Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide
Takamasa Oono, … , Michio Sata, Takehiko Sasazuki
Takamasa Oono, … , Michio Sata, Takehiko Sasazuki
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1589-1596. https://doi.org/10.1172/JCI13256.
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Article

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

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

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Figure 1

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Histopathology of the peripheral nervous system in affected H3 TKO mice....
Histopathology of the peripheral nervous system in affected H3 TKO mice. (a–c) The sciatic nerves from TKO (a), B2L TKO (b), and disease-affected H3 TKO mice (c) were stained with toluidine blue. (d) Electron micrograph of the same H3 TKO sciatic nerve shown in c, showing accumulation of lymphoid cells (arrowheads) around macrophages containing degenerated myelin sheaths within phagosomes (arrows). (e–h) Double immunofluorescence histochemistry of the sciatic nerve from an affected H3 TKO mouse shows infiltration of many CD11b+ cells (e and f, green) and CD4+ cells (e, red), and small numbers of NK1.1+ cells (f, red). Immunoreactivity for CD4 (g and h, green) is colocalized with that for αβ TCR (g, red), but not with that for NK1.1 (h, red). (i–m) The presence or absence of CD11b+ macrophages (green) and CD4+ T cells (red) in the facial (i), trigeminal (j), vagus (k), and optic (l) nerves, and in the spinal cord (SC), and dorsal (DR) and ventral (VR) roots of the spinal nerve (m) of affected H3 TKO mice. All peripheral nerve types sustain massive infiltration of CD4+ T cells and CD11b+ macrophages (i–k and m, DR and VR), whereas the central nervous tissues are intact (l and m, SC). Each fluorescence image is superimposed on the phase-contact image of the same field (e, f, and m). The scale bar represents 40 μm in a–c, 5 μm in d, 50 μm in e, f, and i–l, 25 μm in g and h, and 80 μm in m.