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Wolff A.S.B.,University of Bergen | Sarkadi A.K.,Debrecen University | Marodi L.,Debrecen University | Karner J.,University of Tartu | And 12 more authors.
Journal of Clinical Immunology | Year: 2013

Purpose: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients. Methods: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles. Results: Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling - 8 months before onset of APS-I - and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects. Conclusion: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization. © 2013 Springer Science+Business Media New York.

Breivik L.,University of Bergen | Oftedal B.E.V.,University of Bergen | Boe Wolff A.S.,University of Bergen | Bratland E.,University of Bergen | And 2 more authors.
Clinical Immunology | Year: 2014

An important characteristic of autoimmune polyendocrine syndrome type 1 (APS 1) is the existence of neutralizing autoantibodies (nAbs) against the type I interferons (IFN) -α2 and -ω at frequencies close to 100%.Type 1 IFN autoantibodies are detected by antiviral neutralizing assays (AVA), binding assays with radiolabelled antigens (RLBA), enzyme-linked immunosorbent assay (ELISA), or by reporter-based cell assays. We here present a simple and reliable version of the latter utilizing a commercially available cell line (HEK-Blue IFN-α/β).All 67 APS 1 patients were positive for IFN-ω nAbs, while 90% were positive for IFN-α2 nAbs, a 100% and 96% correlation with RLBA, respectively. All blood donors and non-APS 1 patients were negative. The dilution titer required to reduce the effect of IFN-ω nAbs correlated with the RLBA index.This cell-based autoantibody assay (CBAA) is easy to perform, suitable for high throughput, while providing high specificity and sensitivity. © 2014 Elsevier Inc.

Thalange N.,Norwich University | Bereket A.,Marmara University | Larsen J.,Novo Nordisk AS | Hiort L.C.,Novo Nordisk AS | Peterkova V.,Institute of Paediatric Endocrinology
Diabetic Medicine | Year: 2013

Aims: This 52-week, randomized, multinational, open-label, parallel-group, non-inferiority trial investigated the efficacy and safety of basal-bolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in combination with insulin aspart, in subjects aged 2-16 years with Type 1 diabetes mellitus. Methods: Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight were followed over 52 weeks. Results: After 52 weeks, insulin detemir was shown to be non-inferior to NPH insulin with regard to HbA1c [mean difference insulin detemir-NPH: 1.30 mmol/mol, 95% CI -1.32 to 3.92 (0.12%, 95% CI -0.12 to 0.36) in the full analysis set and 1.41 mmol/mol, 95% CI -1.26 to 4.08 (0.13%, 95% CI -0.12 to 0.37) in the per protocol analysis set]. Hypoglycaemic events per subject-year of exposure of 24-h and nocturnal hypoglycaemia were significantly lower with insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.60-0.97, P = 0.028 and 0.62, 95% CI 0.47-0.84, P = 0.002, respectively). Weight standard deviation (sd) scores (body weight standardized by age and gender) decreased with insulin detemir, but increased slightly with NPH insulin (change: -0.12 vs. 0.04, P < 0.001). At end of the trial, median insulin doses were similar in both treatment groups. Conclusions: Insulin detemir was non-inferior to NPH insulin after 52 weeks' treatment of children and adolescents aged 2-16 years, and was associated with a significantly lower risk of hypoglycaemia, together with significantly lower weight sd score when compared with NPH insulin. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Orlova E.M.,Institute of Paediatric Endocrinology | Bukina A.M.,Research Center for Medical Genetics | Kuznetsova E.S.,Institute of Paediatric Endocrinology | Kareva M.A.,Institute of Paediatric Endocrinology | And 3 more authors.
Hormone Research in Paediatrics | Year: 2010

Background: Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging. Aim: We aimed to provide clinical and mutational data for a large number of APS-1 patients in the Russian population. Methods: We analyzed clinical variations and component prevalence in APS-1 patients. DNA screening for autoimmune regulator (AIRE) gene mutations was performed in established APS-1 patients and in patients with the single components of chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, or alopecia. Results: We identified 46 patients from 42 families with APS-1. Eighteen different components were present in the patients, including very rare conditions - bone dysplasia and retinitis pigmentosa. We identified 10 different mutations, 3 of which were novel (M1T, E298K, c1053-1060del). The common Finnish mutation, R257X, was the most frequent in our population, present in 64/92 (70%) of the alleles. Conclusion: We found that the R257X AIRE mutation is common in Russian APS-1 patients. The majority of children with hypoparathyroidism and chronic mucocutaneous candidiasis were carriers of the AIRE mutations. Copyright © 2010 S. Karger AG, Basel.

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