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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.