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

Area of Science:

• Neuroimmunology
• Multiple Sclerosis Pathogenesis
• Therapeutic Development

Background:

• Chronic active lesions (CAL) in multiple sclerosis (MS) contribute to disease progression, including progression independent of relapse activity (PIRA).
• Understanding the impact of targeting specific lymphocyte populations is crucial for developing advanced MS therapies to manage chronic inflammation.

Purpose of the Study:

• To bioinformatically predict the effects of lymphocyte depletion in CAL.
• To assess the in vivo MRI changes in paramagnetic rims (PRL) in MS patients treated with anti-CD20 antibodies compared to untreated patients.

Main Methods:

• Analysis of published lymphocyte single-cell transcriptomes from MS lesions.
• Gene-regulatory-network machine-learning to predict effects of lymphocyte subpopulation depletion.
• In vivo MRI assessment of PRL changes over approximately 2 years in treated and untreated MS patients.

Main Results:

• CD20 B-cells constituted only 4.3% of lymphocytes in CAL, but their depletion was predicted to impact microglial genes related to iron metabolism, hypoxia, and antigen presentation.
• No disappearance of treated PRL was observed over follow-up; no treatment effect on PRL volume, magnetic susceptibility, or T1 time.
• Progression independent of relapse activity (PIRA) occurred in 20% of treated patients, more frequently in those with four or more PRL.

Conclusions:

• Anti-CD20 therapies did not fully resolve paramagnetic rims (PRL) after 2-year MRI follow-up, despite predicted effects on microglia-mediated inflammatory networks.
• Potential reasons for limited efficacy include low B-cell turnover in MS lesions, inefficient blood-brain barrier penetration of anti-CD20 antibodies, and a scarcity of B-cells within CAL.