High Frequency of Cytolytic 21-Hydroxylase–Specific CD8+ T Cells in Autoimmune Addison’s Disease Patients

摘要

The mechanisms behind destruction of the adrenal glands in autoimmune Addison’s disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in 90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase–specific T cells detectable in 20 patients with Addison’s disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8+ and CD4+ T cell responses in a large proportion of Addison’s patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8+ and CD4+ 21-hydroxylase–specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer–guided isolation of 21-hydroxylase–specific CD8+ T cells showed their ability to lyse 21-hydroxylase–positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.