HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

Kazuyuki Kawamura, Takashi Yamamura, Kazumasa Yokoyama, De Hua Chui, Yoshinori Fukui, Takehiko Sasazuki, Hidetoshi Inoko, Chella S. David, Takeshi Tabira

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Abstract

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(-/-) mice expressing HLA-DR2 (DRB1*1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested attic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory loci 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.

Original languageEnglish (US)
Pages (from-to)977-984
Number of pages8
JournalJournal of Clinical Investigation
Volume105
Issue number7
StatePublished - Apr 2000

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HLA-DR2 Antigen
Proteolipids
Transgenic Mice
T-Lymphocytes
Peptides
Proteins
HLA-DRB1 Chains
Cell Line
Histocompatibility
Multiple Sclerosis
Autoimmune Diseases of the Nervous System
Central Nervous System Diseases
Cerebrum
Paresis
Hashimoto's encephalitis
Nervous System Diseases
Cerebral Cortex
Cerebellum
Haplotypes
Epitopes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kawamura, K., Yamamura, T., Yokoyama, K., Chui, D. H., Fukui, Y., Sasazuki, T., ... Tabira, T. (2000). HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice. Journal of Clinical Investigation, 105(7), 977-984.

HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice. / Kawamura, Kazuyuki; Yamamura, Takashi; Yokoyama, Kazumasa; Chui, De Hua; Fukui, Yoshinori; Sasazuki, Takehiko; Inoko, Hidetoshi; David, Chella S.; Tabira, Takeshi.

In: Journal of Clinical Investigation, Vol. 105, No. 7, 04.2000, p. 977-984.

Research output: Contribution to journalArticle

Kawamura, K, Yamamura, T, Yokoyama, K, Chui, DH, Fukui, Y, Sasazuki, T, Inoko, H, David, CS & Tabira, T 2000, 'HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice', Journal of Clinical Investigation, vol. 105, no. 7, pp. 977-984.
Kawamura K, Yamamura T, Yokoyama K, Chui DH, Fukui Y, Sasazuki T et al. HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice. Journal of Clinical Investigation. 2000 Apr;105(7):977-984.
Kawamura, Kazuyuki ; Yamamura, Takashi ; Yokoyama, Kazumasa ; Chui, De Hua ; Fukui, Yoshinori ; Sasazuki, Takehiko ; Inoko, Hidetoshi ; David, Chella S. ; Tabira, Takeshi. / HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice. In: Journal of Clinical Investigation. 2000 ; Vol. 105, No. 7. pp. 977-984.
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abstract = "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(-/-) mice expressing HLA-DR2 (DRB1*1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested attic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory loci 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.",
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