How Epstein-Barr virus shapes immune responses in multiple sclerosis

In a recent study published in the journal PLOS Pathogens, researchers investigated humoral and cell-mediated immune responses to Epstein-Barr virus (EBV) in multiple sclerosis (MS) patients, post-infectious mononucleosis (POST-IM) patients, and EBV-seropositive healthy controls (HC) up to six months following disease resolution. They also evaluated central nervous system (CNS) antigenic targeting by anti-EBV cell-mediated immune responses.

Study: Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis. Image Credit: Kateryna Kon / ShutterstockStudy: Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis. Image Credit: Kateryna Kon / Shutterstock


MS is a chronic inflammatory CNS disease that has become increasingly common in recent decades. EBV is a possible precursor to MS, although the underlying processes remain unclear. Previous studies report that immune responses to EBV may react to brain proteins resembling viral proteins, resulting in an adaptive immune response rather than infection.

The contribution of EBV-induced immune responses to the loss of CNS tissue in MS is unclear. Elevated antibodies to the "EBNA complex" are associated with an increased risk of MS, indicating that additional latent cycle antigens may potentially cause pathogenic responses. The primary distinction amongst EBV types globally is sequence divergence in EBNAs 2A, 3B, and 3C.

About the study

In the present study, researchers investigated immunological responses to EBV in people with multiple sclerosis, healthy controls, and those infected with the virus asymptomatically or symptomatically.

The researchers recruited participants from the Queen Elizabeth Hospital in Birmingham and the Guest Hospital in Dudley. Participants provided blood samples and were not receiving treatment or experiencing clinical relapse at the time of blood donation. The researchers selected healthy controls among laboratory personnel, testing positive for EBV-specific antibodies, and POST-IM donors, who tested positive for heterophile antibodies. They provided blood four to six months after symptom resolution. Most patients were in the early disease stages with median expanded disability status scores (EDSS) of 1.0.

The researchers matched individuals based on age, biological sex,  and human leukocyte antigen (HLA)-DRB1*15:01. They studied ex vivo helper-T cells or clusters of differentiation 4-expressing (CD4+) cells and cytotoxic CD8-expressing T cell responses to EBV using in vitro-transformed autologous lymphoblastoid cell lines (LCLs) using a panel of overlapping 15-mer peptides. They evaluated EBV load using quantitative polymerase chain reaction (qPCR) and assessed immunoglobulin G (IgG) titers to EBV antigens using enzyme-linked immunosorbent assays (ELISA), immunofluorescent imaging, and Western blotting.

The team used flow cytometry to examine EBV-targeted T cell populations and multiplexed beaded arrays to measure tetanus toxoid-targeted antibody responses. They used electrophoresis to evaluate EBNA protein serology and performed intracellular cytokine staining (ICS) to evaluate cell-mediated responses to EBV ex vivo. They tested in vitro-extended immunological cross-reactivity against nine Modified Vaccinia Ankara (MVA) viral pathogens expressing nine central nervous system autoantigens.


MS patients had similar levels of EBV in their peripheral blood mononuclear cells (PBMC) as EBV-seropositive healthy controls. Serological IgG titers against virus capsid antigen (VCA) and EBNA1 were significantly higher, but those against EBNA-2 and 3 antigens were more frequent in MS patients. Responses to tetanus toxoids were similar between groups, indicating that the increase in serum IgG titers against VCA was specific to EBV antigens rather than general humoral dysregulation.

Ex vivo experiments showed that cell-mediated reactions to autologous Epstein-Barr virus-transformed B lymphocytes and EBNA1 were unaltered quantitatively. However, MS patients produced considerably more interleukin-2 (IL-2) against particular stimuli. EBV-targeted polyclonal T lymphocyte lines from MS patients and healthy controls exhibited significant autoantigen recognition, with numerous neuronal proteins emerging as common targeted molecules, including myelin basic-type protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin-associated oligodendrocyte basic-type protein (MOBP), and proteolipid protein (PLP).

T-cell and antibody responses to EBNA1 exhibited slight positive associations. T-cell clones from MS patients have dual specificity for EBNA1 and MOG antigens. EBNA1-specific T cells from MS patients generate granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFNγ), and IL-2, and uncontrolled EBV carriage does not play a significant role in MS pathology. IM patients do not often suffer from neurological problems. Immunocompromised individuals, such as those infected with the human immunodeficiency virus, have no elevated risk of CNS autoimmunity and are less likely to acquire MS. Pathogenic antibodies, such as EBNA1 IgG, may not be sufficient to cause MS pathology; further study could assess their ability to bind self-protein.

The study found that antibody titers against EBNA2 and EBNA3 proteins are dysregulated in MS patients, showing that the EBV-specific T cell repertoire might target the CNS. The data suggest that EBV has a complicated and multidimensional role in MS formation and progression, which may explain the high level of illness heterogeneity across individuals. A better knowledge of EBV's function in CNS autoimmunity is required, and future EBV therapeutics, such as immunization or adoptive T-cell therapy, must be designed with prudence. LCL- and EBNA1-specific T cell responses in MS were comparable, albeit slightly elevated, to healthy controls, indicating that MS patients had adequate viral immune control.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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