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Introduction: Immunotherapy is one of the greatest advancements in oncological patient care. The broader the treatment application, the more common the adverse events associated with the therapy. Immune checkpoint inhibitors (ICI) are currently used in numerous malignancies. These drugs influence the immune cells' interactions, which translates to interruption of immune evasion and increased anti-tumor activity. However, the disruption of immunological signaling pathways often leads to adverse events, such as endocrinological insufficiencies, among which thyroid is the most common. Moreover, the co-appearance of several insufficiencies has been previously described. Case report: A 73-year-old female treated with durvalumab due to non-small cell lung carcinoma was admitted to the emergency unit due to symptoms of ketoacidosis. She had a history of well-controlled type 2 diabetes mellitus and autoimmune thyroiditis. Laboratory results showed increased anti-GAD antibodies, while the low C-peptide level indicated type 1 diabetes mellitus. Moreover, over the course of longer observation, the patient presented with abrupt aggravation of her autoimmune thyroiditis. Conclusions: The new onset of endocrinological insufficiencies is a rare adverse event of immunotherapy. Clinicians must pay particular attention to any signs indicating these life-threatening conditions. In case of the appearance of any endocrinological adverse event, the close cooperation of oncologists and endocrinologists is required to enhance patients' quality of life. [ABSTRACT FROM AUTHOR]

Infantile refractory diarrhea presents after first few days of life leading to intestinal insufficiency. It is a diagnostic challenge due to varied etiologies like food senstive enteropathy, anatomical defects and dysmotility disorders, transport and enzymatic defects, pancreatic malabsorption - cystic fibrosis (CF), primary epithelial causes like microvillus inclusion disease (MVID), tufting enteropathy and heparan sulfate deficiency, immunodeficiencies, metabolic diseases and autoimmune enteropathy. It is refractory to treatment making the patient dependent on total parenteral nutrition. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), is one of the rarest causes of intractable diarrhea. It occurs due to mutations in the FOXP3 gene, leading to dysfunction of T-regulatory cells and is characterised by diarrhoea, diabetes, and dermatitis. We aim to evaluate various causes of infantile refractory chronic diarrhea, and to present one such case of IPEX syndrome from this part of the world due to mutation not been reported in literature so far. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare, fatal autoimmune disorder caused by mutations in the FOXP3 gene leading to the disruption of signaling pathways involved in regulatory T-lymphocyte function. This paper reviewed the clinical data of an IPEX child with respiratory and gastrointestinal symptoms as main symptoms, and summarized treatment and nursing experience. During the treatment, comprehensive interventions such as airway management, individualized nutrition support, medication care, psychological care of primary caregivers, skin care and healthcare education were carried out to reduce the incidence of complications and improve the recovery of the patient. (X-连锁多内分泌腺病肠病伴免疫失调综合征(IPEX)在临床上极为罕见。本文回顾医院收治1例以免疫系统低下引起的呼吸系统症状以及消化系统症状为主的IPEX患儿的临床资料, 总结护理经验。治疗期间, 给予患儿呼吸道管理和个体化营养干预, 加强用药护理、主要照顾者心理护理、皮肤护理和健康教育, 降低并发症发生风险, 促进患儿康复。)

Autoimmune polyendocrine syndromes (APSs) encompass a heterogeneous group of rare diseases characterized by autoimmune activity against two or more endocrine or non-endocrine organs. Three types of APSs are reported, including both monogenic and multifactorial, heterogeneous disorders. The aim of this manuscript is to present the main clinical and epidemiological characteristics of APS-1, APS-2, and IPEX syndrome in the pediatric age, describing the mechanisms of autoimmunity and the currently available treatments for these rare conditions. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked, known as IPEX syndrome, is a rare heterogeneous condition. Zhu-Tokita-Takenouchi-Kim Syndrome (ZTTK) is an autosomal dominant condition arising from a mutation in the SON gene, which is involved in mRNA splicing. A case showing interactions of mutations in these two genes is described in which both conditions become non-typical. [ABSTRACT FROM AUTHOR]

