Finding an elusive predictive MS biomarker

[frodo]

Finding an elusive predictive MS biomarker

https://www.science.org/doi/full/10.112 ... ol.adq7284

Abstract

Whole-proteome autoantibody profiling reveals an immunological signature that predates the clinical onset of multiple sclerosis.

Several studies indicate that the biological and clinical onsets of multiple sclerosis (MS) do not coincide. Neuroinflammation is believed to start several years before the earliest manifestation of symptoms, indicating the existence of a prodromal phase that could be targeted therapeutically to halt the disease course and prevent subsequent relapses. Robust biomarkers that can reliably identify this preclinical period, thus anticipating the first clinical attack of MS, are currently lacking.

In other autoimmune conditions, autoantibodies are often detected before the overt clinical phase, highlighting their predictive potential.

Zamecnik and colleagues used phage immunoprecipitation sequencing (PhIP-Seq) technology to assess autoantibody reactivity in 250 patients with MS (PwMS) who had provided samples to the Department of Defense Serum Repository both before and after diagnosis. The authors sought to identify autoantibody-antigen interactions with PhIP-Seq, which uses oligonucleotide library synthesis and bacteriophage display to present the whole human proteome for autoantibody screening. The autoantibody repertoires identified were unique to each patient and remarkably stable over time.

Further analysis revealed an immunogenic cluster (IC) in approximately 10% of PwMS, which was enriched for peptides from 54 proteins in pre- and post-onset samples. Notably, these enriched peptides had a unique motif, defined by seven amino acids, that is also found in proteins from several human pathogens, supporting the hypothesis that molecular mimicry may contribute to MS pathogenesis. In addition, serum neurofilament light levels were elevated in pre-onset samples from PwMS compared with controls, particularly in those identified by the IC, further substantiating the hypothesis that immune-mediated neuroaxonal damage precedes the clinical phase of MS. To validate these findings, the authors conducted PhIP-Seq analysis of a separate cohort of PwMS and found similar enrichment of the IC motif. A final validation demonstrated that cerebrospinal fluid and serum from PwMS recognized IC-defining peptides using a bead-based immunofluorescence assay.

This study identifies a pattern of autoantibody reactivity specific to a subset of PwMS that occurs both before and after the clinical onset of the disease. This candidate MS biomarker holds tremendous clinical significance because it could enable disease prediction, prompt earlier diagnoses, and facilitate patient stratification for future clinicopathologic studies.