients, who later developed a disease rebound upon treatment cessation, displayed a distinct transcriptional pathogenicity profile associated with altered migratory properties. Accordingly, increased brain infiltration of patient Th17 cells was illustrated in a humanized mouse model and brain histology from a rebound patient. Therefore, peripheral blood-accumulated MCAM+CCR6+Th17 cells might be involved in rebound pathophysiology, and monitoring of changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk assessment in the future.