The immune system’s reaction to the common Epstein-Barr virus (EBV) can ultimately damage the brain and contribute to multiple sclerosis (MS), suggests research from Karolinska Institutet, which provides new insight into the long-suspected link between the two.
In the chronic inflammatory disease MS, the immune system attacks the central nervous system and causes nerve damage. It has long been known that everyone who develops MS has had an infection with the Epstein-Barr virus (EBV) – a common virus that often infects young people, sometimes causing glandular fever but often without any obvious symptoms.
But exactly how this virus contributes to MS has always been unclear.
This latest research, published in Cell, shows that when the immune system fights EBV, certain T cells – which normally attack the virus – can also react to a protein in the brain called Anoctamin-2 (ANO2). This phenomenon is called molecular mimicry – immune cells mistaking the body’s own proteins for those of the virus.
The researchers found that these cross-reactive T cells are significantly more common in people with MS than in healthy controls. The study builds on previous research showing that at misdirected antibodies after EBV infection may play a role.
“Our results provide mechanistic evidence that immune responses to EBV can directly damage the brain in MS. It is a complex neurological disease, and it may be that the molecular mechanisms vary between patients,” said the study’s first author, Olivia Thomas, assistant Professor at the Department of Clinical Neuroscience at Karolinska Institutet.
The study is based on analyses of blood samples from people with MS and compared with healthy controls.
The researchers were able to isolate T cells that react to both the EBV protein EBNA1 and ANO2 from people with MS. In addition, experiments in a mouse model showed that these cells can exacerbate MS-like symptoms and cause damage to the brain.
According to the researchers, the results may help explain why some people develop MS after an EBV infection while others do not.
“The discovery opens up new treatments that target these cross-reactive immune cells. Since several EBV vaccines and antiviral drugs are now being tested in clinical trials, the results may be of great importance for future preventive and therapeutic efforts,” says Professor Tomas Olsson, who with Associate Professor Andre Ortlieb Guerreiro-Cacais led the study at the institution.
The study is a collaboration between several research groups at Karolinska Institutet and has been funded by, among others, the Swedish Research Council, the EU's Horizon programme, the Swedish Brain Foundation and the Swedish Neurological Association.
Study details
Anoctamin-2-specific T Cells Link Epstein-Barr Virus to Multiple Sclerosis,
Olivia Thomas, Urszula Rykaczewska, Tomas Olsson et al.
Published in Cell on 13 January 2026.
Highlights
• Anoctamin-2 (ANO2) is targeted by T cells in approximately 57% of persons with MS
• EBNA1 and ANO2 T cell responses are cross-reactive in humans and mice
• ANO2 and EBNA1 T cells have overlapping TCR repertoires and pathogenic phenotypes
• ANO2 immunisation or ANO2-specific T cell transfer in mice leads to worsened MS-like disease
Summary
Epstein-Barr virus (EBV) infection constitutes a prerequisite for multiple sclerosis (MS) development, and cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies was previously demonstrated in persons with MS (pwMS). Here, we show that ANO2-specific CD4+ T cells are more frequent in pwMS. Immunisation of SJL/J mice with ANO2 or EBNA1 led to cross-reactive CD4+ T cell and antibody responses. ANO2 pre-immunization led to exacerbated experimental autoimmune encephalomyelitis (EAE), an effect mediated by CD4+ T cells, as confirmed by adoptive transfer experiments. T cell clones with cross-reactivity to EBNA1 and ANO2 could be isolated from natalizumab-treated pwMS, and sequencing of EBNA1- and ANO2-specific T cell receptors (TCRs) revealed a significant repertoire overlap. We thus report the first mechanistic evidence that EBNA1 CD4+ T cells can target the MS autoantigen ANO2, thereby establishing a link between EBV infection and neuro-inflammation.
See more from MedicalBrief archives:
Epstein-Barr virus may be leading cause of Multiple Sclerosis – Harvard cohort study
How Epstein-Barr virus is linked to MS – Swedish study
Misdiagnosis of multiple sclerosis found to be common
Strong evidence that Epstein-Barr could be the culprit behind lupus