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| Item Type: | Preprint |
|---|---|
| Title: | Intrathecal antibodies cross-react with EBV BRRF2 and human antigens in multiple sclerosis |
| Creators: |
Schulte-Frankenfeld, Poul M.  ORCID: https://orcid.org/0000-0003-0244-9226, Decker, Tim, Bünger, Isabel ORCID: https://orcid.org/0000-0001-8845-2447, Bamberg, Sarah ORCID: https://orcid.org/0009-0004-0406-771X, Thakar, Manjusha ORCID: https://orcid.org/0009-0005-8886-6443, Morgenlander, William R. ORCID: https://orcid.org/0000-0001-7205-3732, Schindler, Patrick ORCID: https://orcid.org/0000-0002-8846-121X, Oto, Carolin ORCID: https://orcid.org/0000-0002-9768-5143, Sperber, Pia S. ORCID: https://orcid.org/0000-0002-9534-2374, Schmitz-Hübsch, Tanja ORCID: https://orcid.org/0000-0003-4833-5937, Kornau, Hans-Christian ORCID: https://orcid.org/0000-0003-4187-7549, Schmitz, Dietmar ORCID: https://orcid.org/0000-0003-2741-5241, Jarius, Sven ORCID: https://orcid.org/0000-0003-4849-2545, Longbrake, Erin E. ORCID: https://orcid.org/0000-0002-1179-3937, Yandamuri, Soumya ORCID: https://orcid.org/0000-0002-0325-6488, O'Connor, Kevin C. ORCID: https://orcid.org/0000-0002-7056-419X, Schwake, Carolin ORCID: https://orcid.org/0000-0003-3669-7244, Ayzenberg, Ilya ORCID: https://orcid.org/0009-0007-9491-2180, Pardo, Carlos A. ORCID: https://orcid.org/0000-0002-4128-5335, Paul, Friedemann ORCID: https://orcid.org/0000-0002-6378-0070, Calabresi, Peter A. ORCID: https://orcid.org/0000-0002-7776-6472, Ruprecht, Klemens ORCID: https://orcid.org/0000-0003-1962-6014, Larman, H. Benjamin ORCID: https://orcid.org/0000-0001-7863-196X and Kreye, Jakob ORCID: https://orcid.org/0000-0003-2913-1015
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| Abstract: | Intrathecal antibody synthesis is a hallmark of multiple sclerosis (MS). Although some intrathecally synthesized antibodies in MS are known to target viral antigens, the spectrum of their antigenic specificities remains incompletely defined. We combined proteome-wide antibody profiling by Phage ImmunoPrecipitation Sequencing (PhIP-Seq) with cross-compartment analytics (MICAR) to study intrathecal antibody synthesis at peptide resolution in paired CSF and serum samples from individuals with MS (n = 40) and non-MS controls (n = 83). While intrathecal antibody responses in MS were polyspecific and included reactivities to various viruses, we identified a subset of individuals with a convergent intrathecal antibody reactivity to a previously described motif within the Epstein-Barr virus (EBV) protein BRRF2 (BRRF2 408–415 ). This motif-directed response showed co-reactivity with multiple CNS-expressed human antigens. In an independent cohort of n = 909 individuals with MS and n = 311 controls, including individuals with NMOSD and MOGAD, serum antibodies to BRRF2 408–415 were detected in 8.36% of MS individuals and in 0.64% of non-MS controls, corresponding to an odds ratio for MS of 14.1 (95% CI: 4.4–86.04). Within MS individuals, BRRF2 408–415 seropositivity was associated with increased intrathecal IgG synthesis. Cross-reactivity of antibodies to BRRF2 408–415 with human targets, including TRIM71 and RTN2, was confirmed by competition ELISA and cell-based assays. Together, these data define an intrathecal EBV BRRF2-linked antibody signature with human target cross-reactivity in a subset of MS individuals. This signature identifies a highly specific serological marker in MS and may support future stratification of the heterogeneous MS spectrum. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.08.14.744882 |
| Date: | 18 August 2026 |
| Official Publication: | https://doi.org/10.64898/2026.08.14.744882 |
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