Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.
Objective: To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project.Methods: A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms.Results: 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofeverregistry. Most of the patients (1388; 74%), reside in western Europe,294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosisof a monogenic autoinflammatory diseases have been enrolled; geneticanalysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. Conclusion: A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment,and to perform large scale comparative studies between different conditions.
COBISS.SI-ID: 29584857
Objectives This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the child's immunological profile with their mothers. Methods A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening.Children were examined at 3, 9, 24 months and 5 years. Results 134 children were analysed (female sex in 65 cases, birth weight 3000g, height 48,3 cm). Sixteen per cent had a preterm birth ((37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Fourchildren displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotonywith psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-ß2 glycoprotein-I (anti-ß2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-Ž2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-ß2GPI IgG were correlated with the same mother's antibodies before 6 months of age (p(0.05). Conclusion Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.
COBISS.SI-ID: 658860
OBJECTIVES: Influenza vaccination in children with rheumatic diseases is oftenrecommended, but not frequently performed. Our aim was to assess the safety and efficacy of annual influenza vaccination in a longitudinal follow-up study of an unselected group of children with juvenile idiopathic arthritis (JIA). METHODS: Thirty-one children with stable JIA (10 boys, 21 girls, mean age 11.0 years) receiving various therapies and 14 children in a control group (10 boys, 4 girls, mean age 11.9 years) were vaccinated with theannual influenza vaccine Begrivac 2008/2009. The children in both groups were followed for adverse events and infections 6 months after vaccination. Autoantibodies production and antibody titers against three vaccine viruses were determined in serial samples taken before, 1 and 6 months after vaccination. RESULTS: Eleven (35%) children with JIA and 5 (36%) children in the control group reported short-term adverse events. A JIA flare was observedone month after vaccination in 4 (13%) patients, and in the following five months in 7 (23%) patients. The response to vaccination after one month was significant in the control and study groups as a whole, but not in a subgroup of 4 children receiving anti-TNF-Ž therapy. After six months, no significant differences in the protective titers against vaccine viruses amongthe patient and control groups were observed. Changes in the mean values of autoantibodies after vaccination were found only for IgG aCL in the JIA group. CONCLUSIONS: No long-term adverse events were reported after influenzavaccination in JIA and control group. Thirty-five percent of childrenwith JIA experienced flare of the disease after vaccination. Protective antibodies against at least 2 vaccine viruses 6 months after vaccination were detected in all patients.
COBISS.SI-ID: 657580
Objectives: Familial Mediterranean fever (FMF) is an autosomal-recessive disorder caused by mutations in MEFV gene. Eastern Mediterranean populations have the highest number of carriers, whereas western Mediterranean populations are less frequently affected. The aim of this study was to determine the carrier rate and spectrum of MEFV gene mutations in apparently healthy populations and in suspected FMF patients from central and southeastern European (CSEE) countries. Methods: We screened 507 apparently healthy persons from 5 CSEE countries. Exons 2 and 10 of the MEFV gene were PCR amplified and subsequently sequenced with ABI prism310 genetic analyzer. Six most common mutations in the MEFV gene were tested: V726A, K695R, M694V, M694I, M680I in exon 10, and E148Q in exon 2. In suspected FMF patients we screened all MEFV exons in selected cases. Results: The overall carrier frequency of all MEFV mutations was higher than expected (9.3%). In the whole cohort we did not find any apparently healthy persons with two mutations. Heterozygous mutations were found in apparently healthy subjects from different CSEE countries as follows: Macedonia 16%, Serbia 11%, Bosnia and Herzegovina 8%, Slovenia 6% and Hungary 5%. The most common mutation in healthy controls was K695R, appearing in 40% of mutated alleles. The most common mutation in suspected FMF patients was M694V, followed by K695R. Conclusion: We found higher than expected carrier rate of MEFV gene mutations in populations from CSEE countries. It is interesting to note that 40% of detected carriers carry the K695R mutation.
COBISS.SI-ID: 582060