Sameer Ghazi

Background: Multiple sclerosis (MS) is classified as an autoimmune disorder wherein the immune system attacks the myelin sheath, the protective covering of neurons in the brain and spinal cord.^1,2 The pathogenesis of MS involves lymphocytes, which originate in secondary lymphoid organs, migrating to the central nervous system (CNS), initiating inflammatory responses through degradation of myelin produced by oligodendrocytes.¹ Current therapies for multiple sclerosis (MS) include the use of monoclonal antibodies such as natalizumab alongside S1P modulators and teriflunomide. ² Recent advances have demonstrated that targeting B-lymphocytes for destruction might be more advantageous. ³ Imaging techniques, particularly magnetic resonance imaging (MRI), have been instrumental in confirming the effectiveness of B-lymphocyte targeted therapies by imaging techniques.⁴ These findings underscore the importance of focusing research on B-lymphocyte mechanisms and their roles in MS pathology to develop targeted therapeutic interventions that could potentially alter the course of the disease.

Objective: To examine the involvement of B-lymphocytes in the neuroinflammatory mechanisms underlying multiple sclerosis, with the aim of promoting the development of innovative therapeutics targeting these particular cells.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: “anti-CD20 therapeutics”, ” multiple sclerosis pathogenesis”, “novel therapies for multiple sclerosis”, “multiple sclerosis review articles”.

Results:  Studies in mice models for multiple sclerosis, including experimental autoimmune encephalomyelitis (EAE), provide insights into the effects of reducing B-cell proliferation on neuroinflammation.⁵ Inhibition of B-cell activating factor (BAFF), a cytokine that stimulates B-lymphocyte division, using agents like recombinant BAFF-R or NgR3-peptide and NgR-Fc fusion proteins, significantly decreases lymphocytic infiltrates in the central nervous system (CNS).⁵ To isolate the role of B-lymphocytes, a study demonstrated that a mice model of B-lymphocyte dependent EAE (using the antigen brain-derived myelin oligodendrocyte glycoprotein) produced a similar symptomatic profile to that of humans with MS.⁶ For example, optic neuritis was measured with FluoroMyelin and Olig2 dyes, which demonstrated myelin damage, while preserving oligodendrocyte cells and retinal ganglion cells.⁶ This is a specific outcome that supports the the B-cell model of MS.⁶ Furthermore, a 10-week study portrayed how the addition of anti-BAFF therapy in EAE mice models showed a significant measurable difference in leptomeningeal inflammation through MRI enhancement reduction.⁷ When anti-CD20 monoclonal antibodies were provided to human myelin oligodendrocyte glycoprotein-EAE mice in another experiment, there was significant attenuated brain volume loss.⁸ A clinical trial with ocrelizumab-treated patients demonstrated cessation of new lesion formation, effectively halting approximately 40% of whole brain volume loss over time.⁴ Additionally, there was no clear evidence of ongoing myelin loss within the ocrelizumab-treated cohort, indicating its ability to preserve myelin integrity over time.⁴

Conclusion: Recent research underscores the pivotal role B-cells play in the development of multiple sclerosis, pointing to new avenues for therapeutic intervention. Clinical applications of this knowledge, particularly the use of anti-CD20 drugs like ocrelizumab, have notably improved patient outcomes compared to traditional treatments. Ongoing investigations into B-cell activation and proliferation could further revolutionize pharmacotherapy for multiple sclerosis, offering new hopes for management and treatment of the disease. 

Works Cited:

1.  Olek MJ. Multiple Sclerosis. Ann Intern Med. 2021;174(6):ITC81-ITC96. doi:10.7326/AITC202106150
2. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review. JAMA. 2021;325(8):765-779. doi:10.1001/jama.2020.26858
3. Hauser SL, Cree BAC. Treatment of Multiple Sclerosis: A Review. Am J Med. 2020;133(12):1380-1390.e2. doi:10.1016/j.amjmed.2020.05.049
4. Kolind S, Gaetano L, Assemlal HE, et al. Ocrelizumab-treated patients with relapsing multiple sclerosis show volume loss rates similar to healthy aging. Mult Scler Houndmills Basingstoke Engl. 2023;29(6):741-747. doi:10.1177/13524585231162586
5. Bakhuraysah MM, Theotokis P, Lee JY, et al. B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF. Sci Rep. 2021;11(1):2890. doi:10.1038/s41598-021-82346-6
6. Joly S, Mdzomba JB, Rodriguez L, Morin F, Vallières L, Pernet V. B cell-dependent EAE induces visual deficits in the mouse with similarities to human autoimmune demyelinating diseases. J Neuroinflammation. 2022;19(1):54. doi:10.1186/s12974- 022-02416-y
7. Gupta K, Kesharwani A, Rua S, et al. BAFF blockade in experimental autoimmune encephalomyelitis reduces inflammation in the meninges and synaptic and neuronal loss in adjacent brain regions. J Neuroinflammation. 2023;20(1):229. doi:10.1186/s12974-023-02922-7
8. Pol S, Liang S, Schweser F, et al. Subcutaneous anti-CD20 antibody treatment delays gray matter atrophy in human myelin oligodendrocyte glycoprotein-induced EAE mice. Exp Neurol. 2021;335:113488. doi:10.1016/j.expneurol.2020.113488