| Title: |
B cell depletion therapy does not resolve chronic active multiple sclerosis lesions. |
| Authors: |
Maggi, P.; Bulcke, C.V.; Pedrini, E.; Bugli, C.; Sellimi, A.; Wynen, M.; Stölting, A.; Mullins, W.A.; Kalaitzidis, G.; Lolli, V.; Perrotta, G.; El Sankari, S.; Duprez, T.; Li, X.; Calabresi, P.A.; van Pesch, V.; Reich, D.S.; Absinta, M. |
| Publication Year: |
2023 |
| Collection: |
Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| Subject Terms: |
Adult; Humans; Multiple Sclerosis/metabolism; B-Lymphocytes; Blood-Brain Barrier/metabolism; Magnetic Resonance Imaging; Iron; Anti-CD20 treatment; Machine learning; Paramagnetic rims; Single cell RNA sequencing; Susceptibility-based MRI |
| Description: |
Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS). |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
2352-3964 |
| Relation: |
EBioMedicine; https://iris.unil.ch/handle/iris/98908; serval:BIB_4C906A17A400; 001040162200001 |
| DOI: |
10.1016/j.ebiom.2023.104701 |
| Availability: |
https://iris.unil.ch/handle/iris/98908; https://doi.org/10.1016/j.ebiom.2023.104701 |
| Accession Number: |
edsbas.6BA0FC07 |
| Database: |
BASE |