21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison's disease.
ABSTRACT 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.
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ABSTRACT: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene and, as a syndrome, is characterized by chronic mucocutaneous candidiasis and the presentation of various autoimmune diseases. During the last decade, research on APECED and AIRE has provided immunologists with several invaluable lessons regarding tolerance and autoimmunity. This review describes the clinical and immunological features of APECED and discusses emerging alternative models to explain the pathogenesis of the disease.Annals of the New York Academy of Sciences 12/2011; 1246:77-91. · 4.38 Impact Factor
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ABSTRACT: OBJECTIVE: While thyrotropin receptor (TSHR) is recognized as the main autoantigen in Graves' disease (GD), the actual antigen specificity of T cells which infiltrate the thyroid and the orbit is unknown. Identifying T cell responses to TSHR peptides has been difficult in the past due to the low frequency of autoreactive T cells and to the diversity of the putative epitopes identified by proliferation assays. METHODS: We used the Interferon gamma ELISPOT assay to identify T cell reactivity to TSHR peptides in GD patients. Peripheral blood T cells were exposed in vitro to four pools of 10 overlapping TSHR peptides. RESULTS: T cells from 11/31 (35%) GD patients and 1/22 (4%) healthy controls reacted to at least one peptide pool (p=0.009). Mean time since diagnosis was 3.2 years in responder patients and 5.6 years in non-responders (p=0.07). In two patients, T cell reactivity was observed shortly after radioiodine treatment and not thereafter. CONCLUSIONS: Our findings demonstrate that the ELISPOT assay is effective to test T cell reactivity in GD patients and that GD patients have significantly more Interferon gamma responses towards TSHR peptides than controls. The data suggest that screening for T cell responses in GD patients might be more efficient in recent-onset disease or after radioiodine treatment. This article is protected by copyright. All rights reserved.Clinical Endocrinology 06/2013; · 3.40 Impact Factor
Article: Autoimmune polyendocrine syndromes.[Show abstract] [Hide abstract]
ABSTRACT: Autoimmune polyendocrine syndromes (APS), also called polyglandular autoimmune syndrome (PGAS), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organs, although non-endocrine organs can be affected. The two major autoimmune polyendocrine syndromes, (type1-type2/APS-1 and APS-2), both have Addison's disease as a prominent component, but exist also APS-3 and APS-4. The major autoimmune polyendocrine syndromes have a strong genetic component with the type 2 syndrome occurring in multiple generations and the type I syndrome in siblings. It is well recognized that more than 20years may elapse between the onset on one endocrinopathy and the diagnosis of the next, for example, almost 40-50% of subjects with Addison's disease will develop an associated endocrinopathy. The discovery of the polyendocrine autoimmune syndromes offered the possibility to understand autoimmune disorders with particular interest for type 1A diabetes and the neuroendocrine immunology (NEI) is further contributing to understand the links.Autoimmunity reviews 09/2013; · 6.37 Impact Factor