{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:20:02Z","timestamp":1790202002547,"version":"4.1.0"},"reference-count":20,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T00:00:00Z","timestamp":1711843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)\u2010associated neurological immune\u2010related adverse events (nirAE).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A systematic literature review was made, with case observations of a melanoma and a non\u2010small cell lung cancer (NSCLC) patient who developed ICI\u2010associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two patients receiving ipilimumab\/nivolumab for melanoma and chemotherapy\/pembrolizumab for NSCLC developed nirAE in the form of myocarditis\/myositis\/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c\u2010LETM), respectively. Intrathecal inflammation with chemokine C\u2010X\u2010C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4\/CD8 T cell ratio in blood, and depressed programmed death\u20101 (PD\u20101) expression on CSF T cells; the c\u2010LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first\u2010line treatment. The NSCLC case improved upon administration of B cell\u2010depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI\u2010associated LETM case with intrathecal CXCL13 elevation, three cases with ICI\u2010associated aquaporin\u20104 antibody neuromyelitis spectrum disorder, and evidence of B cell\u2010mediated toxicity based on antibody\u2010mediated immune pathologies in ICI\u2010associated immune\u2010related adverse events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI\u2010associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and\/or recruitment of cognate immune cells.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.16279","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T06:30:20Z","timestamp":1711953020000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Beyond T cell toxicity \u2013 Intrathecal chemokine CXCL13 indicating B cell involvement in immune\u2010related adverse events following checkpoint inhibition: A two\u2010case series and literature review"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1568-089X","authenticated-orcid":false,"given":"Ferdinand","family":"Otto","sequence":"first","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Seiberl","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Bieler","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-5595","authenticated-orcid":false,"given":"Tobias","family":"Moser","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waltraud","family":"Kleindienst","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Wallner\u2010Essl","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology Christian\u2010Doppler University Hospital, Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Koelblinger","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wipfler","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Harrer","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE  Salzburg Austria"},{"name":"Department of Dermatology and Allergology Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,31]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00600-w"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0000000000000669"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.06.012"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-1240"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ensci.2021.100324"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2016.12.001"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5695"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0617-x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703481"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2018.1489246"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000967"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.547"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002588"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-020-00975-7"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12841"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-021-00272-1"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01440"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.044703"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.3923"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10870-6"}],"container-title":["European Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.16279","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T12:18:37Z","timestamp":1717762717000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ene.16279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,31]]},"references-count":20,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1111\/ene.16279"],"URL":"https:\/\/doi.org\/10.1111\/ene.16279","archive":["Portico"],"relation":{},"ISSN":["1351-5101","1468-1331"],"issn-type":[{"value":"1351-5101","type":"print"},{"value":"1468-1331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,31]]},"assertion":[{"value":"2023-08-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e16279"}}