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Updated: Jan 17, 2026
Author Spotlight: Novel Assay for Studying B-Cell Responses in Multiple Sclerosis Research
Published on: December 1, 2023
Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis
Olivia G Thomas1, Urszula Rykaczewska1, Marina Galešić2
1Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden.
Abstract:
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. Immunization 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 neuroinflammation.
Insights
Epstein-Barr virus (EBV) infection links to multiple sclerosis (MS). EBV's EBNA1 protein can trigger CD4+ T cells that mistakenly target the body's own ANO2 protein, causing neuroinflammation in MS patients.
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Epstein-Barr virus (EBV) infection is a known risk factor for multiple sclerosis (MS).
- Previous studies indicated cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies in individuals with MS (pwMS).
Purpose of the Study:
- To investigate the role of EBNA1-specific T cells in targeting the autoantigen ANO2 in MS.
- To establish a mechanistic link between EBV infection and MS-associated neuroinflammation.
Main Methods:
- Quantification of ANO2-specific CD4+ T cells in pwMS.
- Induction of cross-reactive immune responses in mice by immunizing with ANO2 or EBNA1.
- Assessment of experimental autoimmune encephalomyelitis (EAE) severity following ANO2 pre-immunization.
- Isolation and characterization of cross-reactive T cell clones and T cell receptors (TCRs) from pwMS.
Main Results:
- ANO2-specific CD4+ T cells were found to be more frequent in pwMS.
- Immunization with ANO2 or EBNA1 in mice induced cross-reactive CD4+ T cell and antibody responses.
- ANO2 pre-immunization exacerbated EAE in a CD4+ T cell-dependent manner.
- T cell clones recognizing both EBNA1 and ANO2 were isolated from natalizumab-treated pwMS, showing significant TCR repertoire overlap.
Conclusions:
- This study provides the first mechanistic evidence that EBNA1-specific CD4+ T cells can target the MS autoantigen ANO2.
- These findings establish a direct link between EBV infection and the neuroinflammatory processes in multiple sclerosis.
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