{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T06:06:00Z","timestamp":1771394760385,"version":"3.50.1"},"reference-count":23,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The early identification of patients with highly active multiple sclerosis (HAMS) is crucial for guiding therapeutic decisions and initiating high-efficacy treatment strategies. This study aimed to characterize peripheral immune profiles that can distinguish between patients who are candidates for intensive therapy at disease onset and in later stages. Using spectral flow cytometry, we identified distinct immune signatures to differentiate early-stage patients from those with refractory, long-standing disease. In newly diagnosed individuals, decreased herpesvirus entry mediator (HVEM) expression on effector T helper (Th) cells distinguished HAMS from non HAMS cases. In contrast, patients with therapeutic resistance exhibited reduced CD28 expression on na\u00efve regulatory and CD8+ T cells. Disability progression was associated with elevated HVEM on classical monocytes, decreased CD70 on CD56bright natural killer cells (NK), and lower programmed cell death protein 1 (PD-1) expression on memory Th cells. Notably, CD28 expression on terminal effector CD8+ T cells and HVEM levels on plasmablasts emerged as strong predictors of progression independent of relapse activity, while higher PD-1 memory Th cell frequencies predicted clinical stability. This study identifies two panels of immune biomarkers: one distinguishing candidates for early high-efficacy intervention, and another defining patients with refractory disease. The immunological landscape of HAMS evolves across disease stages. In addition, we defined progression-associated markers detectable at the outset of follow-up, enabling the timely recognition of patients at heightened risk of disability accumulation, discriminating between neurodegeneration-driven and inflammation-driven mechanisms of progression.<\/jats:p>","DOI":"10.3390\/ijms27041907","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T14:55:47Z","timestamp":1771253747000},"page":"1907","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Checkpoint Signatures Reveal Stage-Specific Biomarkers for High-Activity Multiple Sclerosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9171-2606","authenticated-orcid":false,"given":"MariPaz","family":"L\u00f3pez-Molina","sequence":"first","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Torres Iglesias","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Vidal","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3767-4074","authenticated-orcid":false,"given":"Nerea","family":"D\u00edaz Gamero","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1lvaro","family":"S\u00e1nchez-Pascual","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Chamorro","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0093-9707","authenticated-orcid":false,"given":"Roberto","family":"Lozano-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Immune Innate Response Group, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumor Immunology Laboratory, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo","family":"S\u00e1enz de Santa Mar\u00eda-Diez","sequence":"additional","affiliation":[{"name":"Immune Innate Response Group, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumor Immunology Laboratory, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"del Prado-Montero","sequence":"additional","affiliation":[{"name":"Immune Innate Response Group, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumor Immunology Laboratory, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"L\u00f3pez-Collazo","sequence":"additional","affiliation":[{"name":"Immune Innate Response Group, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumor Immunology Laboratory, La Paz Hospital Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) of Respiratory Diseases (CIBERES), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Exuperio","family":"D\u00edez-Tejedor","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5481-0514","authenticated-orcid":false,"given":"Fernando","family":"Laso-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"},{"name":"Translational Stroke Laboratory (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Guti\u00e9rrez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8765-6341","authenticated-orcid":false,"given":"Laura","family":"Otero-Ortega","sequence":"additional","affiliation":[{"name":"Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research IdiPAZ, La Paz University Hospital, Universidad Aut\u00f3noma de Madrid, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41573-022-00477-5","article-title":"Thinking outside the box: Non-canonical 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