Innate Immune Dysregulation Precedes Clinical Onset in Neuromyelitis Optica
Neuromyelitis optica spectrum disorder (NMOSD) is a disabling inflammatory central nervous system (CNS) disease characterized by pathogenic aquaporin 4 (AQP4) autoantibodies. The biological events that precede clinical onset remain unknown. In a unique longitudinal NMOSD cohort from the U.S. Department of Defense Serum Repository, with samples collected up to 24 years before onset, we applied discovery proteomics (~5,400 proteins), pan-viral antibody profiling (VirScan), and in silico analyses to characterize preclinical NMOSD versus matched healthy controls. Innate immune activation, particularly CXCL1 elevation, was the dominant immunological feature of preclinical NMOSD, preceding onset by ~12.7 years. AQP4-IgG was detectable more than 3 years before onset, while CNS injury markers increased only after disease manifestation. VirScan identified enhanced CMV-specific antibody reactivity following AQP4- IgG seroconversion, and network analyses revealed interactions between NMOSD-associated and CMV-derived proteins. Together, these findings establish a novel multi-hit model of NMOSD, with implications for understanding antibody-mediated autoimmunity more broadly.