Autoimmune primary adrenal insufficiency -current diagnostic approaches and future perspectives

The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress. There are several underlying causes for adrenal insufficiency, where an autoimmune attack by the immune system is the most common cause. A number of genes are known to confer early onset adrenal disease in monogenic inheritance patterns, usually genetic encoding enzymes of adrenal steroidogenesis. Autoimmune primary adrenal insufficiency is usually a polygenic disease where our information recently has increased due to genome association studies. In this review, we go through the physiology of the adrenals before explaining the different reasons for adrenal insufficiency with a particular focus on autoimmune primary adrenal insufficiency. We will give a clinical overview including diagnosis and current treatment, before giving an overview of the genetic causes including monogenetic reasons for adrenal insufficiency and the polygenic background and inheritance pattern in autoimmune adrenal insufficiency. We will then look at the autoimmune mechanisms underlying autoimmune adrenal insufficiency and how autoantibodies are important for diagnosis. We end with a discussion on how to move the field forward emphasizing on the clinical workup, early identification, and potential targeted treatment of autoimmune PAI

Interferon autoantibodies as signals of a sick thymus

Type I interferons (IFN-I) are key immune messenger molecules that play an important role in viral defense. They act as a bridge between microbe sensing, immune function magnitude, and adaptive immunity to fight infections, and they must therefore be tightly regulated. It has become increasingly evident that thymic irregularities and mutations in immune genes affecting thymic tolerance can lead to the production of IFN-I autoantibodies (autoAbs). Whether these biomarkers affect the immune system or tissue integrity of the host is still controversial, but new data show that IFN-I autoAbs may increase susceptibility to severe disease caused by certain viruses, including SARS-CoV-2, herpes zoster, and varicella pneumonia. In this article, we will elaborate on disorders that have been identified with IFN-I autoAbs, discuss models of how tolerance to IFN-Is is lost, and explain the consequences for the host

Autoantibody Repertoire in APECED Patients Targets Two Distinct Subgroups of Protiens

High titer autoantibodies produced by B lymphocytes are clinically important features of many common autoimmune diseases. APECED patients with deficient autoimmune regulator (AIRE) gene collectively display a broad repertoire of high titer autoantibodies, including some which are pathognomonic for major autoimmune diseases. AIRE deficiency severely reduces thymic expression of gene-products ordinarily restricted to discrete peripheral tissues, and developing T cells reactive to those gene-products are not inactivated during their development. However, the extent of the autoantibody repertoire in APECED and its relation to thymic expression of self-antigens are unclear. We here undertook a broad protein array approach to assess autoantibody repertoire in APECED patients. Our results show that in addition to shared autoantigen reactivities, APECED patients display high inter-individual variation in their autoantigen profiles, which collectively are enriched in evolutionarily conserved, cytosolic and nuclear phosphoproteins. The APECED autoantigens have two major origins; proteins expressed in thymic medullary epithelial cells and proteins expressed in lymphoid cells. These findings support the hypothesis that specific protein properties strongly contribute to the etiology of B cell autoimmunity.Peer reviewe

Genome-wide copy number variation (CNV) in patients with autoimmune Addison's disease

<p>Abstract</p> <p>Background</p> <p>Addison's disease (AD) is caused by an autoimmune destruction of the adrenal cortex. The pathogenesis is multi-factorial, involving genetic components and hitherto unknown environmental factors. The aim of the present study was to investigate if gene dosage in the form of copy number variation (CNV) could add to the repertoire of genetic susceptibility to autoimmune AD.</p> <p>Methods</p> <p>A genome-wide study using the Affymetrix GeneChip^®Genome-Wide Human SNP Array 6.0 was conducted in 26 patients with AD. CNVs in selected genes were further investigated in a larger material of patients with autoimmune AD (n = 352) and healthy controls (n = 353) by duplex Taqman real-time polymerase chain reaction assays.</p> <p>Results</p> <p>We found that low copy number of <it>UGT2B28 </it>was significantly more frequent in AD patients compared to controls; conversely high copy number of <it>ADAM3A </it>was associated with AD.</p> <p>Conclusions</p> <p>We have identified two novel CNV associations to <it>ADAM3A </it>and <it>UGT2B28 </it>in AD. The mechanism by which this susceptibility is conferred is at present unclear, but may involve steroid inactivation (<it>UGT2B28</it>) and T cell maturation (<it>ADAM3A</it>). Characterization of these proteins may unravel novel information on the pathogenesis of autoimmunity.</p

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.Peer reviewe

Практикум по анатомии человека. Нервная система. Органы чувств. Эндокринные железы

