Over 2.8 million individuals are living with multiple sclerosis (MS) which occurs when the brain and spinal cord become damaged due to inflammation. Persons with MS (pwMS) experience various symptoms such as vision disturbance, cognitive dysfunction and problems with balance and mobility. Around 85% of pwMS experience unpredicted relapses of severe symptoms followed by remission for months to years and a small proportion have gradually worsening symptoms over time. Unfortunately, both forms eventually lead to permanent disability. We don’t know the exact causes for MS, but several genetic and lifestyle factors have been identified such as smoking, obesity, vitamin D levels, socioeconomic factors and also viruses. 

 

Autoimmune diseases occur when the body’s own immune system damages tissues leading to inflammation and, in the case of MS, the central nervous system is affected which causes neurological symptoms. In some autoimmune diseases, an initial infection may trigger the immune response that causes the damage and strong evidence supports a role for Epstein-Barr virus (EBV) in the development of MS. 

 

EBV is the common cause of infectious mononucleosis – also called glandular fever or the “kissing disease” – and is the strongest known environmental risk factor linked to MS. Around 90% of adults become infected with EBV throughout their life yet only a small proportion develop the disease, and one particular study in 2022 showed that almost all pwMS acquire the virus at least 1 year before the disease onset. However, despite this link, we still do not know exactly how the virus may contribute to MS development and there are currently several theories. Due to the delay between EBV infection and MS onset, it is unlikely that the disease develops from uncontrolled infection (although this remains a possibility). Instead, we think that the immune response to EBV – which would normally fight EBV infection – may be damaging the brain in MS, and pwMS have altered immune responses to parts of the virus compared to healthy people. There is evidence that both T cells and antibodies are involved in disease, and we investigated how this might occur by studying patients from Sweden. 

 

In a recent study published in Science Advances, we investigated how the immune response to EBV may be different in pwMS by looking at the blood of 700 pwMS and 700 control subjects. We specifically looked at how two components of the immune system – called antibodies and T cells – response to EBV may differ. Antibodies are proteins produced by B cells of the immune system in response to infections, and similarly T cells act as soldiers of the immune system to remove infected cells from the body.  

 

We first confirmed previous findings that pwMS have higher antibody responses in their blood to a part of EBV called EBNA1 and went on to show that these EBNA1 antibodies could cross-react with a protein in the body called alpha-crystallin B (CRYAB). This means that EBNA1 antibodies can also attack CRYAB and may contribute to inflammation in pwMS. Up to 27% of pwMS had increased levels of CRYAB antibodies compared to only 16.9% of controls, and individuals in the study who had antibody responses to both EBNA1 and CRYAB were up to 9 times more likely to have MS than control subjects. 

 

It was also found that T cell responses to EBNA1 and CRYAB were increased in the blood of pwMS treated with the drug natalizumab. Natalizumab therapy works by blocking immune cells from entering the brain of MS patients, preventing damage and leading to their accumulation in the blood. Further investigation of these T cells suggested that they likely cross-react in a similar way to antibodies. CRYAB has a role in dampening down inflammation and therefore, if immune responses against EBNA1 are also mistakenly targeting CRYAB, they may contribute to tissue damage in MS.  

 

These results build upon previous findings of similar cross-reactivity between EBNA1 immune responses, and two other proteins expressed in the brain called Anoctamin-2 and GlialCAM and suggests that other proteins can be targeted by EBV immune responses in MS. Whilst current therapies are effective at reducing relapse rates, many have severe side effects and none ultimately prevent disease progression. Further understanding of how immune responses to EBV may lead to MS will help us to develop future personalised treatments with fewer side effects and the potential to cure MS.