21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison's disease

In autoimmune adrenal deficiency autoantibodies target the 21-hydroxylase (21OH) protein However it is presumed that autoreactive T cells rather than antibodies are the main effectors of adrenal gland destruction but their identification is still lacking We performed a T-cell epitope mapping study using 49 overlapping 20mer peptides covering the 21OH sequence in patients with isolated Addison s disease Autoimmune Polyendocrine Syndrome 1 and 2 IFN gamma ELISPOT responses against these peptides were stronger broader and more prevalent among patients than in controls whatever the disease presentation Five peptides elicited T-cell responses in patients only (68% sensitivity 100% specificity) Blocking experiments identified IFN gamma-producing cells as CD8 T lymphocytes with two peptides frequently recognized in HLA-B8+ patients and a third one targeted in HLA-B35+ subjects In particular the 21OH(431-450) peptide was highly immunodominant as it was recognized in more than 30% of patients all carrying the HLA-B8 restriction element This 21OH(431-450) region contained an EPLARLEL octamer (21OH(431-438)) predicted to bind to HIA-B8 with high affinity Indeed circulating EPLARLEL-specific CD8 T cells were detected at significant frequencies in HLA-B8+ patients but not in controls by HIA tetramer staining This report enlightens disease-specific T-cell biomarkers and epitopes targeted in autoimmune adrenal deficiency (c) 2010 Elsevier Ltd All rights reserved