Autoimmune regulator gene,Aire, is involved in central tolerance to the DM20 isoform of proteolipid protein and the prevention of autoimmune inflammation

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 (MOG35–55) or proteolipid protein peptide (PLP178–191). PLP178–191 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 PLP178–191 induced more severe EAE in Aire-deficient mice than in the wild-type mice. In contrast, MOG35–55 induced EAE of a similar grade in the wild-type and Aire-knockout mice. In recall response assays to PLP178–191, T cells from Aire-deficient mice produced significantly more interleukin (IL)-17 and interferon (IFN)-γ than the wild-type mice did. Adoptive transfer of CD4+ T cells purified from PLP178–191-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 PLP178–191-, but not MOG35–55-specific immunoglobulin G autoantibodies. Conclusion Aire is involved in establishing central tolerance to PLP178–191, but not to MOG35–55, and its deficiency induces spontaneous autoreactivity to PLP178–191.