High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.

Dawoodji A, Chen JL, Shepherd D, Dalin F, Tarlton A, Alimohammadi M, Penna-Martinez M, Meyer G, Mitchell AL, Gan EH, Bratland E, Bensing S, Husebye ES, Pearce SH, Badenhoop K, Kämpe O, Cerundolo V

J. Immunol. 193 (5) 2118-2126 [2014-09-01; online 2014-07-25]

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.

Affiliated researcher

PubMed 25063864

DOI 10.4049/jimmunol.1400056

Crossref 10.4049/jimmunol.1400056

pii: jimmunol.1400056
pmc: PMC4821366
mid: EMS67426

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