Endocrinopathies in Inborn Errors of Immunity.

Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.

The Kynurenine Pathway-New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies.

The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells' differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies-type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.

COVID-19 Vaccination for Endocrine Patients: A Position Statement from the Korean Endocrine Society.

Since the first outbreak of coronavirus disease 2019 (COVID-19), ongoing efforts have been made to discover an efficacious vaccine against COVID-19 to combat the pandemic. In most countries, both mRNA and DNA vaccines have been administered, and their side effects have also been reported. The clinical course of COVID-19 and the effects of vaccination against COVID-19 are both influenced by patients' health status and involve a systemic physiological response. In view of the systemic function of endocrine hormones, endocrine disorders themselves and the therapeutics used to treat them can influence the outcomes of vaccination for COVID-19. However, there are very limited data to support the development of clinical guidelines for patients with specific medical backgrounds based on large clinical trials. In the current severe circumstances of the COVID-19 pandemic, position statements made by clinical specialists are essential to provide appropriate recommendations based on both medical evidence and clinical experiences. As endocrinologists, we would like to present the medical background of COVID-19 vaccination, as well as precautions to prevent the side effects of COVID-19 vaccination in patients with specific endocrine disorders, including adrenal insufficiency, diabetes mellitus, osteoporosis, autoimmune thyroid disease, hypogonadism, and pituitary disorders.

Multiplex Autoantibody Detection in Patients with Autoimmune Polyglandular Syndromes.

The diagnosis of autoimmune polyglandular syndrome (APS) types 1/2 is difficult due to their rarity and nonspecific clinical manifestations. APS-1 development can be identified with assays for autoantibodies against cytokines, and APS-2 development with organ-specific antibodies. In this study, a microarray-based multiplex assay was proposed for simultaneous detection of both organ-specific (anti-21-OH, anti-GAD-65, anti-IA2, anti-ICA, anti-TG, and anti-TPO) and APS-1-specific (anti-IFN-ω, anti-IFN-α-2a, and anti-IL-22) autoantibodies. Herein, 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies or non-autoimmune endocrine pathologies and from healthy donors were analyzed. The prevalence of autoantibodies differed among the groups of healthy donors and patients with non-, mono- and multi-endocrine diseases. APS-1 patients were characterized by the presence of at least two specific autoantibodies (specificity 99.5%, sensitivity 100%). Furthermore, in 16 of the 18 patients, the APS-1 assay revealed triple positivity for autoantibodies against IFN-ω, IFN-α-2a and IL-22 (specificity 100%, sensitivity 88.9%). No anti-cytokine autoantibodies were found in the group of patients with non-APS-1 polyendocrine autoimmunity. The accuracy of the microarray-based assay compared to ELISA for organ-specific autoantibodies was 88.8-97.6%. This multiplex assay can be part of the strategy for diagnosing and predicting the development of APS.

Inflammatory markers in autoimmunity induced by checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized. METHODS: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1ß, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA). RESULTS: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems. CONCLUSION: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.

Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases.

Coronaviruses and Endocrine System: A Systematic Review on Evidence and Shadows.

Coronaviruses are a big family of viruses that can infect mammalians and birds. In humans they mainly cause respiratory tract infections, with a large spectrum of severity, from mild, self-limited infections to highly lethal forms as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and Coronavirus Disease 2019 (COVID-19). Scanty data are reported for the involvement of endocrine glands in human coronaviruses, in particular SARS-CoV-2. In this review, we summarize endocrinological involvement in human coronaviruses, including data on animal coronaviruses. Avians, ferrets and bovine are affected by specific coronavirus syndromes, with variable involvement of endocrine glands. SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a target receptor, so ACE2 plays a central role in viral transmission and initial organ involvement. Autoptic studies on SARS patients revealed that thyroid, parathyroid, pituitary gland, endocrine pancreas and especially adrenals and testis could be impaired by different mechanisms (direct damage by SARS-CoV, inflammation, vascular derangement and autoimmune reactions) and few clinical studies have evidenced functional endocrine impairment. Only few data are available for COVID-19 and gonads and endocrine pancreas seem to be involved. International endocrinological societies have brought some recommendations for the COVID-19 pandemic, but further studies need to be performed, especially to detect long-term hormonal sequelae.

New era of therapy for endocrine autoimmune disorders.

The new era of immune and reconstitution therapy of autoimmune disorders is ongoing. However, endocrine autoimmune diseases comprise a group of elaborating pathologies where the development of new treatment strategies remains slow. Substitution of the missing hormones is still standard practice, taking care of the devastating symptoms but not the cause of disease. As our knowledge of the genetic contribution to the aetiology of endocrine disorders increases and early diagnostic tools are available, it is now possible to identify persons at risk before they acquire full-blown disease. This review summarizes current knowledge and treatment of endocrine autoimmune disorders, focusing on type 1 diabetes, Addison's disease, autoimmune thyroid diseases and primary ovarian insufficiency. We explore which new therapies might be used in the different stages of the disease, focus on legalized therapy and elaborate on the ongoing clinical studies for these diseases and the research front, before hypothesizing on the way ahead.

