Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls

• 成果类型: Article
• 署名作者: Sattarnezhad, Neda; Kockum, Ingrid; Thomas, Olivia G.; Liu, Yicong; Ho, Peggy P.; Barrett, Alison K.; Comanescu, Alexandros I.; Wijeratne, Tilini U.; Utz, Paul J.; Alfredsson, Lars; Steinman, Lawrence; Robinson, William H.; Olsson, Tomas; Lanz, Tobias, V
• 署名单位: Stanford University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System; Karolinska Institutet; Karolinska Institutet; Karolinska University Hospital; Karolinska Institutet; Stanford University; Stanford University; Karolinska Institutet; Geriatric Research Education & Clinical Center; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15051
• DOI: 10.1073/pnas.2424986122
• 发表日期: 2025-03-18
• 关键词: epstein-barr-virus; b-cells; RISK; igg; autoimmunity; replication; responses; smoking

摘要

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which is linked to Epstein-Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood. We previously described molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM). Here, we investigated antibody responses against EBNA1 and GlialCAM in a large cohort of 650 MS patients and 661 matched population controls and compared them to responses against CRYAB and ANO2. We confirmed that elevated IgG responses against EBNA1 and all three CNS-mimic antigens associate with increased MS risk. Blocking experiments confirmed the presence of cross-reactive antibodies and molecular mimicry between EBNA1 and GlialCAM, and accompanying antibody responses against adjacent peptide regions of GlialCAM suggest epitope spreading. Antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 are elevated in MS patients carrying the main risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increase MS risk significantly and in an additive fashion. In addition, antibody reactivities against more than one EBNA1 peptide and more than one CNS-mimic increase the MS risk significantly but modestly. Overall, we show that molecular mimicry between EBNA1 and GlialCAM is likely an important molecular mechanism contributing to MS pathology.