We described a case of IPEX syndrome successfully controlled with dupilumab, an anti-IL4 receptor alpha subunit inhibitor. IPEX syndrome is a rare and generally fatal genetic disorder characterized by immune dysregulation, polyendocrinopathy and enteropathy, mostly diagnosed in early childhood. Nonetheless, cases reported in the last 20 years demonstrated that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features. A 21-year-old caucasian man presented with immune dysregulation (hypereosinophilia and elevated IgE), proteinlosing enteropathy, polyendocrinopathy (thyroiditis, osteoporosis, delayed puberty), weight loss, eczema manifestations and celiac disease. IPEX syndrome was diagnosed because of the presence of a hemizygous mutation in FOXP3 gene (c.543C>T (p.S181S) in the exon 5). During the course of the disease, the patient developed erosive proctitis, pyoderma gangrenosum, and erythema nodosum. Symptoms improved only after enteral and parenteral corticosteroid therapy and the patient soon developed steroid-dependence. Notwithstanding various therapies including azathioprine, sirolimus, tacrolimus, adalimumab, vedolizumab, the patient failed to achieve a good control of symptoms without steroids. Almost exclusive enteral nutrition with a hypoallergenic, milk-protein free, amino acid-based food for special medical purposes. He continued to lose weight (BMI 14.5 kg/m2) with a consequent high limitation of physical activity and a progressive worsening of the quality of life. In consideration of the poor response to conventional immunosuppressants and the presence of type 2 inflammatory manifestations, treatment with dupilumab at an initial dose of 600 mg, followed by a maintenance dose of 300 mg every other week, according to atopic dermatitis labeled dose, was started and combined to oral budesonide 6 mg/day and 6-mercaptopurine 75 mg/day. The patient experienced a rapid improvement in bowel and skin symptoms, leading to a progressive tapering of steroids. By our knowledge, this is the first report of IPEX syndrome successfully treated by antiIL-4/IL-13 therapy. In this case dupilumab demonstrated to be an effective, safe and steroid-sparing option. [ABSTRACT FROM AUTHOR]

Aim: Screening for coeliac disease in asymptomatic children with new-onset type 1 diabetes is controversial. The aim of this study was to analyse whether the confirmation of coeliac disease in children with new-onset type 1 diabetes and positive screening results can be postponed. Methods: This was a multicentre population-based cohort study based on the German/Austrian/Swiss/Luxembourgian Prospective Diabetes Follow-up Registry (Diabetes Patienten Verlaufsdokumentation [DPV]). Participants aged ≤18 years diagnosed with type 1 diabetes between 1995 and June 2021 and with elevated IgA tissue transglutaminase antibodies (anti-tTGA) at diabetes onset on screening for coeliac disease were included. We compared outcomes of participants with a diabetes duration of more than 1 year between those in whom coeliac disease was confirmed histologically within the first 6 months and those in whom coeliac disease was confirmed between 6 and 36 months after diabetes diagnosis. Results: Of 92,278 children and adolescents with a diagnosis of type 1 diabetes, 26,952 (29.2%) had documented anti-tTGA data at diabetes onset. Of these, 2340 (8.7%) had an elevated anti-tTGA level. Individuals who screened positive were younger (median age 9.0 vs 9.8 years, p<0.001) and more often female (53.1% vs 44.4%, p<0.001). A total of 533 participants (22.8% of those who screened positive) had a documented biopsy, of whom 444 had documented histological confirmation of coeliac disease. Of 411 participants with biopsy-proven coeliac disease within the first 36 months of diabetes and follow-up data, histological confirmation was performed in 264 (64.2%) within the first 6 months and in 147 (35.8%) between 6 and 36 months after diabetes onset. At follow-up (median diabetes duration 5.3 years and 5.1 years, respectively), estimated median HbA1c levels (62.8 mmol/mol vs 62.2 mmol/mol [7.9% vs 7.8%]), cardiovascular risk markers (lipids, rate of microalbuminuria, blood pressure), rates of acute diabetes complications (diabetic ketoacidosis, severe hypoglycaemia) and the proportions of participants reaching anti-tTGA levels within the normal range did not differ between groups. Participants with delayed histological confirmation of coeliac disease showed no negative effects on growth or weight gain during the observation period. Conclusions: Our study suggests that the histological confirmation of coeliac disease in asymptomatic individuals with new-onset type 1 diabetes could be postponed. [ABSTRACT FROM AUTHOR]

