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

• Published in: The Journal of immunology (1950) Vol. 166; no. 12; pp. 7588 - 7599
• Main Authors: Weissert, Robert, de Graaf, Katrien L, Storch, Maria K, Barth, Silvia, Linington, Christopher, Lassmann, Hans, Olsson, Tomas
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.06.2001
• Subjects: Alleles; Amino Acid Sequence; Animals; Animals, Congenic; Autoantigens - analysis; Autoantigens - immunology; B-Lymphocytes - immunology; Cells, Cultured; Central Nervous System - immunology; Central Nervous System - pathology; Chromatography, Affinity; Encephalomyelitis, Autoimmune, Experimental - etiology; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Epitopes, B-Lymphocyte - analysis; Epitopes, B-Lymphocyte - immunology; Epitopes, T-Lymphocyte - analysis; Epitopes, T-Lymphocyte - immunology; Female; Genes, MHC Class I; Genes, MHC Class II; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - isolation & purification; Histocompatibility Antigens Class II - metabolism; Histocompatibility Antigens Class II - physiology; Immune Tolerance; Lymphoid Tissue - immunology; Lymphoid Tissue - pathology; Medicin och hälsovetenskap; Molecular Sequence Data; Myelin Proteins; Myelin-Associated Glycoprotein - administration & dosage; Myelin-Associated Glycoprotein - immunology; Myelin-Associated Glycoprotein - metabolism; Myelin-Oligodendrocyte Glycoprotein; Nasal Mucosa - immunology; Peptide Fragments - administration & dosage; Peptide Fragments - immunology; Peptide Fragments - metabolism; Peptide Mapping; Protein Binding - genetics; Protein Binding - immunology; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Species Specificity; T-Lymphocytes - immunology; Vaccination
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.12.7588

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.B(a)/D(a) 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.B(a)/D(a) and RT1(n) haplotypes. Notably, there was no detectable T cell response against this encephalitogenic MOG sequence in the RT1(n) haplotype in peripheral lymphoid tissue. However, CNS-infiltrating lymphoid cells displayed high IFN-gamma, TNF-alpha, 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 RT1(l) and RT1(u) 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.