Acute infectious mononucleosis generates persistent, functional EBNA-1 antibodies with high cross-reactivity to alpha-crystalline beta 2025 Luzuriaga+

Highlights
• Infectious mononucleosis induces EBNA-1 antibodies that bind and fix complement
• HLA-DRB1∗15:01+ individuals have higher EBNA-1 antibodies
• EBNA-1 antibodies target peptides with sequence homologies to human proteins
• CRYAB antibodies cross-reactive with EBNA-1 are detected in most individuals

Summary

We investigate the magnitude, specificity, and functional properties of Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1)-specific antibodies in young adults over the course of primary infection. EBNA-1-specific binding antibodies, as well as antibodies capable of antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD), are detected. These antibodies primarily target a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides.

Higher EBNA-1 binding and ADCD antibodies are observed in individuals with at least one HLA-DRB1∗15:01 allele. Alpha-crystallin beta (CRYAB) binding and complement-fixing antibodies are detected at 6 months and 1 year following infectious mononucleosis, and CRYAB antibodies are resistant to denaturation, consistent with an affinity-matured response. Blocking experiments show that CRYAB antibodies are cross-reactive with EBNA-1.

Altogether, high levels of functional EBNA-1 antibodies are generated in primary EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine whether these responses contribute to autoimmunity.

Open access