Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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.
Authors: Leonie Müller-Jensen, Debanjana Chakravarty, Gianmarco Bellucci, Yuan Ding, Michelle Hughes, Alejandro M. Garcia, Carson E. Moseley, Ravi Dandekar, John W. Rose, Lisa K. Peterson, Ka-Ho Wong, Bradley Demarest, Noel Carlson, David E. Horvat, Keith Groshans, Nathan Tagg, Spencer R. Osbourn, Sithembile L. Mabila, Ruba Bou-Chahine, Victor Wang, M. Mateo Paz Soldan, Sean J. Pittock, Bruce A. C. Cree, Scott S. Zamvil, Ari J. Green, Adil Harroud, Sergio E. Baranzini, Michael R. Wilson, Stacey L. Clardy, Ahmed Abdelhak, Tammy L. Smith
Institutions: University of California, San Francisco, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Charité – Universitätsmedizin Berlin, Montreal Neurological Institute and Hospital, McGill University, University of Utah, ARUP Institute for Clinical and Experimental Pathology, VA Salt Lake City Healthcare System, Alexander T. Augusta Military Medical Center, MultiCare Health System, Duke University, Defense Health Agency, MedVadis Research, Mayo Clinic, George E. Wahlen Department of VA Medical Center, Karolinska Institutet
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7222916898