Impaired control of autoimmunity increases pediatric multiple sclerosis risk in EBNA-1-seropositives and -seronegatives

Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS). Epstein–Barr virus (EBV) encodes for EBNA-1 381-452 , which induces autoreactive immune responses against distinct CNS derived proteins (GlialCAM 370-389 , CRYAB 2-21 , MBP 205-224 , ANO2 135-154 ). Although EBV infection is considered essential for MS development, CNS-specific autoimmune responses may also be present in putatively EBV EBNA-1-seronegative patients, warranting further investigation. We studied 548 EBV EBNA-1 seropositive and 30 EBV EBNA-1 seronegative pediatric-onset MS (POMS) patients, along with 578 matched controls. CNS specific antibodies were significantly more prevalent in EBV EBNA-1 seropositive POMS patients (92.2%) than in EBV EBNA-1 seropositive controls (56.3%, P + and NKG2D + natural killer (NK) cells. These findings indicate that CNS-specific autoimmunity and impaired NK cell regulation, rather than EBV alone, are central to MS risk.