Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis

Sci Adv. 2023 May 19;9(20):eadg3032. doi: 10.1126/sciadv.adg3032. Epub 2023 May 17.


Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, for which and 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.

MeSH terms

  • Animals
  • Epstein-Barr Virus Infections* / complications
  • Herpesvirus 4, Human
  • Mice
  • Multiple Sclerosis*
  • alpha-Crystallins*


  • EBV-encoded nuclear antigen 1
  • alpha-Crystallins