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.
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.
Deraos
George
G
Department of Chemistry, University of Patras, Patras 26500, Greece.
Chatzantoni
Kokona
K
Matsoukas
Minos-Timotheos
MT
Tselios
Theodore
T
Deraos
Spyros
S
Katsara
Maria
M
Papathanasopoulos
Panagiotis
P
Vynios
Demitrios
D
Apostolopoulos
Vasso
V
Mouzaki
Athanasia
A
Matsoukas
John
J
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*
D000939:Epitopes; D008024:Ligands; D004676:Myelin Basic Protein; D010455:Peptides; D010456:Peptides, Cyclic; D002956:Citrulline