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*
Experimental Neuroimmunology Laboratory, Department of Neurology, University of Tübingen, Tübingen, Germany;
Neuroimmunology Unit, Center of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden;
Brain Research Institute, Neuroimmunology, University of Vienna, Vienna, Austria; and
Max Planck Institute for Neurobiology, Martinsried, Germany
We dissected the requirements for disease induction of myelin
oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune
encephalomyelitis in MHC (RT1 in rat) congenic rats with overlapping
MOG peptides. Immunodominance with regard to peptide-specific T cell
responses was purely MHC class II dependent, varied between different
MHC haplotypes, and was linked to encephalitogenicity only in
RT1.Ba/Da rats. Peptides derived from the MOG
sequence 91–114 were able to induce overt clinical signs of disease
accompanied by demyelinated CNS lesions in the
RT1.Ba/Da and RT1n haplotypes.
Notably, there was no detectable T cell response against this
encephalitogenic MOG sequence in the RT1n haplotype in
peripheral lymphoid tissue. However, CNS-infiltrating lymphoid cells
displayed high IFN-
, TNF-
, and IL-4 mRNA expression suggesting a
localization of peptide-specific reactivated T cells in this
compartment. Despite the presence of MOG-specific T and B cell
responses, no disease could be induced in resistant RT1l
and RT1u haplotypes. Comparison of the number of different
MOG peptides binding to MHC class II molecules from the different RT1
haplotypes suggested that susceptibility to MOG-experimental autoimmune
encephalomyelitis correlated with promiscuous peptide binding to RT1.B
and RT1.D molecules. This may suggest possibilities for a broader
repertoire of peptide-specific T cells to participate in disease
induction. We demonstrate a powerful MHC class II regulation of
autoaggression in which MHC class II peptide binding and peripheral T
cell immunodominance fail to predict autoantigenic peptides relevant
for an autoaggressive response. Instead, target organ responses may be
decisive and should be further explored.
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