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-A b 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-A b -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-A b -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-A b -Eα52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-A b -Eα52-68 complex, probably caused by incomplete negative thymocyte selection.

Animal Models of Autoimmune Neuropathy

“…There are a few other interesting models of SAP. Transgenic mice expressing the MHC class II IA b molecule that presents a single peptide Eα52-68 develop inflammatory neuropathy mediated by CD4 + T cells at 10 weeks or older (Oono et al 2001). In contrast with B7-2 KO NOD mice in which the incidence of neuropathy is higher in females than males, no sex difference was found in the study of Oono and colleagues.…”

HLA Class II peptide‐binding and autoimmunity

“…These observations suggest that the peptide repertoire for DQ0302 and I‐A g7 may be less diverse compared to other MHC molecules. In the extreme case where the MHC‐bound peptide repertoire in the thymus for T cell selection is limited to a single peptide, I‐A b Eα class I null mice develop a spontaneous organ specific autoimmune disease (19). These mice represent an extreme case in which autoreactive T cells can escape into the periphery under conditions where the selecting peptide repertoire on thymic APCs is severely limited. Selection of potential autoreactive T cells that are biased towards recognizing the “shared epitope” present on rheumatoid arthritis (RA) susceptible MHC molecules has also been proposed as a possible pathogenic mechanism in RA.…”

Untitled

“…Oono and coworkers [87] produced transgenic mice that express Eα 52–68 covalently bound to the I-A b molecule as their only MHC peptide complex. These mice spontaneously develop a CD4 + Th cell dependent peripheral nervous system-specific autoimmune disease.…”

“…These mice spontaneously develop a CD4 + Th cell dependent peripheral nervous system-specific autoimmune disease. Neuritis in these TCR transgenic mice shares many of the histopathological features found in experimental autoimmune neuritis, including demyelination and axon degeneration [87]. Serum from these transgenic mice did not stain peripheral nerves and could not transfer the disease to other animals [87].…”