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. IFNγ 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 IFNγ-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 HLA-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 HLA tetramer staining. This report enlightens disease-specific T-cell biomarkers and epitopes targeted in autoimmune adrenal deficiency.
Rottembourg
Diane
D
Endocrinology Service, CHU Sainte-Justine, Department of Pediatrics, Université de Montréal, H3T 1C5 Montréal, Canada.
Deal
Cheri
C
Lambert
Marion
M
Mallone
Roberto
R
Carel
Jean-Claude
JC
Lacroix
André
A
Caillat-Zucman
Sophie
S
le Deist
Françoise
F
D000224:Addison Disease / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D058501:Enzyme-Linked Immunospot Assay; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015795:HLA-B8 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D016884:Polyendocrinopathies, Autoimmune / Q000175:diagnosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D013255:Steroid 21-Hydroxylase / Q000737:chemistry / Q000276:immunology*
D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D015795:HLA-B8 Antigen; D010446:Peptide Fragments; D007371:Interferon-gamma; D013255:Steroid 21-Hydroxylase