A novel approach to identify cross-identity peptides between Epstein-Barr virus and central nervous system proteins in Guillain-Barré syndrome and multiple sclerosis

Abstract

AbstractBackgroundGuillain-Barré Syndrome (GBS) and multiple sclerosis are autoimmune diseases associated with an immune system attack response against peripheral and central nervous system autoantigens, respectively. Given the potential of Epstein-Barr virus (EBV) as a risk factor for both multiple sclerosis and GBS, the present study aimed to identify crucial residues among potential EBV CD4+ T lymphocyte epitopes and nervous system proteins.MethodsPublic databases (Allele Frequency Net Database, Immune Epitope Database, Genevestigator and Protein Atlas) were used to select proteins abundant in the nervous system, EBV immunogenic proteins, and HLA haplotypes. Computational tools were employed for predicting HLA-binding peptides and immunogenicity. For this, we developed immuno-cross, a Python tool (https://github.com/evoMOL-Lab/immuno-cross) to compare residue identity among nonamers.ResultsWe found ten proteins from the nervous system and 28 from EBV, which were used for predicting the binding peptides of 21 common HLAs in the world population. A total of 1411 haplotypes were distributed among 51 pairs of HLAs. Simulations were performed to determine whether nonamers from the EBV and nervous system proteins targeted TCR-contact residues. Then, three selection criteria were used, based on the relevance of each contact in the TCR-peptide-MHC interaction. The primary contact has to be located at position P5, and the positions P2, P3, and P8 were weighed as secondary, and P4, P6, and P7 were considered tertiary. Nonamers of EBV proteins and myelin proteins were combined in pairs and compared based on predefined selection criteria. The Periaxin protein had the highest number of nonamers pairs among PNS proteins, with 35 pairs. Four nonamers pairs from APLP1, two from CNP, and two from MBP bind to alleles of the haplotype DR-15.ConclusionsThe new approach proposed herein revealed that peptides derived from nervous system and EBV proteins share identical residues at critical contact points, which supports molecular mimicry. These findings suggest cross-reactivity between them and that the nonamer pairs identified with this approach have the potential to be an autoantigen. Experimental studies are needed to validate these findings.