Zachary Payne

Background: Multiple Sclerosis (MS) is a neurological disease affecting myelinated nerves of the central nervous system (CNS).¹ The destruction of myelin of nerve axons in the disease leads to a variety of CNS symptoms.^1-5 Important factors which increase risk for MS include being female, smoking, obesity, and Vitamin D deficiency.^2,6 Epstein-Barr virus (EBV) is a herpes virus which infects B cells in our immune system.³ EBV is a prevalent virus with over 90% of the adult population being affected worldwide.⁴ Those diagnosed with MS are much more likely to be EBV positive.¹

Objective: In this narrative review, we explored how the complex relationship between Multiple Sclerosis and the Epstein-Barr virus may be a key target for new therapies for MS patients.

Search Methods: An online search in PubMed database was conducted from 2018 to 2023 using the following keywords: “Multiple sclerosis”, “Epstein-Barr Virus”, “Autoreactive B-Cells”, “Defective T-Cells”.

Results: Brain sections from MS patients were analyzed for the presence of CD8+ cytotoxic T-cells.⁷ MHC class 1 pentamers coupled to immunodominant peptides from EBV and coded latent and lytic proteins, as well as cmv proteins and influenza A virus proteins as controls, were used as stainings.⁷ CD8+ T-cells were specific to EBV and contributed to local inflammation.⁷ Activation of Autoimmunitive B-cells are believed to be responsible for proliferation of MS.⁸ Normally, activated CD4+ T-Cells interact with B-cells through a T-Cell receptor, peptide, and MHC Class 2 signal followed by the Binding of CD40L and CD40.⁸ These multiple signals lead to the activation of B-cells which release inflammatory cytokines.⁸ 12 patients were enrolled in an open label dose escalation Phase 1 study and were given four doses of humanized anti-CD40L IV infusions every other week.⁸ The treatment was well tolerated and there was a decrease in inflammation and an increase in anti-inflammatory cytokines such as CD25+ T-cells and IL-10.⁸ FOXP3 is essential for the production and normal function of regulatory T-cells which play an important role in preventing autoimmunity and normally produce anti-inflammatory cytokines such as interleukin-10 and TGF-beta.⁹ When regulatory T-cells lack this critical transcription factor, cytotoxic T-cells become defective and autoimmune disorders can occur.⁹ CNS tissue from patients with multiple sclerosis, Parkinson’s disease, and healthy controls were stained with specific antigens to proteins such as FOXP3.⁹ Autopsies of the CNS tissue found FOXP3 expressing cells were sparse in MS patients.⁹ An open label phase one trial treated MS patients with escalating doses of EBV specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1, and latent membrane protein 2.¹⁰ Patients showed clinical Improvement with both symptomatic and objective neurological Improvement with a reduction in fatigue, reduced IgG production, and improved quality of life.¹⁰

Conclusions: Studies found CD8 positive Cytotoxic T-Cells in CNS tissue of MS patients were specific to EBV. CNS tissue of MS patients also presented with absent FOXP3 expressing regulatory T-Cells. The blocking of autoreactive EBV infected B-Cells via humanized anti-CD40L IV infusions leads to improved clinical outcomes among MS patients. Additionally, EBV Specific T-Cell therapy showed clinical improvement in MS patients.

Works Cited:

1. 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
2. Kim D, Witt EE, Schubert S, et al. Peripheral T-Cells, B-Cells, and Monocytes from Multiple Sclerosis Patients Supplemented with High-Dose Vitamin D Show Distinct Changes in Gene Expression Profiles. Nutrients. 2022;14(22):4737. Published 2022 Nov 9. doi:10.3390/nu14224737
3. Houen G, Trier NH, Frederiksen JL. Epstein-Barr Virus and Multiple Sclerosis. Front Immunol. 2020;11:587078. Published 2020 Dec 17. doi:10.3389/fimmu.2020.587078
4. Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis [published correction appears in JCI Insight. 2020 Oct 15;5(20):]. JCI Insight. 2018;3(22):e124714. Published 2018 Nov 15. doi:10.1172/jci.insight.124714
5. Bar-Or A, Pender MP, Khanna R, et al. Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies [published correction appears in Trends Mol Med. 2021 Apr;27(4):410-411]. Trends Mol Med. 2020;26(3):296-310. doi:10.1016/j.molmed.2019.11.003
6. Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019;26(1):27-40. doi:10.1111/ene.13819
7. Serafini B, Rosicarelli B, Veroni C, Mazzola GA, Aloisi F. Epstein-Barr Virus-Specific CD8 T Cells Selectively Infiltrate the Brain in Multiple Sclerosis and Interact Locally with Virus-Infected Cells: Clue for a Virus-Driven Immunopathological Mechanism. J Virol. 2019;93(24):e00980-19. Published 2019 Nov 26. doi:10.1128/JVI.00980-19
8. Fadul CE, Mao-Draayer Y, Ryan KA, et al. Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1096. Published 2021 Oct 15. doi:10.1212/NXI.0000000000001096
9. Bell L, Lenhart A, Rosenwald A, Monoranu CM, Berberich-Siebelt F. Lymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells. Front Immunol. 2020;10:3090. Published 2020 Jan 15. doi:10.3389/fimmu.2019.03090
10. Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis [published correction appears in JCI Insight. 2020 Oct 15;5(20):]. JCI Insight. 2018;3(22):e124714. Published 2018 Nov 15. doi:10.1172/jci.insight.124714