• Citer

B cell depletion therapy does not resolve chronic active multiple sclerosis lesions

par Maggi, Pietro ;Bulcke, Colin Vanden;Pedrini, Edoardo;Bugli, Céline;Sellimi, Amina;Wynen, Maxence;Stölting, Anna;Mullins, William W.A.;Kalaitzidis, Grigorios;Lolli, Valentina ;Perrotta, Gaetano ;El Sankari, Souraya;Duprez, T.;Li, Xu;Calabresi, Peter Arthur;Van Pesch, Vincent;Reich, Daniel S;Absinta, Martina
Référence EBioMedicine, 94, 104701
Publication Publié, 2023-08

Article révisé par les pairs

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: 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).