Gut microbiota and metabolites in the pathogenesis of endocrine disease.

Type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT) are the two most common autoimmune endocrine diseases that have rising global incidence. These diseases are caused by the immune-mediated destruction of hormone-producing endocrine cells, pancreatic beta cells and thyroid follicular cells, respectively. Both genetic predisposition and environmental factors govern the onset of T1D and HT. Recent evidence strongly suggests that the intestinal microbiota plays a role in accelerating or preventing disease progression depending on the compositional and functional profile of the gut bacterial communities. Accumulating evidence points towards the interplay between the disruption of gut microbial homeostasis (dysbiosis) and the breakdown of host immune tolerance at the onset of both diseases. In this review, we will summarize the major recent findings about the microbiome alterations associated with T1D and HT, and the connection of these changes to disease states. Furthermore, we will discuss the potential mechanisms by which gut microbial dysbiosis modulates the course of the disease, including disruption of intestinal barrier integrity and microbial production of immunomodulatory metabolites. The aim of this review is to provide broad insight into the role of gut microbiome in the pathophysiology of these diseases.

ASIA syndrome and endocrine autoimmune disorders.

An adjuvant is an immunological or pharmacological substance or group of substances that can be added to a given agent to enhance its effect in terms of efficacy, effectiveness and potency. Different mechanisms have been hypothesized underlying the action of the adjuvant, including boosting immune (innate and adaptive) response: this generally results in sparing the necessary amount of the agent and can potentially reduce the frequency of the needed number of therapeutic interventions. Adjuvants can be commonly found in vaccines, immunization products, mineral oils, cosmetics, silicone breast implants and other therapeutic/medical devices, being usually safe and effective. However, in a fraction of genetically susceptible and predisposed subjects, the administration of adjuvants may lead to the insurgence of serious side-effects, called "autoimmune/inflammatory syndrome by adjuvants" (ASIA) or Shoenfeld's syndrome. The present review is aimed at focusing on the "endocrine pebbles" of the mosaic of autoimmunity and of the ASIA syndrome, collecting together 54 cases of sub-acute thyroiditis, 2 cases of Hashimoto's thyroiditis, 11 cases of primary ovarian failure/primary ovarian insufficiency, 13 cases of autoimmune diabetes type 1, and 1 case of autoimmune adrenal gland insufficiency occurred after exposure to adjuvants.

Check point inhibitors and autoimmunity: Why endocrinopathies and who is prone to?

Immunotherapy has transformed the treatment of cancer by restoring the power of the immune system against tumor cells. Disruption of the innate immune inhibition has introduced a large and growing spectrum of immune-related adverse effects (irAEs), with the endocrine system being a prominent target to autoimmune damage. What makes the endocrine system a prominent target when facing an unleashed immune system? Why are the endocrine irAEs mostly irreversible and unresponsive to glucocorticoid therapy? Is it possible to identify those prone to develop irAEs? The presents review describes the unique characteristics of the endocrine system and its crosstalk with the immune system. In a broader perspective, the iatrogenic side effects of immunotherapy provide a unique opportunity to explore the genetic, humoral and cytotoxic immune confounders.

Autoimmune Pituitary Disease: New Concepts With Clinical Implications.

Some endocrine disorders, including hypophysitis and isolated adrenocorticotropic hormone (ACTH) deficiency, are caused by an autoimmune response to endocrine organs. Although the pathogenesis of some autoimmune endocrine diseases has been elucidated, it remains obscure for most. Anti-PIT-1 hypophysitis (anti-PIT-1 antibody syndrome) is a newly described pituitary autoimmune disease characterized by acquired and specific growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies. This disorder is associated with a thymoma or neoplasm that ectopically expresses pituitary-specific transcription factor 1 (PIT-1) protein. Circulating anti-PIT-1 antibody is a disease marker, and PIT-1-reactive cytotoxic T cells (CTLs) play a pivotal role in disease development. In addition, isolated ACTH deficiency appears to be caused by autoimmunity to corticotrophs; however, the pathogenesis remains unclear. A recently described case of isolated ACTH deficiency with large cell neuroendocrine carcinoma (LCNEC) showed ectopically expressed proopiomelanocortin (POMC), and circulating anti-POMC antibody and POMC-reactive CTLs were also detected. As CTL infiltrations around corticotrophs were also observed, isolated ACTH deficiency may be associated at least in part with a paraneoplastic syndrome. Although several underlying mechanisms for pituitary autoimmunity have been proposed, these observations highlight the importance of paraneoplastic syndrome as a cause of pituitary autoimmune disease. In this review, we focus on the pathophysiology and connection of anti-PIT-1 hypophysitis and isolated ACTH deficiency and discuss the state-of-art knowledge for understanding pituitary autoimmunity.

