Investigação in silico de peptídeos de proteínas do sistema nervoso como candidatos de mimetismo molecular na síndrome de Guillain-Barré e na esclerose múltipla desencadeadas pelo vírus Epstein-Barr

Abstract

Guillain-Barré Syndrome (SBG) and multiple sclerosis are autoimmune diseases associated with an immune response against peripheral (PNS) and central nervous system autoantigens, respectively. Most studies on the immunopathology of SBG investigate the cross-reaction between myelin sheath ganglioside antigens and carbohydrates from the bacteria Campylobacter jejuni. However, SBG has a spectrum of subtypes, and, particularly, the demyelinating form has little evidence of a relationship with C. jejuni or of autoimmunity against gangliosides. The immunopathology of multiple sclerosis is better known, and several autoantigens are known. As the Epstein-Barr virus (EBV) may represent a potential risk factor for both multiple sclerosis and the demyelinating form of SBG, the present investigation aims to identify crucial residues among potential EBV CD4+ T lymphocyte epitopes and nervous system proteins as a means of suggesting how infection by this virus may contribute to the pathogenesis of disease. We utilized biological databases 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. Additionally, we developed a Python algorithm to compare residue identity among nonamers. We found 10 proteins from the nervous system and 28 from EBV, which were used to predict the binding peptides of 21 common HLAs in the world population. We located 1411 haplotypes distributed among 51 pairs of HLAs. Simulations were performed to determine whether nonamers from the EBV and nervous system proteins targeted TCR-contact residues. Three selection criteria were proposed according to the relevance of each contact for TCR-peptide-MHC interaction. The main contact must be located in position P5, while positions P2, P3 and P8 are secondary and P4, P6 and P7 are tertiary. Nonamers of EBV proteins and myelin proteins were combined in pairs and compared based on predefined selection criteria. The Periaxin protein, which has never been studied as a source of autoantigens, has the highest number of nonamer clusters among PNS proteins, with 35 pairs. Four clusters of nonamers from APLP1, two from CNP, and two from MBP bind to alleles of the haplotype DR-15, known as a risk factor for multiple sclerosis. The new approach proposed here, based on sequence identity at critical contact residues of the TCR, has revealed that several peptides derived from nervous system and EBV proteins share identical residues at these critical contact points. This suggests the possibility of crossreactivity between them. The nonamer pairs discovered in this study have the potential to support further investigations into autoantigens through laboratory experiments.