Multiple sclerosis, viruses, and B cell depleting therapy : a meeting at the immune system

Multiple sclerosis (MS) is a highly heterogeneous disease with a complex and undiscovered etiology. Two of the strongest established risk factors for developing MS are carriage of the HLA-DRB1*15:01 allele and Epstein-Barr virus (EBV) infection with a still unknown potential mechanistic link between them. Today, many treatments are effective in preventing relapse disease activity with B cell depleting therapies (BCDTs) being of particular interest since they also target the immune cells that are infected by EBV. However, BCDTs come with the price of blunting humoral immune responses to viruses and might lead to increased risk for infections, such as COVID-19. In this thesis, we aimed to investigate the cellular and humoral immune responses to SARS-CoV-2 and EBV in health and MS, and after BCDT.

In Paper I, we focused on the adaptive immune responses to SARS-CoV-2 infection in healthy controls (HC) and persons with MS (pwMS) currently treated with different disease-modifying therapies, mainly BCDTs. The levels and functionality of SARS-CoV-2 specific T cells were similar between pwMS on BCDTs and HC. A blunted humoral response was observed in some, but not all, pwMS on BCDTs. Seroconversion in this group seemed to be affected by time since the last infusion and the number of B cells in the blood, and this laid the basis for the following project.

In Paper II, we thus aimed to identify reliable markers for seroconversion after SARS-CoV-2 mRNA vaccination in pwMS on rituximab (RTX). Both B cell levels in blood and RTX drug concentration in plasma were found to be more reliable markers of seroconversion than time since the last infusion, suggesting that individual differences in B cell repopulation and drug clearance rate affect seroconversion following vaccination.

In Paper III, we examined potential factors that might affect B cell repopulation dynamics in pwMS on BCDTs. We measured the plasma and cerebrospinal fluid (CSF) levels of two factors important for the survival and differentiation of B cells, namely B cell activating factor (BAFF) and A proliferation inducing ligand (APRIL). We identified distinct immune cell subsets and CSF markers to be associated with BAFF in MS, and during B cell depletion and repopulation.

Lastly, in Paper IV, we characterized the immune response to chronic EBV infection in health and MS with regard to genetic predisposition, disease activity, and the subsequent effect of BCDTs. Similar proportions of individuals with detectable EBV viral load in whole blood were detected in HC and untreated pwMS, but MS-related HLAs were shown to be associated with specific arms of the humoral and cellular immune response. Treatment with BCDT decreased EBV viral load and EBV-specific T cell responses to distinct EBV proteins.

In summary, this thesis provides important information about how BCDTs affect the adaptive immune response to new infections and vaccinations in pwMS and identifies biomarkers that could be used for the prediction of seroconversion following vaccination. Additionally, it adds new insights into the complexity of the EBV-specific immune responses in health and MS and identifies factors that need to be considered when trying to disentangle possible mechanisms by which EBV might cause MS.

List of scientific papers

I. Asplund Högelin, K.#, Ruffin, N.#, Pin, E., Månberg, A., Hober, S., Gafvelin, G., Grönlund, H., Nilsson, P., Khademi, M., Olsson, T., Piehl, F., & Al Nimer, F. Development of humoral and cellular immunological memory against SARS-CoV-2 despite B cell depleting treatment in multiple sclerosis. iScience. 2021;24(9):103078. #Shared authorship.
https://doi.org/10.1016/j.isci.2021.103078

II. Asplund Högelin, K., Ruffin, N., Pin, E., Hober, S., Nilsson, P., Starvaggi Cucuzza, C., Khademi, M., Olsson, T., Piehl, F., & Al Nimer, F. B-cell repopulation dynamics and drug pharmacokinetics impact SARSCoV-2 vaccine efficacy in anti-CD20-treated multiple sclerosis patients. Eur J Neurol. 2022;29(11):3317-3328.
https://doi.org/10.1111/ene.15492

III. Asplund Högelin, K., Isac, B., Khademi, M., & Al Nimer, F. B cell activating factor levels are linked to distinct B cell markers in multiple sclerosis and following B cell depletion and repopulation. Clin Immunol. 2024;258:109870.
https://doi.org/10.1016/j.clim.2023.109870

IV. Asplund Högelin, K., Pahlevan Kakhki, M., Gao, Y., Margerie, L., Huang, J., Khademi, M., Gyllenberg, A., Olsson, T., Kockum, I., Buggert, M., Al Nimer, F. Detailed characterization of the immune response to Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment. [Manuscript]