Hla-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice.
In multiple sclerosis (MS) patients who carry the Class II major histocompatibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We have addressed this issue, using mice transgenic for the human MHC class II region carrying the HLA-DR2 (DRB1* 1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restricted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immunized with this portion of PLP. The TCLs were CD4+ and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively transferred into RAG-2/2 mice expressing HLA-DR2 (DRG1* 1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to the cerebrum and cerebellum, in association with scattered demyelinating lesions in the deep cerebral cortex. These results support a pathogenic role for PLP95-116-specific T cells in HLA-DR2+ MS patients, and shed light on the possible correlation between autoimmune target epitope and disease phenotype in human CNS autoimmune diseases.
Kawamura
K
K
Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
Yamamura
T
T
Yokoyama
K
K
Chui
D H
DH
Fukui
Y
Y
Sasazuki
T
T
Inoko
H
H
David
C S
CS
Tabira
T
T
D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015802:HLA-DR2 Antigen / Q000096:biosynthesis / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000276:immunology*; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D015802:HLA-DR2 Antigen; D059811:HLA-DRB1 Chains; D018991:Myelin Proteolipid Protein; D009687:Nuclear Proteins; D010446:Peptide Fragments; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2