Human serum antibodies against EBV latent membrane protein 1 cross-react with a-synuclein

Abstract

Objectives: To identify the epitope on a-synuclein (a-syn) to which antibodies against the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) bind and to determine whether antibodies targeting this mimicry domain are present in human sera. Methods: Reactivity of the a-syn-cross-reacting anti-LMP1 monoclonal antibody CS1-4 to a synthetic peptide containing the putative mimicry domain was compared to those in which this domain was mutated and to murine and rat a-syn (which differ from human a-syn at this site) in Western blots. Using ELISA, sera from EBV1 (n 5 4) and EBV2 (n 5 12) donors as well as those with infectious mononucleosis (IM; n 5 120), and Hodgkin disease (HD; n 5 33) were interrogated for antibody reactivity to synthetic peptides corresponding to regions of a-syn and LMP1 containing the mimicry domain. Results: CS1-4 showed strong reactivity to wild-type human a-syn, but not to the mutant peptides or rodent a-syn. Control EBV2 and EBV1 sera showed no reactivity to a-syn or LMP1 peptides. However, a significant proportion of IM and HD sera contained immunoglobulin M (IgM) (59% and 70%, in IM and HD, respectively), immunoglobulin G (IgG) (40% and 48%), and immunoglobulin A (IgA) (28% and 36%) antibodies to both peptides, as well as a significant correlation in the titers of IgM (r 5 0.606 and 0.664, for IM and HD, respectively), IgG (0.526 and 0.836), and IgA (0.569 and 0.728) antibodies targeting LMP1 and a-syn peptides. Conclusions: Anti-EBV-LMP1 antibodies cross-reacting with a defined epitope in a-syn are present in human patients. These findings may have implications for the pathogenesis of synucleinopathies.