Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment.

BACKGROUND: Heterozygous gain-of-function mutations in PI3K110δ lead to lymphadenopathy, lymphoid hyperplasia, EBV and cytomegalovirus viremia, and sinopulmonary infections. OBJECTIVE: The known role of natural killer (NK) cell function in the control of EBV and cytomegalovirus prompted us to investigate the functional and phenotypic effects of PI3K110δ mutations on NK cell subsets and cytotoxic function. METHODS: Mutations in patients were identified by using whole-exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patients' cells using flow cytometry, standard Cr51 cytotoxicity assays, and quantitative confocal microscopy. RESULTS: PI3K110δ mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were restored partially after initiation of treatment with rapamycin in 3 patients. CONCLUSION: We describe novel NK cell functional deficiency caused by PI3K110δ mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing a further rationale for its use in patients with this disease.

A Novel STAT3 Mutation in a Qatari Patient With Hyper-IgE Syndrome.

Autosomal dominant hyper-IgE syndrome caused by mutations in the transcription factor STAT3 (AD-HIES) is characterized by a collection of immunologic and non-immune features including eczema, recurrent infections, elevated IgE levels, and connective tissue anomalies. We report the case of a Qatari child with a history of recurrent staphylococcal skin infections since infancy, who was found to have a novel, de novo mutation in STAT3 (c.1934T>A, p.L645Q). The absence of mucocutaneous candidiasis and undetectable IgE levels until the age of 7 years prolonged the time to molecular confirmation of the cause for the patient's immune deficiency. STAT3 p.L645Q was found to have decreased transcriptional capacity. The patient also had low levels of Th17 cells and STAT3 phosphorylation was impaired in patient-derived cells. Nearly 100 unique mutations in STAT3 have been reported in association with AD-HIES.

The pattern and genetics of pediatric extrinsic asthma risk factors in polluted environment.

AIM: The aim of the present study is to determine the effect of polluted environment on extrinsic of asthma and allergic diseases among school children. DESIGN: This is case and control study. SETTING: The study was carried out among school children living and attending the school in industrial and residential area during the period of October 2004 and June 2005. SUBJECTS: The study based on age, sex, and ethnicity of 716 cases (with asthma) and 716 controls (without asthma) school children living in both urban and in industrial polluted with oil refinery and chemical pollutant. METHODS: The International study of asthma and allergies in childhood (ISAAC) and some additional questionnaires were used to collect the data of the school children. The questionnaire included information about: socio-demographic characteristics; respiratory symptoms; associated respiratory illness; family history of allergic diseases among first-degree relatives of asthmatic children; behavioural factors which could be additive to asthma. Univariate and multivariate statistical analyses were performed. RESULTS: The proportion of children in the asthmatic group who reported symptoms was significantly higher than in non-asthmatic group (<0.0001). The asthmatic group reported that 47.5% morning time breathlessness, shortness of breath (61.4%), wheeze after exercise (65.4%), phlegm (45.3%) and chronic cough (42.2%). Male asthmatics had a average age at onset of symptoms of 6.9% (+/-4.8%) years compared with female asthmatics who had higher age at onset of symptoms, 7.6 (+/-5.9). Male asthmatics also had longer duration of symptoms (7.5 +/- 4.9 in males and 6.4 +/- 4.6 years in females). Significantly odds ratios were found higher in asthmatic compared to controls for pneumonia, bronchitis, atopy (allergic rhinitis and atopic dermatitis), sinusitis, croup, parental asthmas, parental atopy including parental allergic rhinitis, atopic dermatitis and parental smoking (p < 0.0001). The logistic regression model showed that shortness of breath, bronchitis, pneumonia, sinusitis, parental asthma, allergic rhinitis, atopic dermatitis, croup, pets ownership and parental smoking were significant risk factors for asthma CONCLUSION: The present study provides some evidence that exposure to outdoor air pollutants increases the risk of childhood asthma and allergic diseases in school children. The results are consistent with the hypothesis that long term exposure to NOx and CO levels suggests that emissions from photochemical air pollution and oil refinery contributes to adverse health effects in Qatar.