Minh Le

Background:  Multiple Sclerosis (MS) is one of the most common neurological autoimmune diseases and has been increasing in prevalence.^1,2 There are several types of MS, relapsing remittent (RRMS), secondary progressive (SPMS), and primary progressive MS (PPMS) with differing prognosis and treatment options, but they have several demyelinating lesions. An interesting development in the research of MS, is the emerging acceptance that B cells are important to MS, although the mechanism is still unclear.³ Understanding of multiple sclerosis has been increasing, but there are many key aspects of both the development and the cause of the disease that are not well understood.¹

Research Objective:  The purpose of this literature review is to analyze recent research concerning Multiple Sclerosis focusing on how the activities of immunoglobulins and their progenitors, B cells, may be involved in Multiple Sclerosis to fill the existing knowledge gap.

Methods:  Literature search was conducted on PubMed employing the following MESH terms: multiple sclerosis, Multiple Sclerosis / immunology, multiple sclerosis/epidemiology, Multiple Sclerosis etiology, Multiple Sclerosis / therapy, Multiple Sclerosis / pathology, Multiple Sclerosis / cerebrospinal fluid, Multiple Sclerosis / physiopathology, Multiple Sclerosis/blood, Multiple Sclerosis/Virology, Multiple Sclerosis/genetics, Multiple Sclerosis, Relapsing-Remitting / blood, Multiple Sclerosis, Relapsing-Remitting / drug therapy, Multiple Sclerosis, Relapsing-Remitting / immunology, Multiple Sclerosis / drug therapy with only published articles from 2017-2023 being included. Results were restricted to abstracts, reviews, clinical studies, and clinical trials. The abstracts of articles were then read to determine relevancy to research about immunoglobulins or B cells and their potential relevance to MS.

Results:  In one epidemiological study, the researchers found that exposure to cigarette smoke and Epstein Barr Virus (EBV) were the only strong risk factors that correlated with developing MS.⁴ Another research article, employing flow cytometry, BCR testing, and protein microarrays suggested a mechanism behind EBV increasing the risk of developing MS.⁵ MS39p2w174, a monoclonal antibody found in patients with MS, was isolated and shown to have a strong binding affinity to (leading to the targeting of) both EBNA1 (a protein essential to EBV) and GlialCAM, which is essential for Glial cells.⁵ Another article suggests that B cells may kill neuronal cells.⁶ B cells were isolated from the CSF of MS patients and lysed. The supernatant was placed on cytotoxic assays and induced apoptosis in model neuronal cells.⁶ Using proliferation assays, HLA-DR15 was found to increase the proliferation of immune cells through the blood brain barrier.⁷Additionally, an antigen designated RASGRP2 was determined by unbiased epitope discovery to be expressed by cortical neurons and B cells and recognized by CD4+ T cells.⁷ Flow cytometry of the contents of lesions demonstrated that CD19+ (B cells) are present in  statistically significant greater amounts than normal, while CD3+ (T cells) were not.⁸ By using drugs to deplete either B or T cells, B cells were shown to be essential to the autoproliferation to T cells while the reverse was not true.⁷

Ublituximab reduced CD20+ cells, non-plasma B cells, without lowering T cell counts, and lowered relapse rates and lesions in patients with RRMS but did not reduce the rate of disability.⁹ Another study found that Rituximab reduces relapse rates in both RRMS and SPMS, although this was inconsistent with other research on the drug.^10,11

Conclusions:  Recent research has greatly improved the understanding of Multiple Sclerosis. While there are many aspects of the disease that remain unknown or incompletely understood, there is strong evidence for the role of EBV in MS with a potential mechanism being misidentification of GlialCAM as an EBV protein. Furthermore, research has shown the importance of B cells in MS with treatment applications. One of the interesting findings was that lesion counts are not associated with disability with could change the way MS is evaluated for disability risk.

Works Cited.

1. Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019;26(1):27-40. doi:10.1111/ene.13819
2. Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816-1821. doi:10.1177/1352458520970841
3. Yu X, Graner M, Kennedy PGE, Liu Y. The Role of Antibodies in the Pathogenesis of Multiple Sclerosis. Front Neurol. 2020;11:533388. Published 2020 Oct 20. doi:10.3389/fneur.2020.533388
4. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
5. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7
6. Lisak RP, Nedelkoska L, Benjamins JA, et al. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J Neuroimmunol. 2017;309:88-99. doi:10.1016/j.jneuroim.2017.05.004
7. Jelcic I, Al Nimer F, Wang J, et al. Memory B Cells Activate Brain-Homing, Autoreactive CD4⁺ T Cells in Multiple Sclerosis. Cell. 2018;175(1):85-100.e23. doi:10.1016/j.cell.2018.08.011¹¹
8. Eggers EL, Michel BA, Wu H, et al. Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients. JCI Insight. 2017;2(22):e92724. Published 2017 Nov 16. doi:10.1172/jci.insight.92724
9. Lovett-Racke AE, Yang Y, Liu Y, et al. B cell depletion changes the immune cell profile in multiple sclerosis patients: One-year report. J Neuroimmunol. 2021;359:577676. doi:10.1016/j.jneuroim.2021.577676
10. Zecca C, Bovis F, Novi G, et al. Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience. Mult Scler. 2020;26(12):1519-1531. doi:10.1177/1352458519872889
11. Brancati S, Gozzo L, Longo L, Vitale DC, Drago F. Rituximab in Multiple Sclerosis: Are We Ready for Regulatory Approval?. Front Immunol. 2021;12:661882. Published 2021 Jul 6. doi:10.3389/fimmu.2021.661882