Case summary: A 6-year-old male neutered domestic longhair cat was referred for investigation of weight loss, hyporexia, vomiting and diarrhoea. The cat was diagnosed with primary hypoadrenocorticism, exocrine pancreatic insufficiency, cobalamin deficiency and a chronic enteropathy, and started on therapeutic treatment. Diabetes mellitus developed 4.5 months later, and the cat was started on insulin therapy. The cat was euthanased 10 months following the diagnosis of hypoadrenocorticism due to the development of status epilepticus, which was not associated with glucose or electrolyte abnormalities. Histopathological assessment of the adrenal glands at post-mortem examination documented lymphoplasmacytic adrenalitis, with the lymphocytic population being predominant. Immunohistochemical staining classified the lymphocytic infiltrate as T-cell rich, supportive of the cat's hypoadrenocorticism being due to autoimmune disease. Relevance and novel information: This case documents the novel use of immunohistochemical staining in combination with histopathology to further assess the adrenal glands in non-neoplastic-associated primary hypoadrenocorticism in a cat. This identified similar pathological changes to those previously described in dogs with autoimmune primary hypoadrenocorticism. Additionally, this is the first report of a cat with multiple endocrine disease that included primary hypoadrenocorticism and highlights that monitoring for the development of additional endocrine disease should be advised in these cases. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine syndromes (APSs) encompass a heterogeneous group of rare diseases characterized by autoimmune activity against two or more endocrine or non-endocrine organs. Three types of APSs are reported, including both monogenic and multifactorial, heterogeneous disorders. The aim of this manuscript is to present the main clinical and epidemiological characteristics of APS-1, APS-2, and IPEX syndrome in the pediatric age, describing the mechanisms of autoimmunity and the currently available treatments for these rare conditions.

Purpose of reviewAdvances in human genetics and investigations in animal models of autoimmune disease have allowed insight into the basic mechanisms of immunologic tolerance. These advances allow us to understand the pathogenesis of type 1 diabetes and other autoimmune diseases as never before. Here, we discuss the tolerance mechanisms of the autoimmune polyendocrine syndromes and their relevance to type 1 diabetes.Recent findingsDefects in central tolerance with alteration of self-antigen expression levels in the thymus are a potent cause of autoimmunity. Peripheral tolerance defects that alter T-cell activation and signaling also play an important role in the pathogenesis of diabetes and other associated autoimmune disorders, with multiple modest defects working in concert to produce disease. Regulation of the immune response through the action of regulatory T cells is a potent mode of tolerance induction in autoimmunity that is important in type 1 diabetes.SummaryRare syndromes of autoimmunity provide a valuable window into the breakdown of tolerance and identify multiple checkpoints that are critical for generation of autoimmunity. Understanding the application of these in type 1 diabetes will allow the development of future immunomodulatory therapies in the treatment and prevention of disease.

The article presents a case of a 10-month-old boy who was rushed to a clinic due to fever with fast breathing. He has a medical history of recurrent lower respiratory tract infections and diarrhoea. He has completely recovered from bronchopneumonia and acute gastroenteritis. Also cited are his possible multisystem conditions, his differential diagnosis, and recommended management principles and prognosis.

Abstract Background Autoimmune metaplastic atrophic gastritis is a chronic progressive inflammatory condition. The clinical spectrum includes pernicious anemia, atrophic gastritis, antibodies to parietal cell antigens and intrinsic factor, achlorhydria, hypergastrinemia and carcinoma. It is rare in paediatric cohorts. Case presentation We present the case of a boy with metaplastic atrophic gastritis in whom immune dysregulation, polyendocrinopathy, enteropathy, X-linked(IPEX) syndrome was confirmed by FOXP3 gene mutation. The patient was referred to the hospital at the age of 3 years with recurrent emesis, diarrhoea and malnutrition. His elder brother died at 9 years of age from acute respiratory distress syndrome and renal tubular acidosis. The patient was allergic to cow milk formula and noodles. Oesophagegastroduodenoscopy revealed redness, erosion and edema throughout the stomach; whitish granules in the duodenal bulb; and edema in the second part of the duodenum. Biopsies showed extensive villous atrophy and goblet cell depletion in the duodenum. He was diagnosed with type-1 diabetes mellitus (T1DM) during the treatment of methylprednisolone. Serum antibodies against glutamic acid decarboxylase and pancreatic islets were detected. The patient’s FOXP3 gene was sequenced; this identified that the patient was hemizygous for a pathogenic variant [NM_014009.3:c.748_750del (p.Lys250del)]. Conclusion Metaplastic atrophic gastritis is rarely reported in patients with IPEX. Clinical gastroenterologists should be aware of IPEX syndrome when facing the complex syndromes of metaplastic atrophic gastritis and endocrinopathy.

