Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis

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.