Cross-Reactive Antibodies Link Multiple Sclerosis to Common Virus

Researchers at Karolinska Institute in Sweden have found further evidence for how the Epstein-Barr virus (EBV) can trigger multiple sclerosis (MS) or drive disease progression. Through a study in humans and in mice, the researchers discovered that some individuals have antibodies against the virus that mistakenly attack a protein in the brain and spinal cord called alpha-crystallin B (CRYAB). Reporting on their findings in Science Advances “Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis,” the team said their findings offer up additional evidence regarding the mechanistic link between EBV infection and MS. “This study provides further evidence that molecular mimicry contributes to pathological mechanisms linking EBV with MS.”

Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system (CNS), which it is believed is caused by an interplay of environmental factors and genetic risk, the authors wrote. It is also well established that Epstein-Barr virus infection is associated with an increased risk of MS and is a prerequisite for disease development, they pointed out. “In addition, aspects of EBV infection interact with both genetic and environmental risk factors, and combinations are associated with markedly increased MS risk.” However, the mechanisms of these associations aren’t fully understood. More than 90% of the population is infected with EBV, so there must be other mechanisms underlying the link between MS and EBV, as only a few people will develop MS.

EBV infects most people early in life and then remains in the body, usually without causing symptoms. The link between EBV and the neurological disease multiple sclerosis (MS) was discovered many years ago and has puzzled researchers ever since. Increasing evidence, including two papers published in Science and Nature last year, suggests that EBV infection precedes MS and that antibodies against the virus may be involved. However, the molecular mechanisms seem to vary between patients and remain largely unknown.

For their study the researchers analysed blood samples from more than 700 persons with MS (pwMS) and 700 healthy individuals. They found that antibodies that bind to the EBV protein Epstein-Barr nuclear antigen 1 (EBNA1), can also bind to a similar protein in the brain and spinal cord called CRYAB, whose role is to prevent protein aggregation during conditions of cellular stress such as inflammation. “CRYAB is expressed in oligodendrocytes in MS lesions and may have a protective effect by down-regulating proinflammatory responses of innate immune cells,” the team noted.

These misdirected, cross-reactive antibodies may damage the nervous system and cause severe symptoms in MS patients, including problems with balance, mobility and fatigue. The antibodies were present in about 23% of MS patients and 7% of control individuals.

“This shows that, whilst these antibody responses are not required for disease development, they may be involved in disease in up to a quarter of MS patients,” said Olivia Thomas, PhD, a postdoctoral researcher at the Department of Clinical Neuroscience, Karolinska Institute and co-first author of the paper. “This also demonstrates the high variation between patients, highlighting the need for personalized therapies. Current therapies are effective at reducing relapses in MS but unfortunately, none can prevent disease progression.”

The researchers also found that there is likely a similar cross-reactivity among T cells of the immune system. “Evidence for T cell cross-reactivity was obtained in mice between EBNA1 and CRYAB, and increased CRYAB and EBNA1 CD4+ T cell responses were detected in natalizumab-treated pwMS,” the team wrote. “This study provides evidence for antibody cross-reactivity between EBNA1 and CRYAB and points to a similar cross-reactivity in T cells, further demonstrating the role of EBV adaptive immune responses in MS development.” Interestingly, they pointed out, “The historical role of CRYAB as an autoantigen in MS has been controversial since its first discovery almost 30 years ago.”

Commenting on the collective results of previous research, the team further stated, “Together, it is possible that CRYAB has a neuroprotective function, which could explain its treatment effect in neuroinflammatory models, while autoreactivity against it could reverse this role … Thus, a role for CRYAB in both neuroprotection and also as an autoantigen target driving autoimmunity is not mutually exclusive.”

“MS is an incredibly complex disease, but our study provides an important piece in the puzzle and could explain why some people develop the disease,” Thomas added. “We have discovered that certain antibodies against the Epstein-Barr virus, which would normally fight the infection, can mistakenly target the brain and spinal cord and cause damage.”

Added co-first author Mattias Bronge, affiliated researcher at the Department of Clinical Neuroscience, Karolinska Institute, “We are now expanding our research to investigate how T cells fight EBV infection and how these immune cells may damage the nervous system in multiple sclerosis and contribute to disease progression.”