Introduction: Polyendocrinopathy type 2 (APS-2) is a rare autoimmune disorder characterized by the coexistence of Addison's disease and autoimmune thyroiditis. Management presents challenges due to the multifaceted nature of the disease, requiring comprehensive evaluation and individualized treatment approaches. This is a case highlighting the management of a patient with APS-2. Case Report: A 53-year-old female patient under observation for Addison's disease and post-irradiation hypothyroidism secondary to Basedow's disease, discovered 5 years prior, fitting within the framework of APS-2, presented for her check-up reporting nausea with epigastric pain and acid reflux. She has a history of positive anti-parietal-cell antibodies (APCA) which led to a gastroscopy one year prior, revealing gastritis due to Helicobacter pylori which was eradicated. For the next eighteen months, the patient experienced stable electrolyte balance and glycemia;however, she reported persistent gastrointestinal symptoms, leading to investigations for suspected autoimmune gastritis. Multiple antibodies tests were conducted, but only the APCA levels continued to increase to a maximum of 320. Therefore, a requested gastroenterology consult advised ruling out iron deficiency and chronic inflammatory syndrome, which were not confirmed, but a thrombocytosis treatment was started (platelets:600G/L), prompting the introduction of antiplatelet medication and a dose of 50000UI/month of vitamin D due to a severe deficiency. The digestive issues were effectively managed using hydrocortisone injections when the patient experienced adrenal decompensations. On the endocrinological plan, the adrenal insufficiency is controlled with hydrocortisone and fludrocortisone due to low cortisol levels (<10mmol/L), the plasmatic renin is elevated (94mUI/L), and the TSH, controlled with levothyroxine, has been fluctuating although remaining within manageable limits, with a maximum value of 5.1mU/L. Over the follow-up period, no treatment adjustments were needed except for the additional hydrocortisone injections and introduction of antiplatelet medication. However, due to multiple decompensations, the patient was advised to undergo panels of tests every three months instead of every year. Discussions : The management of APS-2 requires a multidisciplinary approach to address the complexities of multiple endocrine disorders. Challenges arise from the autoimmune mechanisms, necessitating hormone replacement therapy and monitoring for complications. In this case, the patient's gastrointestinal symptoms, thrombocytosis and vitamin D deficiency underscored the need for comprehensive evaluation and interventions to optimize her quality of life. Conclusions: Polyendocrinopathy type2 presents significant management challenges due to the systemic autoimmune complications that may arise. Comprehensive evaluation and individualized treatment are essential for optimizing patient care and addressing comorbidities. Research is warranted to elucidate the mechanisms driving the progression of polyendocrinopathies. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a clinical syndrome associated with mutations in FOXP3 and consequent abnormalities of T regulatory cells. Affected males typically die in infancy or early childhood from a variety of autoimmune conditions. Reports of recurrent pregnancy loss of male fetuses in these families have been accompanied by descriptions of nonimmune fetal hydrops, with or without additional fetal anomalies. Here, we report an additional family affected by IPEX with a novel mutation leading to recurrent second trimester fetal hydrops and intrauterine fetal demise with associated fetal anomalies. This report underscores how careful genetic and pathologic analysis of even midtrimester fetuses can provide important information impacting an entire family. It also further substantiates the use of broad, symptom-targeted genetic screening panels in cases of recurrent pregnancy loss even in the absence of a remarkable pedigree. [ABSTRACT FROM AUTHOR]

Abstract CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease. Highlights • Novel homozygous missense IL2Rα gene mutation. • Cytofluorimetric analysis as diagnostic tool of CD25 deficiency. • Homology Modeling as method to confirm IL2Rα mutated protein instability. [ABSTRACT FROM AUTHOR]

Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes.Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes.Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of “Primary Immune Deficiency (PID—related) genes.”Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified.Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare life threatening congenital autoimmune disorder caused by mutations in the forkhead box protein 3 (FOXP3) gene. The main typical clinical manifestations of IPEX are enteropathy, type 1 diabetes mellitus, and skin diseases, which usually appear in the first months of life and cause death without treatment. Here, we report a 6-year-old boy with late-onset IPEX syndrome due to a c.1190G>A (p. R397Q) mutation in exon 11 of the FOXP3 gene. The boy had intractable diarrhea, abdominal pain, recurrent infections, and failure to thrive. However, diabetes and skin diseases were not observed in the patient. The patient was received metronidazole, teicoplanin, fluconazole, mycamine, ceftriaxone, azithromycin, and fecal microbiota transplantation for treating infections, methylprednisolone and infliximab for suspicion of Crohn’s disease after admission. Finally, the boy was diagnosed as IPEX syndrome by genetic test and received hematopoietic stem cell transplantation (HSCT). Our findings suggests that IPEX should be considered in cases of late-onset, mild forms, and less typical clinical manifestations to avoid diagnostic delay.

Autoimmune polyendocrinopathies are rare diseases characterized by the coexistence of at least two endocrine diseases linked to an autoimmune mechanism, however sometimes are associated with nonendocrine autoimmune diseases. They are divided into two main subgroups: autoimmune polyendocrinopathy type I and polyendocrinopathies type II-IV. We report a case of a 53-year-old female patient followed for 2 years for Hashimoto's thyroiditis. On admission, she was complaining of polyuropolydipsic syndrome, asthenia, weight loss, abdominal pain and vomiting. The clinical examination noted a dehydrated patient in poor general condition, without fever, tachycardic at 104 beats/min, and polypneic at 24 cycles/min. Laboratory tests revealed hyperglycemia (4.7 g/l), glucosuria, acetonuria, anti-GAD?2000 UI/l antibody, normal TSH. The 8- hour cortisol level and anti-21 hydroxylase antibodies level were normal. In this context, the patient was diagnosed with diabetes type 1 associated with Hashimoto's thyroiditis (autoimmune polyendocrinopathy type III). In conclusion, the autoimmune polyendocrinopathy type III is a rare syndrome, predominantly affecting females. In our patient's case, the initial presentation of the disease was dominated by the autoimmune thyroiditis, which is the most frequent endocrine autoimmunity diagnosed in adults with polyglandular autoimmune syndrome. Therefore, the recommended treatment is based on hormonal substitution. [ABSTRACT FROM AUTHOR]

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells ( Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA-matched sibling donor. We could achieve engraftment and regimen-related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+ CD25+ Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor-derived Tregs and disappearance of anti-villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor-derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals. [Copyright &y& Elsevier]

Purpose: This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. Methods: NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. Results: Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, PamCSK, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. Conclusion: The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype. [ABSTRACT FROM AUTHOR]

Autoimmune Polyglandular Syndrome (APS) Type 1 is a rare hereditary disorder that damages organs in the body. This disease entity is the result of a mutation in the AIRE gene. It is characterized by three classic clinical features-hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis. For a patient to be diagnosed as having APS Type 1 syndrome at least two of these features needs to be present. The third entity may develop as the disease progresses. We report a case of a 35-year-old female patient with a history of seizure from the age of 11 years, who was managed with anticonvulsant drugs. With worsening of the seizure episodes, patient was diagnosed to have hypoparathyroidism together with the manifestations of oral candidiasis, nails dystrophy, enamel hypoplasia, and hypogonadism. A diagnosis of APS-1 was considered. The facility for genetic analysis of the AIRE gene mutation was not accessible, as the test costs were prohibitive and not affordable for the patient. Patient management was directed to treating individual disease components. However, cerebral and dental changes were irreversible. [ABSTRACT FROM AUTHOR]

Congenital diarrheal disorders (CDD) are a group of rare enteropathies related to specific genetic defects. Infants with these disorders have chronic diarrhea, frequently requiring parenteral nutrition support. Etiologies and prognoses are variable. We propose a new classification of CDD into four groups, taking into account the specific etiology and genetic defect: 1) defects in digestion, absorption, and transport of nutrients and electrolytes; 2) disorders of enterocyte differentiation and polarization; 3) defects of enteroendocrine cell differentiation; and 4) dysregulation of the intestinal immune response. The present review focuses on the recent advances made in understanding the pathophysiology of CDD that could potentially improve the clinical approach to these conditions. [ABSTRACT FROM AUTHOR]

