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

This is the authors' abstract. We don't add key points for this paper.

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 < 0.0001). However, high CNS specific antibody levels were also found in 56.6% of EBV EBNA-1 seronegative POMS patients and 17.4% of EBV EBNA-1 seronegative controls. These findings suggest that while EBV infection amplifies CNS specific autoimmune responses, high-level CNS autoreactive autoimmune responses can also occur independently of EBV EBNA-1. We further evaluated why only some individuals with high-level CNS autoreactive antibody titers develop MS. Mechanistically, we demonstrate that autoreactive immune responses are effectively controlled by NKG2C + 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.