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Thiopalmitoylation of Myelin Proteolipid Protein Epitopes Enhances Immunogenicity and Encephalitogenicity¹

Judith M. Greer^2,*, Bérangère Denis^3,, Raymond A. Sobel and Elisabeth Trifilieff

^* Department of Medicine, University of Queensland, Royal Brisbane Hospital, Herston, Queensland, Australia; Laboratoire de Chimie Organique des Substances Naturelles, Unité Mixte de Recherche 7509, Centre National de la Recherche Scientifique, Université Louis Pasteur, Strasbourg, France; and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305

Proteolipid protein (PLP) is the most abundant protein of CNS myelin, and is posttranslationally acylated by covalent attachment of long chain fatty acids to cysteine residues via a thioester linkage. Two of the acylation sites are within epitopes of PLP that are encephalitogenic in SJL/J mice (PLP_104–117 and PLP_139–151) and against which increased immune responses have been detected in some multiple sclerosis patients. It is known that attachment of certain types of lipid side chains to peptides can result in their enhanced immunogenicity. The aim of this study was to determine whether thioacylated PLP peptides, as occur in the native protein, are more immunogenic than their nonacylated counterparts, and whether thioacylation influences the development of autoreactivity and experimental autoimmune encephalomyelitis. The results show that in comparison with nonacylated peptides, thioacylated PLP lipopeptides can induce greater T cell and Ab responses to both the acylated and nonacylated peptides. They also enhanced the development and chronicity of experimental autoimmune encephalomyelitis. Synthetic peptides in which the fatty acid was attached via an amide linkage at the N terminus were not encephalitogenic, and they induced greater proportions of CD8⁺ cells in initial in vitro stimulation. Therefore, the lability and the site of the linkage between the peptide and fatty acid may be important for induction of encephalitogenic CD4⁺ T cells. These results suggest that immune responses induced by endogenous thioacylated lipopeptides may contribute to the immunopathogenesis of chronic experimental demyelinating diseases and multiple sclerosis.

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				N. A. Pfender, S. Grosch, G. Roussel, M. Koch, E. Trifilieff, and J. M. Greer Route of Uptake of Palmitoylated Encephalitogenic Peptides of Myelin Proteolipid Protein by Antigen-Presenting Cells: Importance of the Type of Bond between Lipid Chain and Peptide and Relevance to Autoimmunity J. Immunol., February 1, 2008; 180(3): 1398 - 1404. [Abstract] [Full Text] [PDF]