We present the case of a 21-year-old male patient with a history of autoimmune nephritis, peripheral eosinophilia, eosinophilic esophagitis, and enteropathy who developed subacute worsening cardiomyopathy with systolic dysfunction. Diagnostic studies revealed a one-codon deletion in the FoxP3 gene, which led to the diagnosis of immune dysregulation polyendocrinopathy, enteropathy X-linked syndrome. Unfortunately, this patient suffered from cardiopulmonary arrest with resulting anoxic encephalopathy before diagnosis confirmation. Here, we discuss the key issues surrounding the diagnostic and therapeutic approaches to this patient's condition. [ABSTRACT FROM AUTHOR]

Glutamic acid decarboxylase antibodies (GADAs) have been detected in patients with epilepsy, but the clinical determinants of epilepsy associated with GADA have not been defined. We analyzed GADA with a radioimmunoassay in sera of 253 well-characterized patients with epilepsy and 200 control subjects. The positive samples were confirmed by immunohistochemistry and western blotting (WB). Sera were screened for other autoantibodies. GADA were detected in 15 patients (5.9%) and in three control subjects (1.5%) (p = 0.026). Seven patients (2.8%) had high GADA titers [≥1,000 relative units (RUs)/ml], six of whom had temporal lobe epilepsy (TLE). All three GADA-positive control subjects had low titers. Two of the five patients with high GADA titers and available cerebrospinal fluid (CSF) samples had intrathecal synthesis (IS) of GADA; one patient had CSF oligoclonal bands. The prevalence of increased levels of GADA tended to be higher in patients with TLE than in patients with extra-TLE [odds ratio (OR) 1.32, 95% confidence interval (CI) 0.39–4.42; p = 0.657]. The patients with high GADA titers had significantly higher number of other autoantibodies compared to the patients with low GADA titers (p = 0.001) and the patients with normal GADA (p < 0.001). High GADA titers were present in a subgroup of patients; close to 90% had TLE. The immunologic profile of these patients suggests that the most probable origin of their epilepsy is autoimmune. A positive IS of GADA may be a marker of an ongoing immune response that could identify those patients in whom a trial with immunosuppressive therapy might be warranted. [ABSTRACT FROM AUTHOR]

Several studies have suggested that T cell-producing permeability factors might lead to proteinuria in minimal change nephrotic syndrome (MCNS). However, it is still unclear whether T-cell abnormalities cause MCNS. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulation system, which leads to severe autoimmune phenomena including autoimmune enteropathy, atopic dermatitis with high levels of serum immunoglobulin E (IgE), type 1 diabetes mellitus (T1DM), and severe infection such as sepsis, which frequently result in death within the first 2 years of life. This disease is caused by mutations in the FOXP3 gene that result in the defective development of regulatory T (Treg) cells. This report describes a 5-year-old boy with IPEX syndrome with a 3 bp deletion in the FOXP3 gene (c.748–750delAAG, p.250K.del) and a paucity of CD4+ CD25+ FOXP3+ T cells. The boy’s condition was complicated by MCNS in addition to many IPEX-related manifestations, such as atopic dermatitis, T1DM, enteropathy, sepsis and hemolytic anemia. This is the first report of IPEX syndrome complicated by MCNS, and our findings imply that Treg cell dysfunction may be crucial for the development of MCNS. [ABSTRACT FROM AUTHOR]

