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

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 mimi...

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Vydáno v:Proceedings of the National Academy of Sciences - PNAS Ročník 122; číslo 11; s. e2424986122
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 18.03.2025
Témata:
Adult
Case-Control Studies
Cross Reactions
Epstein-Barr Virus Nuclear Antigens - immunology
Female
Herpesvirus 4, Human - immunology
HLA-DRB1 Chains - genetics
HLA-DRB1 Chains - immunology
Humans
Immunoglobulin G - immunology
Male
Middle Aged
Molecular Mimicry - immunology
Multiple Sclerosis - diagnosis
Multiple Sclerosis - genetics
Multiple Sclerosis - immunology
Multiple Sclerosis - virology
molecular mimicry
GlialCAM
antibodies
multiple sclerosis
Epstein–Barr virus
ISSN:1091-6490, 1091-6490
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Shrnutí: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 and combinations of 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.
Bibliografie:ObjectType-Article-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2424986122