Neurology(R) neuroimmunology & neuroinflammation · 2026
Development of a Diagnostic Autoantibody Assay to a Consensus Motif for the Risk Prediction of Epstein-Barr Virus-Related Multiple Sclerosis.
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McCutcheon Krista M, Bodansky Aaron, Ngo Thomas T, Caspar Colette, Quintana Sydney, Asaki James, Zhou Jing, Caillier Stacy J, Sharathchandra Akshay, Waldrop Greer, Dandekar Ravi, Zorn Kelsey, Tubati Asritha, Gupta Sasha, Sabatino Joseph J, Cuneo Richard, Oksenberg Jorge, Wallin Mitchell T, Cree Bruce A C, Hauser Stephen L, Pleasure Samuel, Derisi Joseph, Wilson Michael R, and the UCSF ORIGINS/EPIC team
Аннотация
BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is a chronic progressive, demyelinating autoimmune CNS disease. Autoantibodies to the motif P-(SA)-x-(SGA)-R-(SN)-(LRKH) are a class of predictive markers specific to MS that could add to emerging diagnostic criteria for MS. In this study, we describe the discovery of an MS patient-derived monoclonal antibody (mAb) specific to this motif from memory B cells, and we develop a proof-of-principle autoantibody test to report the prevalence of seropositivity, predict MS early in disease, and identify underlying tolerance-breaking antigens in Epstein-Barr virus (EBV) and the CNS.
METHODS: Peptide tetramers containing the motif were used to screen activated memory B cells, collected from a patient with MS, on the Beacon Optofluidic system. A mAb to the motif and serum samples from clinically diagnosed patients with MS and healthy controls were used to qualify a Luminex xMAP autoantibody serologic test. Antigen discovery methods included phage-immunoprecipitation sequencing (PhIP-Seq), biolayer interferometry, human protein microarrays, isoelectric focusing gels and blots, and immunofluorescence staining of mouse brain cell cultures.
RESULTS: A mAb cloned from an MS patient's memory B cells binds diverse peptides containing the MS signature motif with affinities ranging from 2 to 25 nM. Consensus peptides defined by alanine scanning PhIP-Seq were used to develop an autoimmune IgG test with a sensitivity equivalent to 0.5 ng/mL mAb, a precision of <11%, and a positivity rate of 11% among a cohort of 179 patients with MS (n = 91 healthy and n = 49 unrelated neurologic disease serum samples were negative). Utility of the assay for prodromal MS was demonstrated using retrospective, longitudinal samples from cases in the Department of Defense Serum Repository. The mAb identified EBV tegument protein BRRF2 as a tolerance-breaking antigen with nanomolar affinity, containing the motif with reactivity to oligoclonal bands in CSF from MS signature-positive patients. Immunocytochemical staining of mixed mouse neuronal cells showed the dominant cross-reactive human antigen to be vimentin.
DISCUSSION: We describe a test for MS signature autoantibodies that could be used to support MS diagnosis, prodromal research, and early interventions. The integration of this assay with other emerging biomarkers will advance progress toward a combined predictive risk score for MS.
METHODS: Peptide tetramers containing the motif were used to screen activated memory B cells, collected from a patient with MS, on the Beacon Optofluidic system. A mAb to the motif and serum samples from clinically diagnosed patients with MS and healthy controls were used to qualify a Luminex xMAP autoantibody serologic test. Antigen discovery methods included phage-immunoprecipitation sequencing (PhIP-Seq), biolayer interferometry, human protein microarrays, isoelectric focusing gels and blots, and immunofluorescence staining of mouse brain cell cultures.
RESULTS: A mAb cloned from an MS patient's memory B cells binds diverse peptides containing the MS signature motif with affinities ranging from 2 to 25 nM. Consensus peptides defined by alanine scanning PhIP-Seq were used to develop an autoimmune IgG test with a sensitivity equivalent to 0.5 ng/mL mAb, a precision of <11%, and a positivity rate of 11% among a cohort of 179 patients with MS (n = 91 healthy and n = 49 unrelated neurologic disease serum samples were negative). Utility of the assay for prodromal MS was demonstrated using retrospective, longitudinal samples from cases in the Department of Defense Serum Repository. The mAb identified EBV tegument protein BRRF2 as a tolerance-breaking antigen with nanomolar affinity, containing the motif with reactivity to oligoclonal bands in CSF from MS signature-positive patients. Immunocytochemical staining of mixed mouse neuronal cells showed the dominant cross-reactive human antigen to be vimentin.
DISCUSSION: We describe a test for MS signature autoantibodies that could be used to support MS diagnosis, prodromal research, and early interventions. The integration of this assay with other emerging biomarkers will advance progress toward a combined predictive risk score for MS.