УЧЕБНЫЕ ПОСОБИЯПРАКТИКУМЫАНАТОМИЯНЕРВНАЯ СИСТЕМА /АНАТОМИЯ И ГИСТОЛОГИЯЭНДОКРИННЫЕ ЖЕЛЕЗЫ /АНАТОМИЯ И ГИСТОЛОГИЯОРГАНЫ ЧУВСТВ /АНАТОМИЯ И ГИСТОЛОГИЯМОЗГ СПИННОЙ /АНАТОМИЯ И ГИСТОЛОГИЯМОЗГ РОМБОВИДНЫЙ /АНАТОМИЯ И ГИСТОЛОГИЯМОЗГ СРЕДНИЙ /АНАТОМИЯ И ГИСТОЛОГИЯМОЗГ ПРОМЕЖУТОЧНЫЙ /АНАТОМИЯ И ГИСТОЛОГИЯМОЗГ КОНЕЧНЫЙ /АНАТОМИЯ И ГИСТОЛОГИЯПРОВОДЯЩИЕ ПУТИ /АНАТОМИЯ И ГИСТОЛОГИЯНЕРВНАЯ СИСТЕМА ВЕГЕТАТИВНАЯ /АНАТОМИЯ И ГИСТОЛОГИЯСПИННОМОЗГОВЫЕ НЕРВЫ /АНАТОМИЯ И ГИСТОЛОГИЯПЛЕЧЕВОЕ СПЛЕТЕНИЕ /АНАТОМИЯ И ГИСТОЛОГИЯПОЯСНИЧНО-КРЕСТЦОВОЕ СПЛЕТЕНИЕ /АНАТОМИЯ И ГИСТОЛОГИЯШЕЙНОЕ СПЛЕТЕНИЕ /АНАТОМИЯ И ГИСТОЛОГИЯПрактикум включает цели, мотивационную характеристику изучения темы, методические рекомендации, дополнительную информацию, контрольные тестовые вопросы, клинически ориентированные ситуационные задачи, направленные на оптимизацию изучения анатомии нервной системы, органов чувств, эндокринных желез человека. Экзаменационные вопросы по представленным в практикуме разделам нацеливают студента на необходимый уровень требований и конечный результат изучения дисциплины. Подготовлен в соответствии с программой по анатомии человека для студентов высших медицинских учебных заведений, обучающихся по специальности "Лечебное дело", дополняет учебник и атлас по анатомии человека

Measuring autoantibodies against IL17F and IL-22 in autoimmune polyendocrine syndromme type I by radioligand binding assay using fusion proteins

Autoantibodies against interleukin (IL)-17A, IL-17F and IL-22 have recently been described in patients with autoimmune polyendocrine syndrome type I (APS I), and their presence is reported to be highly correlated with chronic mucocutaneous candidiasis (CMC). The aim of this study was to develop a robust high-throughput radioligand binding assays (RLBA) measuring IL-17F and IL-22 antibodies, to compare them with current enzyme-linked immunosorbent assays (ELISA) of IL-17F and IL-22 and, moreover, to correlate the presence of these antibodies with the presence of CMC. Interleukins are small molecules, which makes them difficult to express in vitro. To overcome this problem, they were fused as dimers, which proved to increase the efficiency of expression. A total of five RLBAs were developed based on IL-17F and IL-22 monomers and homo- or heterodimers. Analysing the presence of these autoantibodies in 25 Norwegian APS I patients revealed that the different RLBAs detected anti-IL-17F and anti-IL-22 with high specificity, using both homo- and heterodimers. The RLBAs based on dimer proteins are highly reproducible with low inter- and intravariation and have the advantages of high throughput and easy standardization compared to ELISA, thus proving excellent choices for the screening of IL-17F and IL-22 autoantibodies

Altered Immune Activation and IL-23 Signaling in Response to Candida albicans in Autoimmune Polyendocrine Syndrome Type 1

ObjectiveAutoimmune polyendocrine syndrome type 1 (APS-1) is a rare, childhood onset disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis (CMC) is one of the three major disease components and is, to date, mainly explained by the presence of neutralizing auto-antibodies against cytokines [interleukin (IL)-17A, IL-17F, and IL-22] from T helper 17 cells, which are critical for the protection against fungal infections. However, patients without current auto-antibodies also present CMC and we, therefore, hypothesized that other immune mechanisms contribute to CMC in APS-1.MethodsWhole blood was stimulated with Candida albicans (C. albicans) in a standardized assay, and immune activation was investigated by analyzing 46 secreted immune mediators. Then, peripheral blood mononuclear cells were stimulated with curdlan, a Dectin-1 agonist and IL-23 inducer, and the IL-23p19 response in monocytes was analyzed by flow cytometry.ResultsWe found an altered immune response in APS-1 patients compared with healthy controls. Patients fail to increase the essential ILs, such as IL-2, IL-17A, IL-22, and IL-23, when stimulating whole blood with C. albicans. A significantly altered IL-23p19 response was detected in patients’ monocytes upon stimulation with curdlan.ConclusionAPS-1 patients have an altered immune response to C. albicans including a dysregulation of IL-23p19 production in monocytes. This probably contributes to the selective susceptibility to CMC found in the majority of patients

Impaired salivary gland activity in patients with autoimmune polyendocrine syndrome type I

Autoimmune polyendocrine syndrome type I (APS-I) is a severe disease caused by mutations in the autoimmune regulator (AIRE) gene. We hypothesized that salivary gland dysfunction could be a possible unexplored component of these patients and here aimed to investigate salivary and lachrymal symptoms in the Norwegian cohort of APS-I patients (N = 41) and the aetiology behind it. Sicca symptoms and possible corresponding underlying factors were assessed by subjective reports combined with objective measures of saliva and tear flow, serological testing, immune fluorescence microscopy, ultrasonography and searching for putative autoantibodies in the salivary glands. In addition, defensin and anti-defensin levels were analysed in patients and compared with healthy controls. Our results indicate mild salivary and/or lachrymal gland dysfunction manifesting in low saliva or tear flow in a total of 62% of APS-I patients. Serum IgG from 9 of 12 patients bound to targets in salivary gland biopsy slides, although the specificity and pattern of binding varied. There was no reactivity against known Sjögren-associated autoantigens in sera from APS-I patients using quantitative methods, but 11% were ANA positive by immunofluorescence microscopy. We identified several putative autoantigens in one patient, although none of these were verified as APS-I specific. We conclude that impaired salivary gland activity is part of the clinical picture of APS-I and our findings could indicate an autoimmune aetiology. We further show that APS-I patients have an altered antimicrobial signature in both sera and saliva, which requires further investigations