by Prof. Johann Sellner, Austria – Co-Chair of the EAN Infectious Disease Panel
For April we have selected Clonally expanded B cells in multiple sclerosis bind Epstein–Barr virus EBNA1 and GlialCAM Nature 603, 321–327 (2022). doi: 10.1038/s41586-022-04432-7.
Multiple sclerosis (MS) is driven by abnormally activated immune cells and subsequent inflammation within the central nervous system (CNS). The consequences include damage to the protective myelin sheath and, ultimately, to the nerve fibres.
An accumulating body of evidence has corroborated the association between prior Epstein–Barr virus (EBV) infection and the development of MS. Indeed, a recent cohort-based study evaluated serum samples from more than 10 million U.S. military personnel, which were collected over a 20-year period1. The authors found a 32-fold increase in the risk of MS after EBV seroconversion. Serum levels of neurofilament light chain, an emerging biomarker for nerve fibre damage, only increased after EBV seroconversion. Thus, this study provided compelling epidemiological evidence that EBV infection precedes the onset of MS.
Our paper of the month describes a study led by Stanford University researchers, which now provides a mechanistic basis for how EBV infection can trigger the patient’s immune cells to attack self-tissue within the CNS.
First, the researchers collected B cells from cerebrospinal fluid (CSF) of nine patients with MS. They studied the antigens that antibodies generated from plasma cells were targeting. Six of the nine patients had antibodies that targeted the EBV transcription factor EBV nuclear antigen 1 (EBNA1). They performed detailed structural analyses of an antibody termed mAb MS39p2w174. This antibody bound to a particular region of EBNA1 referred to as AA365-425 and cross-reacted with the CNS protein GlialCAM. GlialCAM is a cell adhesion molecule expressed by several structures in the CNS, also by the myelin sheath-forming oligodendrocytes. Notably, the two antibody regions important for binding to GlialCAM had undergone somatic hypermutation. Before alteration by somatic hypermutation, the germline antibody could bind to EBNA1, but had little affinity for GlialCAM.
In a second step, the researchers looked at blood samples from MS patients and controls. Most people had antibodies against EBNA1, which is consistent with the widespread prevalence of EBV. However, MS patients had markedly higher levels of antibodies that targeted GlialCAM. Additional analyses in independent MS cohorts corroborated this observation.
Finally, the researchers also demonstrated that immunisation with EBNA1 in a mouse model of MS aggravated the clinical disease course. This observation was due to a strong antibody response against GlialCAM and EBNA1, enhanced immune cell infiltration and CNS demyelination.
The findings suggest that molecular mimicry between EBNA1 and host GlialCAM contributes to the development of MS. The pathogenic antibodies which target GlialCAM develop after somatic hypermutation within the CNS. Genetic susceptibility might play a role for this inadvertent process leading to immune responses against self-antigens.
- Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21;375(6578):296-301.