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An Autoantibody Signature Predictive of MS
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- MS is a multifactorial, immune-mediated, and neurodegenerative disease of the central nervous system. The search continues toward the antigen or group of antigens that trigger the immune response in patients with MS. Many studies attempted to identify the target antigen(s) related to MS, but none could. In this investigation, the authors took a step closer to identifying an autoantibody signature against a common motif in a subset of patients with MS (approximately 10%). Interestingly, NfL levels were higher in this subset of patients than in the rest of the patients with MS. NfL levels were elevated prior to the clinical onset of the disease. Thus, this study also validated several prior observations that MS has a prodromal stage where it is likely that neuronal axonal damage is already happening. The common motif identified in this study has similarities to many human pathogens, including the Epstein–Barr virus, suggesting molecular mimicry as a possible mechanism to be studied further.
- This study moves the field closer to identifying the antigenic targets of the autoreactive immune system in patients with MS. This can be a talking point in the clinic when patients ask about the cause(s) of MS. Additionally, it provides insights into a possible role for molecular mimicry in MS.
abstract
This abstract is available on the publisher's site.
Access this abstract nowAlthough 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.
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An autoantibody signature predictive for multiple sclerosis
Nat. Med. 2024 Apr 19;[EPub Ahead of Print], CR Zamecnik, GM Sowa, A Abdelhak, R Dandekar, RD Bair, KJ Wade, CM Bartley, K Kizer, DG Augusto, A Tubati, R Gomez, C Fouassier, C Gerungan, CM Caspar, J Alexander, AE Wapniarski, RP Loudermilk, EL Eggers, KC Zorn, K Ananth, N Jabassini, SA Mann, NR Ragan, A Santaniello, RG Henry, SE Baranzini, SS Zamvil, JJ Sabatino, RM Bove, CY Guo, JM Gelfand, R Cuneo, HC von Büdingen, JR Oksenberg, BAC Cree, JA Hollenbach, AJ Green, SL Hauser, MT Wallin, JL DeRisi, MR WilsonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
MS is a common neuroinflammatory condition in which an immunopathology related to B cells has recently usurped T cell–driven dogmas. This is largely thanks to the marked therapeutic success of B-cell depletion,1 alongside the near-universal oligoclonal bands detected in the CSF of patients with MS (pwMS). Despite these observations, the identification of autoantibody targets in pwMS has witnessed several false dawns and remains elusive.
To address this outstanding observation, Zamecnik et al employed phage immunoprecipitation sequencing, which presents the entire human peptidome in bacteriophage-expressed chunks of 49 amino acids. If antibodies from patient serum or CSF bind to these peptides, antibody–phage complexes are immunoprecipitated, and DNA sequencing resolves the phage-presented sequences.
Phage immunoprecipitation sequencing was utilized in a cohort selected from more than 10 million individuals enrolled into the Department of Defense Serum Repository, with serum taken upon enrollment (an average of 5 years before MS onset) and, then, at an average of 1 year after the clinical onset of MS. This provided the authors with a unique opportunity to determine whether autoantibodies were sustained before and after MS diagnosis.
In approximately 10% of 250 pwMS, the authors identified longitudinally consistent peptides derived from 54 proteins, which shared a very similar 14 amino-acid motif. Similar enrichment patterns were observed in a validation cohort of samples taken within 30 days of clinical MS onset, but not in 22 other neurological controls, indicating high specificity of the signature. Binding to six peptides within the signature was directly validated and dominated by reactivity to multiple pathogens containing the 14–amino-acid motif.
This study provides strong evidence that an autoantibody signature exists prior to the clinical onset of MS, implicating an early B-cell pathogenesis, and may be of relevance to infection. Further, by studying CSF and serum, the authors shed light on CSF-peripheral communications in pwMS, with therapeutic insights across neurology.2 Finally, it remains intriguing to speculate whether the array of infectious and autoantigens will permit personalized future approaches to understanding MS pathogenesis.
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