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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1401156
This article is part of the Research Topic Neurological Autoimmunity: etiology, infectious complications, treatment strategies and outcomes in antibody-associated syndromes and beyond View all 18 articles

High heterogeneity of cross-reactive immunoglobulins in multiple sclerosis presumes combining of Bcell epitopes for diagnostics: a case-control study Short title Cross-reactive antibodies against a diverse set of peptides define the B cell response in MS patients

Provisionally accepted
Leyla A Ovchinnikova Leyla A Ovchinnikova 1Igor E Eliseev Igor E Eliseev 1Samir S Dzhelad Samir S Dzhelad 1Ksenia M Klimina Ksenia M Klimina 2Taras O Simaniv Taras O Simaniv 3Maria Ivanova Maria Ivanova 3Elena N Ilina Elena N Ilina 2Maria N Zakharova Maria N Zakharova 3Sergey N Illarioshkin Sergey N Illarioshkin 3Yury P Rubtsov Yury P Rubtsov 1,4Alexander G Gabibov Alexander G Gabibov 5,6*Yakov A. Lomakin Yakov A. Lomakin 5*
  • 1 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
  • 2 Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Moscow Oblast, Russia
  • 3 Research Center of Neurology, Moscow, Moscow Oblast, Russia
  • 4 Blokhin National Medical Research Center of Oncology, Ministry of Health, Moscow, Russia
  • 5 Institute of Bioorganic Chemistry (RAS), Moscow, Moscow Oblast, Russia
  • 6 Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia

The final, formatted version of the article will be published soon.

    Multiple sclerosis (MS) is a neuroinflammatory disease triggered by a combination of genetic traits and external factors. Autoimmune nature of MS is proven by the identification of pathogenic T cells, but the role of autoantibody-producing B cells is less clear. A comprehensive understanding of the development of neuroinflammation and the identification of targeted autoantigens are crucial for timely diagnosis and appropriate treatment.An expression library of 44-mer overlapping peptides from a panel of putative autoantigenic human proteins was employed for modified Phage ImmunoPrecipitation Sequencing (PhIP-Seq) to identify B cell peptide epitopes from MS patients. Individual peptides extracted by PhIP-Seq were tested by ELISA to characterize their affinity towards IgG from both MS patients and healthy donors (HD). Three candidate auto-peptides were used for isolating autoreactive antigen-specific IgGs from the serum of MS patients.Autoantibody screening revealed high heterogeneity of IgG response in MS. The autoantigenic genesis of the PhIP-Seq-identified peptides was further strengthened by clinical ELISA testing of 11 HD and 16 MS donors. Validation experiments on independent cohorts of 22 HD and 28 MS patients confirmed statistically significant elevated titers of IgG specific to spectrin alpha chain (SPTAN1) in the serum of MS patients compared to HD. The levels of anti-SPTAN1 IgG correlated in serum and cerebrospinal fluid (CSF). Isolated autoreactive antigen-specific IgG exhibited increased cross-reactivity to a panel of PhIP-Seq-identified antigenic peptides. Serum IgG from MS patients were reactive to latent membrane protein (LMP1) of Epstein-Barr virus, a potential trigger of MS. Discovered antigenic peptides from SPTAN1, protein-tyrosine kinase 6 (PTK6), periaxin (PRX), and LMP1 were tested as potential biomarker panel for MS diagnostics. We concluded that the combination of particular peptides from SPTAN1, PTK6, PRX and LMP1 could be implemented as a four-peptide biomarker panel for MS diagnosis (area under the curve (AUC) of 0.818 for discriminating between HD and MS).This study supports the concept that the specificity of autoreactive IgG in MS is highly heterogeneous. Despite that we suggest that the combination of several B-cell epitopes could be employed as reliable and simple test for MS diagnostics.

    Keywords: Multiple Sclerosis, biomarkers, Epstein-Barr virus, latent membrane protein, Autoantibody, autoantigen, PhIP-Seq, IgG

    Received: 14 Mar 2024; Accepted: 31 Oct 2024.

    Copyright: © 2024 Ovchinnikova, Eliseev, Dzhelad, Klimina, Simaniv, Ivanova, Ilina, Zakharova, Illarioshkin, Rubtsov, Gabibov and Lomakin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Alexander G Gabibov, Institute of Bioorganic Chemistry (RAS), Moscow, 117997, Moscow Oblast, Russia
    Yakov A. Lomakin, Institute of Bioorganic Chemistry (RAS), Moscow, 117997, Moscow Oblast, Russia

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