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 Addison's Disease (AAD) is an endocrine and immunological disease of uncertain pathogenesis resulting from the immune system's destruction of the hormone producing cells of the adrenal cortex. The underlying molecular mechanisms are largely unknown, but it is commonly accepted that a combination of genetic susceptibility and environmental impact is critical. In the present study, we identified multiple hypomethylated gene promoter regions in patients with isolated AAD using DNA isolated from CD4+ T cells. The identified differentially methylated regions were distributed evenly across the 10.5-kb-promoter regions covered by the array, and a substantial number localized to promoters of genes involved in immune regulation and autoimmunity. This study reveals a hypomethylated status in CD4+ T cells from AAD patients and indicates differential methylation of promoters of key genes involved in immune responses.Molecular Immunology 01/2014; 59(2):208–216. · 2.65 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
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ABSTRACT: Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As of yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders like type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I interferons. We therefore hypothesize that exposure to such interferons could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. Here, we investigated possible immunopathological effects of type I and type III interferons on adrenocortical cells in relation to AAD. Both type I and III interferons exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFNγ- and poly (I:C)-induced chemokine secretion. Furthermore, we observed increased expression of HLA class I molecules and upregulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD.Clinical & Experimental Immunology 02/2014; · 3.41 Impact Factor