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While EBV-specific T-cell responses may influence disease progression, the impact of anti-CD20 B-cell depletion therapy (BCDT) on EBV-specific cellular and humoral immunity remains insufficiently characterized, particularly in comparison with healthy controls (HC), untreated people with MS (pwMS), and pwMS on different BCDT agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>Methods<\/jats:p>\n                    <jats:p>\n                      In this cross-sectional study, pwMS receiving BCDT, untreated pwMS at initial diagnosis (MS-ID), and age- and sex-matched HC were enrolled. EBV-specific and polyclonal CD8\n                      <jats:sup>+<\/jats:sup>\n                      and CD4\u207a T-cell responses were quantified and functionally characterized following stimulation with a EBV-derived peptide-mix predominately containing MHC class I binding peptides or Staphylococcus aureus enterotoxin B (SEB) using multiparametric flow cytometry. Anti-EBNA1- and anti-VCA-IgG levels were measured by ELISA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 183 participants were included: 54 pwMS receiving BCDT (mean age 47.0\u00b115.6 years; 31 females), 107 controls (47.2\u00b118.3 years, 54 females), and 22 MS-ID (33.4\u00b111.1 years, 20 females). EBV-specific CD8\u207a and CD4\u207a T-cell levels were similar in controls and MS-ID. In contrast, BCD-treated pwMS showed significantly lower frequencies of EBV-specific CD8\u207a (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.0001) and CD4\u207a T cells (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0004) than controls, and lower EBV-specific CD8\u207a T-cell levels than MS-ID (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0023). In contrast, polyclonally stimulated CD8\u207a T-cell responses were largely comparable across groups, indicating preserved polyclonal T-cell function. EBV-specific CD8\u207a T cells in both patients and controls were predominantly polyfunctional, coexpressing IFN\u03b3, IL-2, and TNF. Longer BCDT duration was associated with lower frequencies of EBV-specific CD8\u207a T cells (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0003). Ofatumumab-treated patients exhibited higher EBV-specific CD8\u207a T-cell frequencies than ocrelizumab-treated patients (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.0001). Despite BCDT, anti-EBNA1- and anti-VCA-IgG levels were significantly higher in pwMS than in MS-ID or controls, and were unrelated to treatment duration, disease duration, disability, or BCDT agents.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Unlike in treatment-na\u00efve pwMS, BCDT is associated with selectively lower EBV-specific T-cell frequencies while EBV-specific and polyclonal T-cell functionality was largely preserved. In contrast, EBV-specific antibody levels were persistently higher despite treatment. Given the remarkably high clinical efficacy of BCDT in this cohort, the findings support a prominent role of EBV-specific cellular immunity in ongoing MS pathophysiology and suggest that reduced EBV-reactive T-cell responses may contribute to this potency. Differences between BCDT agents warrant further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-026-04062-0","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:08:55Z","timestamp":1790593735000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The influence of anti-CD20-directed B cell depletion across different agents on Epstein-Barr virus-specific humoral and cellular immunity in patients with multiple sclerosis"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3311-2546","authenticated-orcid":false,"given":"Jakob","family":"St\u00f6gbauer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Bronder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Saenz K\u00e4mpfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celina","family":"Kron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Gonzalez-Escamilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Tocariu-Krick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Nemeth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlin","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven G.","family":"Meuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"St\u00fcve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Urschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiu","family":"Groppa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Sester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Fousse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"1","key":"4062_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/ene.13819","volume":"26","author":"R Dobson","year":"2019","unstructured":"Dobson R, Giovannoni G. 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