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

Lookup NU author(s): Dr Anna Mitchell, Dr Earn Gan, Professor Simon Pearce

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Abstract

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.


Publication metadata

Author(s): 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, Kampe O, Cerundolo V

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2014

Volume: 193

Issue: 5

Pages: 2118-2126

Print publication date: 01/09/2014

Online publication date: 25/07/2014

Acceptance date: 10/06/2014

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: http://dx.doi.org/10.4049/jimmunol.1400056

DOI: 10.4049/jimmunol.1400056


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