Germline hypomorphic CARD11 mutations in severe atopic disease.

Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.

Transient environmental exposures on the developing immune system: implications for allergy and asthma.

PURPOSE OF REVIEW: Early environmental exposures have been extensively studied as potential causes of the observed increase in allergic disease over time. Transient fetal or neonatal exposures in particular are of interest in that they may occur during critical windows of immune system development. Due to the tremendous complexity of variables in early life, as well as the difficulty in randomizing many interventions, it is very difficult to properly study these exposures. Some progress, however, has been made and some more candidates for study may be emerging. Of particular interest are micronutrients, whose ever-changing use and immunomodulatory capabilities make them prime targets for study. RECENT FINDINGS: New risk factors for atopic disease have emerged from the pool of early life interventions, such as caesarian section, prolonged labor and infant multivitamin supplementation. Data are emerging regarding micronutrient status and supplementation and their effects on the developing immune system and risk for allergic disease. Clinical trials have yet to demonstrate much causality but, in some cases, it is too early to make any judgments. SUMMARY: The gold standard of randomized clinical trials has not borne out a number of proposed early-life allergic risk factors, while other trials are too incomplete to draw any conclusions so far. Properly designed studies for other risk factor interventions may still be achievable, provided that there is a proper understanding of the interventions, populations and outcomes.

Early infant multivitamin supplementation is associated with increased risk for food allergy and asthma.

OBJECTIVE: Dietary vitamins have potent immunomodulating effects in vitro. Individual vitamins have been shown to skew T cells toward either T-helper 1 or T-helper 2 phenotypic classes, suggesting that they may participate in inflammatory or allergic disease. With the exception of antioxidant protection, there has been little study on the effect of early vitamin supplementation on the subsequent risk for asthma and allergic disease. The objective of this study was to determine whether early vitamin supplementation during infancy affects the risk for asthma and allergic disease during early childhood. METHODS: Cohort data were analyzed from the National Center for Health Statistics 1988 National Maternal-Infant Health Survey, which followed pregnant women and their newborns, and the 1991 Longitudinal Follow-up of the same patients, which measured health and disease outcomes. Patients were stratified by race and breastfeeding status. Factors that are known to be associated with alteration of risk for asthma or food allergies were identified using univariate logistic regression. Those factors were then analyzed in multivariate logistic regression models. Early vitamin supplementation was defined as vitamin use within the first 6 months. RESULTS: There were >8000 total patients in the study. The overall incidence of asthma was 10.5% and of food allergy was 4.9%. In univariate analysis, male gender, smoker in the household, child care, prematurity (<37 weeks), being black, no history of breastfeeding, lower income, and lower education were associated with higher risk for asthma. Child care, higher levels of education, income, and history of breastfeeding were associated with a higher risk for food allergies. In multivariate logistic analyses, a history of vitamin use within the first 6 months of life was associated with a higher risk for asthma in black infants (odds ratio [OR]: 1.27; 95% confidence interval [CI]: 1.04-1.56). Early vitamin use was also associated with a higher risk for food allergies in the exclusively formula-fed population (OR: 1.63; 95% CI: 1.21-2.20). Vitamin use at 3 years of age was associated with increased risk for food allergies but not asthma in both breastfed (OR: 1.62; 95% CI: 1.19-2.21) and exclusively formula-fed infants (OR: 1.39; 95% CI: 1.03-1.88). CONCLUSIONS: Early vitamin supplementation is associated with increased risk for asthma in black children and food allergies in exclusively formula-fed children. Additional study is warranted to examine which components most strongly contribute to this risk.