Thiopalmitoylation of myelin proteolipid protein epitopes enhances immunogenicity and encephalitogenicity.
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.
Greer
J M
JM
Neuroimmunology Research Unit, Department of Medicine, University of Queensland, Royal Brisbane Hospital, Herston QLD 4029, Australia. j.greer@medicine.uq.edu.au
Denis
B
B
Sobel
R A
RA
Trifilieff
E
E
D000215:Acylation; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D005260:Female; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D008074:Lipoproteins / Q000008:administration & dosage / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D010169:Palmitic Acids / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D016056:Immunodominant Epitopes; D008074:Lipoproteins; D018991:Myelin Proteolipid Protein; D010169:Palmitic Acids; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); C091863:thiopalmitic acid