Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes: Autoantibodies, Autoantigens, and Their Applicability in Diagnosis and Disease Prediction

Abstract

Recent progress in the understanding of autoimmune adrenal disease, including a detailed analysis of a group of patients with Addison's disease (AD), has been reviewed. Criteria for defining an autoimmune disease and the main features of autoimmune AD (history, prevalence, etiology, histopathology, clinical and laboratory findings, cell-mediated andhumoral immunity, autoantigens and their autoepitopes, genetics, animal models, associated autoimmune diseases, pathogenesis, natural history, therapy) have been described. Furthermore, the autoimmune polyglandular syndromes (APS) associated with AD (revised classification, animal models, genetics, natural history) have been discussed. Of Italian patients with primary AD (n = 317), 83% had autoimmune AD. At the onset, all patients with autoimmune AD (100%) had detectable adrenal cortex and/or steroid 21-hydroxylase autoantibodies. In the course of natural history of autoimmune AD, the presence of adrenal cortex and/or steroid 21-hydroxylase autoantibodies identified patients at risk to develop AD. Different risks of progression to clinical AD were found in children and adults, and three stages of subclinical hypoadrenalism have been defined. Normal or atrophic adrenal glands have been demonstrated by imaging in patients with clinical or subclinical AD. Autoimmune AD presented in four forms: as APS type 1 (13% of the patients), APS type 2 (41%), APS type 4 (5%), and isolated AD (41%). There were differences in genetics, age at onset, prevalence of adrenal cortex/21-hydroxylase autoantibodies, and associated autoimmune diseases in these groups. "Incomplete" forms of APS have been identified demonstrating that APS are more prevalent than previously reported. A varied prevalence of hypergonadotropic hypogonadism in patients with AD and value of steroid-producing cells autoantibodies reactive with steroid 17alpha-hydroxylase or P450 side-chain cleavage enzyme as markers of this disease has been discussed. In addition, the prevalence, characteristic autoantigens, and autoantibodies of minor autoimmune diseases associated with AD have been described. Imaging of adrenal glands, genetic tests, and biochemical analysis have been shown to contribute to early and correct diagnosis of primary non-autoimmune AD in the cases of hypoadrenalism with undetectable adrenal autoantibodies. An original flow chart for the diagnosis of AD has been proposed.

Polyglandular autoimmune syndromes

“…The prevalence of PAS I is lower in Japanese populations (1:10,000,000) [20][21][22][23]. The female/male ratio of PAS I is 0.8-2.4 showing a slight female predominance [7,24]. The manifestation peak is in infancy.…”

Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity

“…In both humans and mice, a defect in Aire results in chronic inflammation of internal organs and production of autoantibodies to the tissues of these organs (10,15). Humans with mutations of the AIRE gene develop autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), a disease that manifests as an autoimmune attack against adrenal and parathyroid glands, stomach, liver, etc.…”

“…Humans with mutations of the AIRE gene develop autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), a disease that manifests as an autoimmune attack against adrenal and parathyroid glands, stomach, liver, etc. (15). In mice lacking Aire, chronic inflammation affects similar organs (10), the precise profile of target tissues being subject to genetic influence (16).…”

Autoimmune polyglandular syndromes in the adults: the genetic and immunological diagnostic criteria

“…Другие аутоиммунные заболевания у пациентов АПС 2-го типа диагностируются с частотой от 1 до 12% случаев (табл. 2) [13]. У пациентов с одним аутоиммунным за-болеванием развитие второго в течение жизни проис-ходит в 25% случаев, а при наличии болезни Аддисо-на -в 50% случаев [14,15].…”

“…При обнаружении повышенного уровня антител рекомендовано выполнение дополнитель-ных тестов (исследование тиреоидной функции, пе-роральный глюкозотолерантный тест, диагностиче-ская биопсия стенки тонкого кишечника и т.д.) [13].…”