After activation by unique cytokines, CD4+ naive T cells differentiate into lineages of helper/effector (TH) and regulatory T (Treg) cells that are characterized by distinct developmental pathways and unique biologic functions. The trusted binary system of TH1 and TH2 has been expanded to include the IL-17–producing TH17 cell lineage, which plays a role in immune responses to infectious agents and maintenance of autoimmune diseases. Acting as counterbalance, Treg cells maintain peripheral tolerance and protect the host from autoaggressive lymphocytes. TH1 cells produce IFN-γ and are involved in cell-mediated immunity, TH2 cells produce IL-4 and contribute to humoral immunity, TH17 cells generate IL-17 and play an important role in immune responses to fungi and extracellular pathogens, and forkhead box protein 3–positive (FOXP3+) Treg cells secrete TGF-β and IL-10 and downregulate effector T cells. Autosomal dominant hyper-IgE syndrome, a rare primary immunodeficiency disorder, is caused by hypomorphic heterozygous mutations of signal transducer and activator of transcription 3 (STAT3), preventing TH17 lineage differentiation and increasing susceptibility to Staphylococcus and Candida species infections. Mutations in the FOXP3 gene interfere with Treg cell development and cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Other single-gene defects resulting in reduced Treg cell function include CD25, signal transducer and activator of transcription 5b, autoimmune regulator, and Wiskott-Aldrich syndrome protein. These observations emphasize the importance of functionally distinct T-cell lineages in maintaining a balanced innate and cognate immune system. [Copyright &y& Elsevier]

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance. Objective: We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome. Methods: In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data. Results: Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity. Conclusion: Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome. [Copyright &y& Elsevier]

Substantial progress in understanding the mechanisms of immune regulation in allergic diseases and asthma has been made during the last year. In asthma, rhinitis, and atopic dermatitis the immune system is activated by allergens, autoantigens, and components of superimposed infectious agents. Immune regulation in the lymphatic organs and in the tissue has an important role in the control and suppression of allergic disease in all stages of the inflammatory process, such as cell migration to tissues, cells gaining an inflammatory and tissue-destructive phenotype in the tissues, and their interaction with resident tissue cells to augment the inflammation. After the discovery of regulatory T cells, the importance of their unique suppressive capacity was strongly emphasized for the suppression of effector T-cell responses. However, it seems that all 3 subsets of effector TH1, TH2, and TH17 cells, as well as regulatory T cells, regulate each other at the level of transcription, major cytokines, and surface molecules. This review highlights key advances in immune regulation that were published in the Journal of Allergy and Clinical Immunology. [Copyright &y& Elsevier]

The lumen of the gastrointestinal tract is exposed daily to an array of dietary proteins. The vast majority of proteins are tolerated through suppression of cellular or humoral responses, a process known as oral tolerance. However, in approximately 6% of children and 4% of adults in the United States, tolerance to a given dietary antigen either is not established or breaks down, resulting in food hypersensitivity. Although food allergies can result in sudden and life-threatening symptoms, their prevalence is remarkably low considering the complexities of the gut-associated mucosal system. Suppression involves signaling by an array of nonprofessional antigen-presenting cells, dendritic cells, and regulatory T cells, as well as lymphocyte anergy or deletion. Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in tolerance has shifted focus of treatment and prevention toward inducing tolerance. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens. In this article we review the mechanisms of tolerance, discuss aberrations in oral tolerance, and provide information on novel prevention and treatment paradigms for food allergy. [Copyright &y& Elsevier]

The article presents abstracts of several pediatric research, including "Impact of Admission-Day Crowding on the Length of Stay of Pediatric Hospitalization," "Pediatric Residents Clinical and Educational Experiences With End-of-Life Care" and "Effect of a Pediatric Practice-Based Smoking Prevention and Cessation Intervention for Adolescents: A Randomized, Controlled Trial."

Originally interpreted within the framework of a binary TH1/TH2 paradigm, our knowledge of the pathogenesis of atopic diseases has broadened to incorporate the contribution of T regulatory cells and the newly described proinflammatory TH17 cell lineage. The commitment of peripheral T-cell clones to undergo differentiation into one of those lineages is shaped by self-reinforcing transcriptional circuitries that center on key transcriptional regulators: T-box expressed in T cells (TH1), GATA-3 (TH2), forkhead box p3 (T regulatory cells), and retinoid-related orphan receptor γτ/retinoid-related orphan receptor α (TH17). These circuits function both to establish the respective lineage phenotype and to enable epigenetic changes that maintain those phenotypes long-term. This evolving view of how signaling and transcriptional networks generate effector T-cell responses suggests novel therapeutic approaches to reprogram effector T-cell lineage commitment in allergic diseases in favor of tolerance induction. [Copyright &y& Elsevier]

