Maintenance of chronic neuroinflammation in multiple sclerosis via interferon signaling and CD8 T cell-mediated cytotoxicity Article Swipe
Syed Ali Raza
,
Yoshimi Enose‐Akahata
,
Anna Blazier
,
Lauren M. Guerra
,
Erin Beck
,
María I. Gaitán
,
Nyater Ngouth
,
Jefte M. Drijvers
,
Eric B. Dammer
,
Devan Moodley
,
Kory Johnson
,
Martina Absinta
,
Timothy J. Turner
,
Richard M. Ransohoff
,
Steven Jacobson
,
Dimitry Ofengeim
,
Ellen Cahir-McFarland
,
Daniel S. Reich
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.06.09.658729
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.06.09.658729
Chronic neuroinflammation and neurodegeneration are critical but unresolved drivers of disability accumulation in progressive multiple sclerosis (MS). Chronic active white matter lesions (CAL), identifiable radiologically as paramagnetic rim lesions (PRL), indicate progression-relevant chronic neuroinflammation. Using single-cell transcriptomics (scRNAseq) and T-cell receptor sequencing (scTCR-seq), we profiled cerebrospinal fluid (CSF) and blood immune cells of 34 radiologically characterized adults with MS (17 untreated, 6 treated with B-cell-depletion) and 5 healthy controls. Coupled with proteomics, we found PRL-associated enrichment of interferon (IFN) signaling and upregulation of TCR signaling in CSF and blood. This was accompanied by clonal expansion of CD8 + T effector memory (TEM) cells, with the highly expanded clonal cells exhibiting T helper type 1 (T H 1) and cytotoxic profiles. Validating the cytotoxic immune profile in blood using flow cytometry, we identified a cellular correlate of PRL exhibiting features of CD8 + T EMRA cells. Despite B-cell depletion, PRL-associated neuroinflammation, driven by myeloid activation and CD8 + T-cell cytotoxicity, persisted. Serum and CSF proteomic networks showed PRL-pertinent signatures, including networks unaffected by B-cell depletion. Using in silico perturbation, we nominated therapeutic targets, including MYD88 , TNF , MYC , TYK2 , JAK2, and BTK , for alleviating chronic neuroinflammation in MS. Our findings highlight mechanisms of chronic neuroinflammation in MS and point to potential biomarkers for monitoring disease progression.
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Concepts
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.06.09.658729
- OA Status
- green
- Cited By
- 1
- References
- 140
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4411208288
All OpenAlex metadata
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https://openalex.org/W4411208288Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.06.09.658729Digital Object Identifier
- Title
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Maintenance of chronic neuroinflammation in multiple sclerosis via interferon signaling and CD8 T cell-mediated cytotoxicityWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-06-11Full publication date if available
- Authors
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Syed Ali Raza, Yoshimi Enose‐Akahata, Anna Blazier, Lauren M. Guerra, Erin Beck, María I. Gaitán, Nyater Ngouth, Jefte M. Drijvers, Eric B. Dammer, Devan Moodley, Kory Johnson, Martina Absinta, Timothy J. Turner, Richard M. Ransohoff, Steven Jacobson, Dimitry Ofengeim, Ellen Cahir-McFarland, Daniel S. ReichList of authors in order
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https://doi.org/10.1101/2025.06.09.658729Publisher landing page
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://doi.org/10.1101/2025.06.09.658729Direct OA link when available
- Concepts
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Neuroinflammation, Multiple sclerosis, Cytotoxicity, Interferon, CD8, Cytotoxic T cell, Immunology, Cancer research, Medicine, Chemistry, Immune system, Inflammation, In vitro, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
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1Total citation count in OpenAlex
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2025: 1Per-year citation counts (last 5 years)
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140Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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