Epstein-Barr Virus-specific T cells in multiple sclerosis (MS) showed significant autoreactivity to central nervous system antigens, indicating a potential mechanism for MS-related damage.
Olivia Thomas, PhD
(Credit: Karolinska Institute)
A new study published in PLOS Pathogens showed that elevated serum Epstein-Barr Virus (EBV)-specific antibody responses in a group of patients with multiple sclerosis (MS) extended beyond the protein EBNA-1, suggesting a more immense dysregulation of EBV-specific antibody responses than formally known in studies. While differences in T cell responses to EBV were harder to identify, the stimulation of EBV-expanded T cell lines with central nervous system (CNS) autoantigens showed significant autoreactivity, suggesting the virus-induced T cells may have a widespread capacity to damage the CNS.1
In peripheral blood mononuclear cells, EBV load remained unchanged in patients with MS compared with healthy EBV-seropositive controls (HC). Although serologically tetanus toxoid responses were unchanged between the groups, immunoglobulin G (IgG) responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated in patients with MS (EBNA1, P = .0079; VCA, P = .0298). Notably, the IgG responses to EBNA2 and the EBNA3 family antigens were more often identified among patients with MS (EBNA2, P = .042; EBNA3, P = .005).
“Our detection of cross-reactive T-cells in healthy individuals suggests that it may be the ability of these cells to access the brain that is important in MS,” lead author Olivia Thomas, PhD, assistant professor in the department of clinical neuroscience at the Karolinska Institute in Sweden,said in a statement.2 “Although our work shows the relationship between EBV and MS is now more complex than ever, it is important to know how far this cross-reactivity extends to fully understand the link between them.”
In the study, researchers evaluated antibody and T cell responses to EBV in patients with MS, healthy controls, and those recovering from mononucleosis, up to 6 months post-infection. The study focused on the ability of EBV-specific T cells to target CNS antigens. Untreated participants from the 3 groups were matched by gender, age, and HLA-DRB1*15:01 where possible. EBV load was measured using quantitative PCR, while IgG responses to key EBV antigens were assessed via ELISA, immunofluorescence, and Western blot. Additionally, tetanus toxoid antibody responses were identified using a multiplex bead array. EBV-specific T cell responses were detected ex vivo by intracellular cytokine staining and cross-reactivity was tested against 9 CNS autoantigens using Modified Vaccinia Ankara viruses.
READ MORE: FDA Clears Indapta Therapeutics’ IND for Cell Therapy IDP-023 in Progressive Multiple Sclerosis
“The discovery of the link between EBVs and MS has huge implications for our understanding of autoimmune disease, but we are still beginning to reveal the mechanisms that are involved. Our latest study shows that following EBV infection there is a great deal more immune system misdirection, or cross-reactivity, than previously thought,” senior author Graham Taylor, PhD, associate professor at the University of Birmingham, said in a statement.2
Authors reported that T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically in the ex vivo assays. Investigators also observed a significant increase of interleukin (IL)-2 production in response to certain stimuli among patients with MS. Furthermore, EBV-specific polyclonal T cell lines in both MS and HC groups revealed high levels of autoantigen recognition by ICS, and various neuronal proteins appeared as common targets such as myelin oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, and myelin-associated oligodendrocyte basic protein.
“Our study has 2 main implications. First, the findings give greater weight to the idea that the link between EBV and multiple sclerosis is not because of uncontrolled virus infection in the body,” Taylor added in a statement.2 “Second, we have shown that the human immune system cross-recognizes a much broader array of EBV and central nervous system proteins than previously thought, and that different patterns of cross-reactivity exist. Knowing this will help identify which proteins are important in MS and may provide targets for future personalized therapies."