The Functional Significance of Endocrine-immune Interactions in Health and Disease.

Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms.

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.

[Justification of the need to normalize vitamin D status for immunoprophylaxis].

Currently, there is an increase in the resistance of microorganisms to the available arsenal of antimicrobial drugs, which makes it necessary to maintain and stimulate the body's own immune-protective properties. The main extraskeletal effect of vitamin D activity is associated with the homeostasis of the immune system. The role of vitamin D in reducing the risk of infection with infectious agents has been studied for a long time. Literature search on the effective use of vitamin D for immunoprophylaxis was carried out in Scopus, Web of Science, PubMed, clinicaltrials.gov databases over the past 10 years for related keywords: vitamin D, immunoprophylaxis. Vitamin D stimulates the synthesis of antimicrobial peptides, cathelicidins and defensins, which exhibit broad-spectrum activity against viruses, bacteria and fungal infections; reduces the concentration of pro-inflammatory cytokines; increases the concentration of anti-inflammatory cytokines. Vitamin D is also involved in cell differentiation, maturation and proliferation of immune cells. The article presents the literature review in order to justify additional intake of vitamin D in case of diagnosis of its deficiency and insufficiency for the purpose of immunoprophylaxis in children and adults, especially in risk groups (elderly age, pregnant women, patients with chronic diseases of respiratory, endocrine and urinary systems, gastrointestinal tract, and infectious diseases). Inclusion of vitamin D in the diet as a dietary supplement, as well as fortification of products with it, can be an effective measure to reduce the risk of both morbidity and mortality, especially during the period of quarantine measures.

Th1 Chemokines in Autoimmune Endocrine Disorders.

CONTEXT: The CXC chemokine receptor CXCR3 and its chemokines CXCL10, CXCL9, and CXCL11 are implicated in the pathogenesis of autoimmune diseases. Here, we review these chemokines in autoimmune thyroiditis (AT), Graves disease (GD), thyroid eye disease (TED), type 1 diabetes (T1D), and Addison's disease (AAD). EVIDENCE ACQUISITION: A PubMed review of the literature was conducted, searching for the above-mentioned chemokines in combination with AT, GD, TED, T1D, and AAD. EVIDENCE SYNTHESIS: Thyroid follicular cells in AT and GD, retroorbital cells in TED (fibroblasts, preadipocytes, myoblasts), ß cells and islets in T1D, and adrenal cells in AAD respond to interferon-γ (IFN-γ) stimulation producing large amounts of these chemokines. Furthermore, lymphocytes and peripheral blood mononuclear cells (PBMC) are in part responsible for the secreted Th1 chemokines. In AT, GD, TED, T1D, and AAD, the circulating levels of these chemokines have been shown to be high. Furthermore, these chemokines have been associated with the early phases of the autoimmune response in all the above-mentioned disorders. High levels of these chemokines have been associated also with the "active phase" of the disease in GD, and also in TED. Other studies have shown an association with the severity of hypothyroidism in AD, of hyperthyroidism in GD, with severity of TED, or with fulminant T1D. CONCLUSION: The reviewed data have shown the importance of the Th1 immune response in different endocrine autoimmune diseases, and many studies have suggested that CXCR3 and its chemokines might be considered as potential targets of new drugs for the treatment of these disorders.

The spectrum of clinical and subclinical endocrinopathies in treatment-naïve patients with celiac disease.

INTRODUCTION: Strong association exists between celiac disease and autoimmune endocrinopathies such as type I diabetes and hypothyroidism; there is a lack of data on the involvement of other endocrine organs such as pituitary-gonadal axis. Furthermore, there is lack of data on the spectrum of involvement of endocrine organs varying from organ autoimmunity to subclinical and clinical disease. We evaluated consecutive treatment-naïve patients with celiac disease (CeD) for clinical and subclinical endocrinopathies. METHODS: Of 154 screened, 74 treatment-naïve patients with CeD were recruited. They underwent hormonal and/or functional assessment of beta cell of pancreas, thyroid gland, pituitary-gonadal axis, and parathyroid glands. RESULTS: Of the 74 patients with CeD, 31 (41.9%) had at least one clinical or subclinical endocrinopathy and 9 (12.2%) had multiple endocrinopathies. Most common of them were clinical or subclinical type I diabetes and autoimmune thyroid disease. Interestingly, 8 (10.8%) patients also were found to have functional hypopituitarism and 7/54 (12.9%) having isolated hypogonadotropic hypogonadism. CONCLUSIONS: Patients with CeD have high percentages of not only clinical endocrinopathy including pituitary-gonadal axis dysfunction but also subclinical endocrinopathy. Whether commencement of gluten-free diet will lead to reversal of subclinical endocrinopathies requires further follow up studies.

Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab.

We investigated risk factors for immune-related adverse events (irAEs) in patients treated with anti-programmed cell death protein1 antibody pembrolizumab. A retrospective medical record review was performed to identify all patients who received at least one dose of pembrolizumab at Samsung Medical Center, Seoul, Korea between June 2015 and December 2017. Three hundred and ninety-one patients were included in the study. Data were collected on baseline characteristics, treatment details, and adverse events. Univariate and multivariate logistic regression models were used to identify risk factors for irAEs. Sixty-seven (17.1%) patients experienced clinically significant irAEs; most commonly dermatologic disorders, followed by pneumonitis, musculoskeletal disorders, and endocrine disorders. Fourteen patients (3.6%) experienced serious irAEs (grade ≥ 3). Most common serious irAEs were pneumonitis (2.3%). Four deaths were associated with irAEs, all of which were due to pneumonitis. In multivariate regression analysis, a higher body mass index (BMI) and multiple cycles of pembrolizumab were associated with higher risk of irAEs (BMI: odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01-1.16; pembrolizumab cycle: OR 1.15, 95% CI 1.08-1.22). A derived neutrophil-lymphocyte ratio (dNLR) greater than 3 at baseline was correlated with low risk of irAEs (OR 0.37, 95% CI 0.17-0.81). Our study demonstrated that an elevated BMI and higher number of cycles of pembrolizumab were associated with an increased risk of irAEs in patients treated with pembrolizumab. Additionally, increased dNLR at baseline was negatively correlated with the risk of developing irAEs.

Autoimmune polyglandular diseases.

Autoimmune polyglandular diseases (APD) are defined as the presence of two autoimmune -induced endocrine failures. With respect to the significant morbidity and potential mortality of APD, the diagnostic objective is to detect APD at an early stage, with the advantage of less frequent complications, effective therapy and better prognosis. This requires that patients at risk be regularly screened for subclinical endocrinopathies prior to clinical manifestation. Regarding the time interval between manifestation of first and further endocrinopathies, regular and long-term follow-up is warranted. Quality of life and psychosocial status are poor in APD patients and involved relatives. Familial clustering is high in patients with APD. Considering the high incidence of one or more endocrinopathies in first-degree relatives of patients with APD, family members should be regularly screened since they may also develop autoimmune endocrinopathies. Multidisciplinary management of these multiplex families in specialized centers is warranted.

Endocrine Disorders Are Prominent Clinical Features in Patients With Primary Antibody Deficiencies.

Background: Primary antibody deficiencies (PADs) and anterior pituitary dysfunction are both rare conditions. However, recent studies have remarkably reported the occurrence of anterior pituitary dysfunction in PAD patients. Methods: In this cross-sectional, single-center study we evaluated the prevalence of endocrine disorders in adult PAD patients. Our study focused on common variable immunodeficiency (CVID), immunoglobulin G (IgG) subclass deficiency (IgGSD), and specific anti-polysaccharide antibody deficiency (SPAD). We assessed hormone levels, performed provocative tests and genetic testing in a subset of patients by direct sequencing of the nuclear factor kappa beta subunit 2 (NFKB2) gene and primary immunodeficiency (PID) gene panel testing by whole exome sequencing (WES). Results: Our results demonstrated that one out of 24 IgGSD/SPAD patients had secondary hypothyroidism and three out of 9 men with IgGSD/SPAD had secondary hypogonadism. Premature ovarian failure was observed in four out of 9 women with CVID and primary testicular failure in one out of 15 men with CVID. In two out of 26 CVID patients we found partial adrenal insufficiency (AI) and in one out of 18 patients with IgGSD/SPAD secondary AI was found. Moreover, in one out of 23 patients with CVID and in two out of 17 patients with IgGSD/SPAD severe growth hormone deficiency (GHD) was found, while one patient with IgGSD/SPAD showed mild GHD. Combined endocrine disorders were detected in two women with CVID (either partial secondary AI or autoimmune thyroiditis with primary hypogonadism) and in three men with IgGSD/SPAD (two with either mild GHD or secondary hypothyroidism combined with secondary hypogonadism, and one man with secondary AI and severe GHD). Genetic testing in a subset of patients did not reveal pathogenic variants in NFKB2 or other known PID-associated genes. Conclusion: This is the first study to describe a high prevalence of both anterior pituitary and end-organ endocrine dysfunction in adult PAD patients. As these endocrine disorders may cause considerable health burden, assessment of endocrine axes should be considered in PAD patients.