title: High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.
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.
authors: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors: Amina
authors: A
authors: Dawoodji
authors: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors: Ji-Li
authors: JL
authors: Chen
authors: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors: Dawn
authors: D
authors: Shepherd
authors: Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, 171 76 Stockholm, Sweden;
authors: Frida
authors: F
authors: Dalin
authors: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors: Andrea
authors: A
authors: Tarlton
authors: Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, 171 76 Stockholm, Sweden;
authors: Mohammad
authors: M
authors: Alimohammadi
authors: Division of Endocrinology, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany;
authors: Marissa
authors: M
authors: Penna-Martinez
authors: Division of Endocrinology, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany;
authors: Gesine
authors: G
authors: Meyer
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors: Anna L
authors: AL
authors: Mitchell
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors: Earn H
authors: EH
authors: Gan
authors: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;
authors: Eirik
authors: E
authors: Bratland
authors: Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors: Sophie
authors: S
authors: Bensing
authors: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;
authors: Eystein S
authors: ES
authors: Husebye
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors: Simon H
authors: SH
authors: Pearce
authors: Division of Endocrinology, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany;
authors: Klaus
authors: K
authors: Badenhoop
authors: Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, 171 76 Stockholm, Sweden; Science for Life Laboratory, Uppsala University 750 03, Uppsala, Sweden.
authors: Olle
authors: O
authors: Kämpe
authors: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom; vincenzo.cerundolo@imm.ox.ac.uk.
authors: Vincenzo
authors: V
authors: Cerundolo
mesh_terms: D000224:Addison Disease / Q000276:immunology* / Q000473:pathology; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000276:immunology / Q000473:pathology; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D006801:Humans; D007111:Immunity, Cellular; D008875:Middle Aged; D010455:Peptides / Q000276:immunology*; D013255:Steroid 21-Hydroxylase / Q000276:immunology*
chemical_list: D010455:Peptides; D013255:Steroid 21-Hydroxylase