Abstract: Regulatory T (Treg) cells are important contributors to the maintenance of immune tolerance in the periphery, and deficiency of Tregs is associated with various immunopathic diseases. Murine models of autoimmune and autoinflammatory disorders have helped to elucidate how Tregs are involved in these diseases. A feature in common between human and mice that lack one or another of the key Treg subsets is the occurrence of mucosal inflammation. The relatively fragile mucosal surface represents a complex system that is normally well equipped to ward off harmful pathogens yet at the same time is inhibitory to destructive inflammatory responses to biologically needed (probiotic) microorganisms, or other common environmental antigens e.g. nutrients. We here discuss the importance of Tregs in maintaining tolerance at mucosal surfaces and the outcomes of deficiency of Treg function. The intestinal tract and its inflammatory diseases provide the “point of departure” for discussion, but similar considerations could apply to other mucosal linings exposed to the environment such as other members of the digestive system. However, the lungs, bile ducts, urogenital tract and other mucosal surfaces are susceptible to poorly understood inflammatory states that possibly depend on dysfunction of Treg cells. Finally there are now potential therapies predicated on reconstitution of effective function of Treg cells. [Copyright &y& Elsevier]

The rare X-linked disorder immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and its murine counterpart scurfy have provided important new insights into the essential role of regulatory T cells (Treg) in maintaining tolerance to self-antigens. Mutations of the FOXP3 gene, identified in patients with IPEX, have helped pinpoint key structural domains of the protein that are essential for its function as a transcriptional regulator. Ongoing work using these and associated models has begun to elucidate factors important for the development, function, and competitive fitness of Treg. This improved understanding is beginning to lead to the identification of other defects that may be present in patients who have the clinical phenotype of IPEX but only wild-type FOXP3. It has also led to improved treatment options for IPEX including immunosuppressive drugs and bone marrow transplantation. We are hopeful that the knowledge gained about mechanisms that regulate FOXP3 expression and Treg function will have a major effect on how other autoimmune and allergic disorders are approached. [Copyright &y& Elsevier]

Summary: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease exceptionally common in Finland. It is associated with a limited T lymphocyte defect, an autoimmune response to various tissues, particularly endocrine glands. Most patients have chronic oral candidosis, which has been suggested to be carcinogenic. In Finland 92 patients have been diagnosed with APECED and 66 of them are alive. Our aim was to study the possible association of APECED with oral and oesophageal carcinoma. We evaluated the medical histories of all 92 patients for morbidity, causes of death, and known risk factors for oral cancer. We invited all current patients for a clinical examination of their oral mucosa. Six of the 92 had developed oral or oesophageal squamous cell carcinoma (SCC) by the mean age of 37 (29–44years) and four of them had died from it. The six represent 10% of the patients older than 25years. Five of the six patients had long-lasting oral candidosis. Four of the six had smoked regularly for 15years or more. One patient had been on immunosuppressive therapy for 6years following kidney transplantation when SCC in her mouth occurred. The partial T cell defect of APECED seems to favour the growth of Candida albicans and predispose to chronic mucositis and SCC. Aggressive control of oral candidosis and close follow-up of oral mucosa is a necessity in patients with APECED. [Copyright &y& Elsevier]

Type 1A diabetes is an organ-specific autoimmune disease resulting from destruction of insulin-producing pancreatic β-cells. The main susceptibility genes code for polymorphic HLA molecules and in particular alleles of class II MHC genes (DR, DQ and DP). Polymorphisms of individual genes outside the MHC also contribute to diabetes risk but recent evidence suggests that there are additional non-HLA genes determining susceptibility linked to the MHC. It is now possible using genetic and autoantibody assays to predict the development of type 1A diabetes in the majority of individuals, and trials of diabetes prevention are underway. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is characterized by progressive inflammation of the liver and destruction of liver parenchyma. Rare in absolute terms, it is nevertheless an important cause of noninfectious chronic liver disease in children. In many ways, the diagnosis and treatment of children with AIH has changed little over the last 10 years. However, in recent years, steady progress in defining the genetic, immunologic and potential environmental triggers that underlie this disease, in addition to increasing experience with a wider array of therapeutic agents, promises to expand our understanding and ability to treat AIH effectively. This review will summarize the current clinical and pathophysiological understanding of AIH in children, along with therapeutic options. [ABSTRACT FROM AUTHOR]