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

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity

Autoimmune polyendocrine syndrome type I. Novel diagnostic assays and immune regulation

Autoimmune polyendocrine syndrome type I (APS-I) is a rare, monogenetic recessively inherited disease caused by mutations in the autoimmune regulator (AIRE) gene. The patients display different endocrine and ectodermal manifestations, where the majority develop at least two of the three main components of autoimmune adrenocortical failure (Addison’s disease), hypoparathyroidism and chronic mucocutaneous candidiasis (CMC). In addition, patients frequently develop autoantibodies against molecular targets in their affected organs and against cytokines of the immune system. In two studies, robust immunoassays detecting APS-I patients with high sensitivity and specificity were developed. Autoantibodies against in vitro transcribed and translated interferon omega (IFN- ) and interleukin (IL) 17F and IL-22 were measured, the latter shown to correlate to CMC. Antibodies against IFN- were confirmed as a universal marker for APS-I, suggesting this assay as an ideal screening tool preceding mutational analyses in suspected APS-I cases. We have shown that single nucleotide polymorphisms and variation in copy number of AIRE have no association with Addison’s disease. However, large deletions in one allele of AIRE together with a concomitant disease-causing mutation were discovered in two APS-I patients, underpinning the importance of copy number analysis. A wide range of immune cell subsets were studied, identifying disturbances in the regulatory T cell compartment together with less CCR6+CXCR3+ T cells and a reduction in CD16+ monocytes in patients with APS-I, possibly resulting in susceptibility for developing autoimmune manifestations. The characterisation of genetic variations in AIRE and of abnormalities in the immune cell subsets contribute to our understanding of the function of AIRE, while establishing immunoassays ease the identification of APS-I patients

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

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

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

T cell receptor assessment in autoimmune disease requires access to the most adjacent immunologically active organ

Next generation sequencing of T and B cell receptors is emerging as a valuable and effective method to diagnose and monitor hematopoietic malignancies. So far, this approach has not been fully explored in regard to autoimmune diseases. T cells develop in the thymus where they undergo positive and negative selection, and the autoimmune regulator (Aire) is central in the establishment of immunological tolerance. Loss of Aire leads to severe multiorgan autoimmune disease with infiltration of autoreactive T cells in affected organs. Here, we have utilized next generation sequencing technology to investigate the T cell receptor repertoire in autoimmunity induced by immunization of mice with a self-antigen, myeloper-oxidase. By investigating the T cell receptor repertoire in peripheral blood, spleen and lumbar lymph nodes from naive and immunized Aire -/- mice and wild type littermates, changes in the usage of V and J genes were evident. Our results identify TCR clonotypes which could be potential targets for immune therapy. Also, Aire -/- autoimmunity is driven by a variety of autoantigens where the autoimmune response is highly polyclonal, and access to the most adjacent immunologically active tissue is required to identify T cell receptor sequences that are potentially unique to the antigen in Aire-/- immunized mice

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