Jm. Greer et al., Thiopalmitoylation of myelin proteolipid protein epitopes enhances immunogenicity and encephalitogenicity, J IMMUNOL, 166(11), 2001, pp. 6907-6913
Proteolipid protein (PLP) is the most abundant protein of CNS myelin, and i
s posttranslationally acylated by covalent attachment of long chain fatty a
cids to cysteine residues via a thioester linkage. Two of the acylation sit
es are within epitopes of PLP that are encephalitogenic in SJL/J mice (PLP1
04-117 and PLP139-151) and against which increased immune responses have be
en detected in some multiple sclerosis patients. It is known that attachmen
t of certain types of lipid side chains to peptides can result in their enh
anced immunogenicity. The aim of this study was to determine whether thioac
ylated PLP peptides, as occur in the native protein, are more immunogenic t
han their nonacylated counterparts, and whether thioacylation influences th
e development of autoreactivity and experimental autoimmune encephalomyelit
is. The results show that in comparison with nonacylated peptides, thioacyl
ated PLP lipopeptides can induce greater T cell and Ab responses to both th
e acylated and nonacylated peptides. They also enhanced the development and
chronicity of experimental autoimmune encephalomyelitis. Synthetic peptide
s in which the fatty acid was attached via an amide linkage at the N termin
us were not encephalitogenic, and they induced greater proportions of CD8() cells in initial in vitro stimulation. Therefore, the lability and the si
te of the linkage between the peptide and fatty acid may be important for i
nduction of encephalitogenic CD4(+) T cells. These results suggest that imm
une responses induced by endogenous thioacylated lipopeptides may contribut
e to the immunopathogenesis of chronic experimental demyelinating diseases
and multiple sclerosis.