title: Citrullination of linear and cyclic altered peptide ligands from myelin basic protein (MBP(87-99)) epitope elicits a Th1 polarized response by T cells isolated from multiple sclerosis patients: implications in triggering disease.
abstract: Derangement of cellular immunity is central in the pathophysiology of multiple sclerosis (MS) and is often manifested by abnormal cytokine production. We investigated cytokine secretion in peripheral blood mononuclear cells (PBMC) of 18 MS patients and 15 controls and correlated cytokine polarization with the nature of antigenic stimulus. We synthesized two novel citrullinated peptides, linear [Cit(91), Ala(96), Cit(97)]MBP(87-99) and cyclo(87-99)[Cit(91), Ala(96), Cit(97)]MBP(87-99) that resulted from citrullination of 91,97 Arg residues in antagonists, linear [Arg(91), Ala(96)]MBP(87-99) and cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) peptides. PBMC from MS patients and controls were cultured with citrullinated peptides, and both peptides caused a Th1 polarization in all MS patients studied. In contrast, culture with noncitrullinated MBP peptides resulted in heterogeneous cytokine secretion that differed between individual patients. Thus, citrullination of self-antigens may potentially trigger disease in susceptible individuals. This finding may open new avenues in drug design of new substances that inhibit citrullination and arrest epitope spreading and worsening of MS.
authors.affiliation: Department of Chemistry, University of Patras, Patras 26500, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Deraos
authors.forename: Kokona
authors.initials: K
authors.lastname: Chatzantoni
authors.forename: Minos-Timotheos
authors.initials: MT
authors.lastname: Matsoukas
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.forename: Spyros
authors.initials: S
authors.lastname: Deraos
authors.forename: Maria
authors.initials: M
authors.lastname: Katsara
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papathanasopoulos
authors.forename: Demitrios
authors.initials: D
authors.lastname: Vynios
authors.forename: Vasso
authors.initials: V
authors.lastname: Apostolopoulos
authors.forename: Athanasia
authors.initials: A
authors.lastname: Mouzaki
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002956:Citrulline / Q000737:chemistry*; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008024:Ligands; D008956:Models, Chemical; D009103:Multiple Sclerosis / Q000209:etiology / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D018417:Th1 Cells / Q000378:metabolism*
chemical_list: D000939:Epitopes; D008024:Ligands; D004676:Myelin Basic Protein; D010455:Peptides; D010456:Peptides, Cyclic; D002956:Citrulline