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Thomas OG, Rykaczewska U, Galešić M, van der Burgt RTM, Hallén N, Ferro F, Bronge M, Marti Z, Li Y, Riqué AH, Lin J, Krstic A, Gromadzka A, Szonder AL, Sorini C, Reina-Campos M, Sun T, Rubio Rodríguez-Kirby LA, Dumral Ö, Berglund R, Kakhki MP, Adzemovic MZ, Zeitelhofer M, Akpinar B, Tengvall K, Nilsson OB, Holmgren E, Cucuzza CS, Högelin KA, Gafvelin G, Fink K, Castelo-Branco G, Needhamsen M, Khademi M, Piehl F, Gräslund T, Alfredsson L, Lund H, Uhlén P, Kockum I, Martin R, Jagodic M, Grönlund H, Guerreiro-Cacais AO, Olsson T
Cell - (-) - [2026-01-00; online 2026-01-00]
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.
Autoimmunity and Serology Profiling [Service]
PubMed 41534529
DOI 10.1016/j.cell.2025.12.032
Crossref 10.1016/j.cell.2025.12.032
pii: S0092-8674(25)01481-3