MHC Class II-Regulated Central Nervous System Autoaggression and T Cell Responses in Peripheral Lymphoid Tissues Are Dissociated in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Abstract

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-γ, TNF-α, 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.

MHC Class II Isotype- and Allele-Specific Attenuation of Experimental Autoimmune Encephalomyelitis

“…Binding assays were performed with a competitive ELISA based on a dissociation-enhanced lanthanide fluoroimmunoassay (Wallac, Turku, Finland) (18). For the competitive ELISA, a 50 nM solution of RT1.D molecules was incubated for 48 h at 37°C with 100 nM biotinylated CLIP 97-120 and 2 M acetylated nonapeptide amide sublibrary or with various concentrations of competitor peptides.…”

“…RT1.D n , RT1.B n , RT1.D l , and RT1.B l molecules were purified from thymic and splenic tissue from LEW.1N (RT1 n ) rats and LEW (RT1 l ) rats by affinity chromatography using the mAbs OX-17 (anti RT1.D) and OX-6 (anti RT1.B), as previously described (18). Binding assays were performed with a competitive ELISA based on a dissociation-enhanced lanthanide fluoroimmunoassay (Wallac, Turku, Finland) (18).…”

“…Mononuclear cells (MNC) from draining lymph nodes, spleen, and CNS were obtained, as described (18). B cells from the spleens of naive rats were purified by magnetic cell separation against CD45RA (Miltenyi Biotec, Bergisch Gladbach, Germany).…”

Experimental Autoimmune Encephalomyelitis

“…We could show that the peptides that induce EAE are binding well to the MHC II molecules that present the peptides to T cells (de Graaf et al, 2008;de Graaf et al, 1999;Weissert et al, 2001;Weissert et al, 1998a). We dissected the binding qualities to purified RT1.B and RT1.D molecules and the T and B cell response to MOG 91-108 in LEW.1N and LEW.1AV1 rats.…”

Current Gene‐Mapping Strategies in Experimental Models of Multiple Sclerosis

“…In the case of MOG, the peptide-stretch aa 91-114 is potently encephalitogenic in RT1.N and in RT1.AVI. This peptide is a good MHC class II molecule binder in these strains and is simultaneously a B-cell epitope [44]. Although the mechanisms for the MHC-regulated encephalitogeneity remain to be clarified, this model system may allow the dissection of MHC-regulated autoaggression versus nonharmful autoimmune responses.…”