Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide.
Organ-specific autoimmune diseases have been postulated to be the result of T cell response against organ-specific self-peptides bound to MHC molecules. Contrary to this paradigm, we report here that transgenic mice lacking MHC class I expression and expressing an MHC class II I-A(b) molecule that presents only a single peptide (E alpha 52-68) spontaneously develops peripheral nervous system-specific autoimmune disease with many of the histopathological features found in experimental allergic neuritis. Reciprocal bone marrow chimeras produced using susceptible and resistant lines revealed that bone marrow-derived cells determined disease susceptibility. While the expression of the I-A(b)-E alpha 52-68 complex in the periphery was readily detectable in both lines, its expression on thymic dendritic cells responsible for tolerance induction was markedly lower in the susceptible line than in the resistant line. Consistent with this, CD4(+) T cells that can be activated by the I-A(b)-E alpha 52-68 complex were found in the susceptible line, but not in the resistant line. Such CD4(+) T cells conferred the disease to the resistant line by adoptive transfer, and administration of Ab specific for the I-A(b)-E alpha 52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-A(b)-E alpha 52-68 complex, probably caused by incomplete negative thymocyte selection.
Oono
T
T
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and Core Research for Evolutional Science and Technology (CREST), Kyushu University, Fukuoka, Japan.
Fukui
Y
Y
Masuko
S
S
Hashimoto
O
O
Ueno
T
T
Sanui
T
T
Inayoshi
A
A
Noda
M
M
Sata
M
M
Sasazuki
T
T
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010446:Peptide Fragments; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D011948:Receptors, Antigen, T-Cell
D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C117647:antigenic peptide Ealpha52-68