Abstract: Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Zamecnik CR, Sowa GM, Abdelhak A, Dandekar R, Bair RD, Wade KJ, Bartley CM, Kizer K, Augusto DG, Tubati A, Gomez R, Fouassier C, Gerungan C, Caspar CM, Alexander J, Wapniarski AE, Loudermilk RP, Eggers EL, Zorn KC, Ananth K, Jabassini N, Mann SA, Ragan NR, Santaniello A, Henry RG, Baranzini SE, Zamvil SS, Sabatino JJ Jr, Bove RM, Guo CY, Gelfand JM, Cuneo R, von Büdingen HC, Oksenberg JR, Cree BAC, Hollenbach JA, Green AJ, Hauser SL, Wallin MT, DeRisi JL, Wilson MR. An autoantibody signature predictive for multiple sclerosis. Nat Med. 2024 Apr 19. doi: 10.1038/s41591-024-02938-3. Epub ahead of print. PMID: 38641750.


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