Citation

Objective To show the role of the autoimmune regulator (Aire), a gene expressed in medullary thymic epithelial cells (mTEC), in the tolerance to encephalitogenic myelin epitopes. Methods C57BL/6J Aire-deficient and wild-type mice were immunized with myelin oligodendrocyte glycoprotein peptide (MOG3555) or proteolipid protein peptide (PLP178191). PLP178191 is contained only in PLP/DM20, an isoform derived from a splice variant of PLP. We evaluated the development of experimental autoimmune encephalomyelitis (EAE) and reported the T cell response to these peptides. Results mTEC from wild-type mice expressed PLP/DM20, but those from Aire-deficient mice only expressed it at low levels. Immunization with PLP178191 induced more severe EAE in Aire-deficient mice than in the wild-type mice. In contrast, MOG3555 induced EAE of a similar grade in the wild-type and Aire-knockout mice. In recall response assays to PLP178191, T cells from Aire-deficient mice produced significantly more interleukin (IL)-17 and interferon (IFN)- than the wild-type mice did. Adoptive transfer of CD4+ T cells purified from PLP178191-immunized Aire-deficient mice induced a more severe EAE than a similar transfer from the immunized wild-type mice. In comparison with wild-type mice, we also found that sera from aged, naive Aire-deficient mice showed higher titers of PLP178191-, but not MOG3555-specific immunoglobulin G autoantibodies. Conclusion Aire is involved in establishing central tolerance to PLP178191, but not to MOG3555, and its deficiency induces spontaneous autoreactivity to PLP178191.