Innate Immune Dysregulation Precedes Clinical Onset in Neuromyelitis Optica
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.
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BibTeX
@misc{mullerjensen2026innate,
title = {{Innate Immune Dysregulation Precedes Clinical Onset in Neuromyelitis Optica}},
author = {Leonie Müller-Jensen and Debanjana Chakravarty and Gianmarco Bellucci and Yuan Ding and Michelle Hughes and Alejandro M. Garcia and Carson E. Moseley and Ravi Dandekar and John W. Rose and Lisa K. Peterson and Ka-Ho Wong and Bradley Demarest and Noel Carlson and David E. Horvat and Keith Groshans and Nathan Tagg and Spencer R. Osbourn and Sithembile L. Mabila and Ruba Bou-Chahine and Victor Wang and M. Mateo Paz Soldan and Sean J. Pittock and Bruce A. C. Cree and Scott S. Zamvil and Ari J. Green and Adil Harroud and Sergio E. Baranzini and Michael R. Wilson and Stacey L. Clardy and Ahmed Abdelhak and Tammy L. Smith},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.757427},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.757427v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Innate Immune Dysregulation Precedes Clinical Onset in Neuromyelitis Optica
AU - Leonie Müller-Jensen
AU - Debanjana Chakravarty
AU - Gianmarco Bellucci
AU - Yuan Ding
AU - Michelle Hughes
AU - Alejandro M. Garcia
AU - Carson E. Moseley
AU - Ravi Dandekar
AU - John W. Rose
AU - Lisa K. Peterson
AU - Ka-Ho Wong
AU - Bradley Demarest
AU - Noel Carlson
AU - David E. Horvat
AU - Keith Groshans
AU - Nathan Tagg
AU - Spencer R. Osbourn
AU - Sithembile L. Mabila
AU - Ruba Bou-Chahine
AU - Victor Wang
AU - M. Mateo Paz Soldan
AU - Sean J. Pittock
AU - Bruce A. C. Cree
AU - Scott S. Zamvil
AU - Ari J. Green
AU - Adil Harroud
AU - Sergio E. Baranzini
AU - Michael R. Wilson
AU - Stacey L. Clardy
AU - Ahmed Abdelhak
AU - Tammy L. Smith
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.757427
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.757427v1
AB - 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.
SN - 2692-8205
ER -