title: Cyclic citrullinated MBP87-99peptide stimulates T cell responses: Implications in triggering disease.
abstract: Amino acid mutations to agonist peptide epitopes of myelin proteins have been used to modulate immune responses and experimental autoimmune encephalomyelitis (EAE, animal model of multiple sclerosis). Such amino acid alteration are termed, altered peptide ligands (APL). We have shown that the agonist myelin basic protein (MBP) 87-99 epitope (MBP87-99) with crucial T cell receptor (TCR) substitutions at positions 91 and 96 (K91,P96(TCR contact residues) to R91,A96; [R91,A96]MBP87-99) results in altered T cell responses and inhibits EAE symptoms. In this study, the role of citrullination of arginines in [R91,A96]MBP87-99peptide analog was determined using in vivo experiments in combination with computational studies. The immunogenicity of linear [Cit91,A96,Cit97]MBP87-99and its cyclic analog - cyclo(87-99)[Cit91,A96,Cit97]MBP87-99when conjugated to the carrier mannan (polysaccharide) were studied in SJL/J mice. It was found that mannosylated cyclo(87-99)[Cit91,A96,Cit97]MBP87-99peptide induced strong T cell proliferative responses and IFN-gamma cytokine secretion compared with the linear one. Moreover, the interaction of linear and cyclic peptide analogs with the major histocompatibility complex (MHC II, H2-IAs) and TCR was analyzed using molecular dynamics simulations at the receptor level, in order to gain a better understanding of the molecular recognition mechanisms that underly the different immunological profiles of citrullinated peptides compared to its agonist native counterpart MBP87-99epitope. The results demonstrate that the citrullination of arginine in combination with the backbone conformation of mutated linear and cyclic analogs are significant elements for the immune response triggering the induction of pro-inflammatory cytokines.
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, VIC 3021, Australia. Electronic address: vasso.apostolopoulos@vu.edu.au.
authors.forename: Vasso
authors.initials: V
authors.lastname: Apostolopoulos
authors.affiliation: Department of Chemistry, University of Patras, 26500, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Deraos
authors.affiliation: Department of Pharmacy, University of Patras, 26500, Greece.
authors.forename: Minos-Timotheos
authors.initials: MT
authors.lastname: Matsoukas
authors.affiliation: Immunology and Vaccine Laboratory, Austin Research Institute, Melbourne, VIC, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Day
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, VIC 3021, Australia.
authors.forename: Lily
authors.initials: L
authors.lastname: Stojanovska
authors.affiliation: Department of Chemistry, University of Patras, 26500, Greece.
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.affiliation: Department of Chemistry, University of Patras, 26500, Greece; ELDrug, Patras Science Park, Patras, Greece.
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Androutsou
authors.affiliation: Department of Chemistry, University of Patras, 26500, Greece; ELDrug, Patras Science Park, Patras, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C115314:myelin basic protein 87-99
keywords: Cyclic peptide; Multiple sclerosis; Myelin basic protein; citrullination