Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide

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Abstract

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-Ab molecule that presents only a single peptide (Eα52-68) 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-Ab–Eα52-68 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-Ab–Eα52-68 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-Ab–Eα52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-Ab–Eα52-68 complex, probably caused by incomplete negative thymocyte selection.

Authors

Takamasa Oono, Yoshinori Fukui, Sadahiko Masuko, Osamu Hashimoto, Takato Ueno, Terukazu Sanui, Ayumi Inayoshi, Mayuko Noda, Michio Sata, Takehiko Sasazuki