Epstein-Barr virus and Sjögren’s syndrome: bioinformatic analysis of possible new pathogenic links via molecular mimicry

INTRODUCTION & OBJECTIVES: Molecular mimicry between autoantigens and microbial antigens has been postulated, and in many cases experimentally confirmed, as a possible trigger of autoimmunity in genetically predisposed subjects. Epstein-Barr virus (EBV) is epidemiologically associated in many studies to primary Sjögren’s syndrome (pSS), and cases of pSS onset after EBV infection have been reported. Recently, molecular mimicry between EBV proteins and the pSS autoantigens lipocalin and alpha-fodrin has been demonstrated. Prompted by these data, we used bioinformatic tools to search for possible molecular mimicry of EBV proteins with two pSS autoantigens, the classical SS-B/La and the newly discovered muscarinic acetylcholine receptor M3 (M3R), targeted by autoantibodies in 90% of patients and involved in salivary secretion. MATERIAL & METHODS: We used the Basic Local Alignment Search Tool to compare the amino acid sequence of SS-B and M3R with those of known EBV proteins (n=2833), and searched for HLA-DR binding motifs in homologous segments. RESULTS: Amino acids (aa) 287-326 of SS-B show significant homology with aa 1358-1393 of the EBV tegument protein BPLF1. The sequence 287-326 includes the known SS-B epitopes 291-302 and 301-318, and contains binding motifs only of the pSS-associated HLA alleles DR3 (two motifs), DR2 and DR4 (one motif each); its viral counterpart contains a HLA-DR3 binding motif. Segments 125-139, 203-214 and 425-449 of M3R are homologous to aa 38-52, 179-190 and 198-222 of EBV latent membrane protein 1, respectively. Simultaneous presence of a HLA-DR binding motif in any of the above M3R segments and its EBV counterpart occurred only in the cases of HLA DR2, DR3, DR4 and DR8 (the latter is not associated in literature to pSS). CONCLUSIONS: Our bioinformatic data agree with, and further support, the idea of a pathogenic link between EBV and pSS, and selectively indicate two EBV proteins, among the 2833 known, that could cross-react with the pSS autoantigens SS-B and M3R. As in the case of lipocalin and alpha-fodrin, experimental testing of our in silico data is necessary to confirm cross-reactivity and define its importance; however, the well documented role of SS-B and M3R in pSS, the high degree of homology between specific segments of pSS autoantigens and EBV proteins, the presence of binding motifs of pSS-associated HLA-DRs in the shared sequences, and the overlap of such sequences with known autoepitopes are elements in favor of pathogenic relevance of the above homologies.