Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound
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 gr...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2023-01, Vol.120 (1), p.e2209944120-e2209944120 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1073/pnas.2209944120 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2209944120</identifier><identifier>PMID: 36574650</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-01, Vol.120 (1), p.e2209944120-e2209944120</ispartof><rights>Copyright National Academy of Sciences Jan 3, 2023</rights><rights>Copyright © 2022 the Author(s). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-c0810298a04aff5d24c364e4c6f0da51c222ff67d3d1870bcc98565b78ced4fc3</citedby><cites>FETCH-LOGICAL-c421t-c0810298a04aff5d24c364e4c6f0da51c222ff67d3d1870bcc98565b78ced4fc3</cites><orcidid>0000-0003-0057-324X ; 0000-0001-5908-4745 ; 0000-0002-3717-5176 ; 0000-0003-4287-2678 ; 0000-0001-5494-9885 ; 0000-0002-7569-8912 ; 0000-0002-4872-9189 ; 0000-0003-3855-4706</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9910615/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9910615/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36574650$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Janoschka, Claudia</creatorcontrib><creatorcontrib>Lindner, Maren</creatorcontrib><creatorcontrib>Koppers, Nils</creatorcontrib><creatorcontrib>Starost, Laura</creatorcontrib><creatorcontrib>Liebmann, Marie</creatorcontrib><creatorcontrib>Eschborn, Melanie</creatorcontrib><creatorcontrib>Schneider-Hohendorf, Tilman</creatorcontrib><creatorcontrib>Windener, Farina</creatorcontrib><creatorcontrib>Schafflick, David</creatorcontrib><creatorcontrib>Fleck, Ann-Katrin</creatorcontrib><creatorcontrib>Koch, Kathrin</creatorcontrib><creatorcontrib>Deffner, Marie</creatorcontrib><creatorcontrib>Schwarze, Anna-Sophie</creatorcontrib><creatorcontrib>Schulte-Mecklenbeck, Andreas</creatorcontrib><creatorcontrib>Metz, Imke</creatorcontrib><creatorcontrib>Meuth, Sven G</creatorcontrib><creatorcontrib>Gross, Catharina C</creatorcontrib><creatorcontrib>Meyer Zu Hörste, Gerd</creatorcontrib><creatorcontrib>Schwab, Nicholas</creatorcontrib><creatorcontrib>Kuhlmann, Tanja</creatorcontrib><creatorcontrib>Wiendl, Heinz</creatorcontrib><creatorcontrib>Stoll, Monika</creatorcontrib><creatorcontrib>Klotz, Luisa</creatorcontrib><title>Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological Sciences</subject><subject>Brain</subject><subject>Brain damage</subject><subject>CCR6 protein</subject><subject>Cerebrospinal fluid</subject><subject>Helper cells</subject><subject>Histology</subject><subject>Inflammation</subject><subject>Interleukin 17</subject><subject>Lymphocytes T</subject><subject>Mice</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - cerebrospinal fluid</subject><subject>Multiple Sclerosis - drug therapy</subject><subject>Natalizumab - pharmacology</subject><subject>Natalizumab - therapeutic 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Heinz</au><au>Stoll, Monika</au><au>Klotz, Luisa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2023-01-03</date><risdate>2023</risdate><volume>120</volume><issue>1</issue><spage>e2209944120</spage><epage>e2209944120</epage><pages>e2209944120-e2209944120</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>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. 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| 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 |
| title | Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound |
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