Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis
Olivia Thomas, Mattias Bronge, Katarina Tengvall, Birce Akpinar, Ola B. Nilsson, Erik Holmgren, Tara Hessa, Guro Gafvelin, Mohsen Khademi, Lars Alfredsson, Roland Martinꝉ, André Ortlieb Guerreiro‐Cacais, Hans Grönlund, Tomas Olsson, Ingrid Kockum
Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, for which Epstein-Barr virus (EBV) infection is a likely prerequisite. Due to the homology between Epstein-Barr nuclear antigen 1 (EBNA1) and alpha-crystallin B (CRYAB), we examined antibody reactivity to EBNA1 and CRYAB peptide libraries in 713 persons with MS (pwMS) and 722 matched controls (Con). Antibody response to CRYAB amino acids 7 to 16 was associated with MS (OR = 2.0), and combination of high EBNA1 responses with CRYAB positivity markedly increased disease risk (OR = 9.0). Blocking experiments revealed antibody cross-reactivity between the homologous EBNA1 and CRYAB epitopes. 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. 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.