Antibodies to the Epstein-Barr virus proteins BFRF3 and BRRF2 cross-react with human proteins


      • Antibodies to the Epstein-Barr virus proteins BFRF3 and BRRF2 are increased in MS.
      • Antibodies to BFRF3 also bind the cytoskeletal protein septin-9.
      • Antibodies to BRRF2 also bind the mitochondrial protein DLST.
      • Most people have autoantibodies to septin-9 and many have autoantibodies to DLST.
      • MS patients are more likely than controls to have high levels of antibodies to one of these two self proteins.


      We hypothesize that the immune response to Epstein-Barr virus (EBV) drives the autoimmune damage in multiple sclerosis (MS). We investigated whether antibodies to two EBV proteins targeted by MS patients cross-react with self proteins. Using affinity columns, immunoprecipitation, and mass spectrometry, we found that antibodies to the EBV protein BFRF3 cross-react with the cytoplasmic protein septin-9, and antibodies to BRRF2 also bind mitochondrial proteins. Using Western blots and ELISA, we demonstrated that MS patients were more likely to have high levels of antibodies to one or another of these self antigens.

      Graphical abstract


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        • Ascherio A.
        • Munger K.L.
        Environmental risk factors for multiple sclerosis. Part I: the role of infection.
        Ann. Neurol. 2007; 61: 288-299
        • Cepok S.
        • Zhou D.
        • Srivastava R.
        • Nessler S.
        • Stei S.
        • Bussow K.
        • et al.
        Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis.
        J. Clin. Invest. 2005; 115: 1352-1360
        • Dooley M.M.
        • de Gannes S.L.
        • Fu K.A.
        • Lindsey J.W.
        The increased antibody response to Epstein-Barr virus in multiple sclerosis is restricted to selected virus proteins.
        J. Neuroimmunol. 2016; 299: 147-151
        • Fussey S.P.
        • Guest J.R.
        • James O.F.
        • Bassendine M.F.
        • Yeaman S.J.
        Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis.
        Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 8654-8658
        • Kuhlenbaumer G.
        • Hannibal M.C.
        • Nelis E.
        • Schirmacher A.
        • Verpoorten N.
        • Meuleman J.
        • et al.
        Mutations in SEPT9 cause hereditary neuralgic amyotrophy.
        Nat. Genet. 2005; 37: 1044-1046
        • Larman H.B.
        • Laserson U.
        • Querol L.
        • Verhaeghen K.
        • Solimini N.L.
        • Xu G.J.
        • et al.
        PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis.
        J. Autoimmun. 2013; 43: 1-9
        • Lindsey J.W.
        • deGannes S.L.
        • Pate K.A.
        • Zhao X.
        Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneous nuclear ribonucleoprotein L.
        Mol. Immunol. 2016; 69: 7-12
        • Lossius A.
        • Johansen J.N.
        • Torkildsen O.
        • Vartdal F.
        • Holmoy T.
        Epstein-Barr virus in systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis-association and causation.
        Viruses. 2012; 4: 3701-3730
        • Mao H.
        • Liu J.
        • Shi W.
        • Huang Q.
        • Xu X.
        • Ni L.
        • et al.
        The expression patterns of Septin-9 after traumatic brain injury in rat brain.
        J. Mol. Neurosci. 2013; 51: 558-566
        • Witte M.E.
        • Mahad D.J.
        • Lassmann H.
        • van Horssen J.
        Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis.
        Trends Mol. Med. 2014; 20: 179-187