BackgroundIgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy.ObjectiveTo investigate the association between filaggrin loss-of-function mutations and peanut allergy.MethodsCase-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL−1) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis.ResultsFilaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients (P = 3.0 × 10−6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10−5; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis.ConclusionFilaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.
The cell-triggering properties of BCR, TCR and FcR depend on structurally related immunoreceptor tyrosine-based activation motifs (ITAMs). Fc gamma RIIB have no ITAM and do not trigger cell activation. When coaggregated to BCR, they inhibit B cell activation. We show here that, when coaggregated to these receptors, Fc gamma RIIB inhibit Fc epsilon RI-, Fc gamma RIIA-, and TCR-dependent cell activation. Inhibition also affected cell activation by single ITAMs, in isolated FcR or TCR subunits. The same tyrosine-based inhibitory motif (ITIM), which is highly conserved in murine and human Fc gamma RIIB and that was previously shown to inhibit BCR-dependent B cell activation, was required to regulate TCR- and FcR-dependent cell activation. Our findings endow Fc gamma RIIB, and thus IgG antibodies, with general immunoregulatory properties susceptible to act on all ITAM-containing receptors.
SummaryBackground Staphylococcus aureus is increasingly implicated as a possible causal factor in the pathogenesis of atopic dermatitis (AD). However, the reported prevalence rates of skin and nasal colonization in the literature vary widely. Objectives This study evaluates the prevalence and odds of skin and nasal colonization with S. aureus in patients with AD. Methods A systematic literature search was conducted. Odds ratios (ORs) for colonization in patients vs. controls and the prevalence of colonization in patients were pooled using the random-effects model. Results Overall, 95 observational studies were included, of which 30 had a control group. The Newcastle-Ottawa Scale was used to assess study quality, with the majority of studies being of fair to poor quality. Patients with AD were more likely to be colonized with S. aureus than healthy controls [OR 19Á74, 95% confidence interval (CI) 10Á88-35Á81]. Differences were smaller in nonlesional skin (OR 7Á77, 95% CI 3Á82-15Á82) and in the nose (OR 4Á50, 95% CI 3Á00-6Á75). The pooled prevalence of S. aureus colonization among patients was 70% for lesional skin, 39% for nonlesional skin and 62% for the nose. In lesional skin, meta-regression showed that the prevalence of colonization increased with disease severity. Study heterogeneity should be taken into consideration when interpreting the results. Conclusions These results demonstrate the importance of colonization with S. aureus in AD. Further evaluation of the mechanisms by which S. aureus influences inflammation is required in addition to the development of targeted strategies to decrease skin and nasal S. aureus load.
Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified 10 novel risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with novel secondary signals at 4 of these). Notably, the new loci include candidate genes with roles in regulation of innate host defenses and T-cell function, underscoring the important contribution of (auto-)immune mechanisms to atopic dermatitis pathogenesis.
BackgroundeHealth potentially enhances quality of care and may reduce health care costs. However, a review of systematic reviews published in 2010 concluded that high-quality evidence on the benefits of eHealth interventions was still lacking.ObjectiveWe conducted a systematic review of systematic reviews and meta-analyses on the effectiveness/cost-effectiveness of eHealth interventions in patients with somatic diseases to analyze whether, and to what possible extent, the outcome of recent research supports or differs from previous conclusions.MethodsLiterature searches were performed in PubMed, EMBASE, The Cochrane Library, and Scopus for systematic reviews and meta-analyses on eHealth interventions published between August 2009 and December 2012. Articles were screened for relevance based on preset inclusion and exclusion criteria. Citations of residual articles were screened for additional literature. Included papers were critically appraised using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement before data were extracted. Based on conclusions drawn by the authors of the included articles, reviews and meta-analyses were divided into 1 of 3 groups: suitable, promising, or limited evidence on effectiveness/cost-effectiveness. Cases of uncertainty were resolved by consensus discussion. Effect sizes were extracted from papers that included a meta-analysis. To compare our results with previous findings, a trend analysis was performed.ResultsOur literature searches yielded 31 eligible reviews, of which 20 (65%) reported on costs. Seven papers (23%) concluded that eHealth is effective/cost-effective, 13 (42%) underlined that evidence is promising, and others found limited or inconsistent proof. Methodological quality of the included reviews and meta-analyses was generally considered high. Trend analysis showed a considerable accumulation of literature on eHealth. However, a similar percentage of papers concluded that eHealth is effective/cost-effective or evidence is at least promising (65% vs 62%). Reviews focusing primarily on children or family caregivers still remained scarce. Although a pooled (subgroup) analysis of aggregate data from randomized studies was performed in a higher percentage of more recently published reviews (45% vs 27%), data on economic outcome measures were less frequently reported (65% vs 85%).ConclusionsThe number of reviews and meta-analyses on eHealth interventions in patients with somatic diseases has increased considerably in recent years. Most articles show eHealth is effective/cost-effective or at least suggest evidence is promising, which is consistent with previous findings. Although many researchers advocate larger, well-designed, controlled studies, we believe attention should be given to the development and evaluation of strategies to implement effective/cost-effective eHealth initiatives in daily practice, rather than to further strengthen current evidence.
The cytoplasmic plaque protein desmoplakin (DP), which is located in desmosomes, plays a major role in epithelial and muscle cell adhesion by linking the transmembrane cadherins to the cytoplasmic intermediate filament network. Mutations of DP may cause striate palmoplantar keratoderma, arrhythmogenic right ventricular dysplasia, skin fragility/woolly hair syndrome, Naxos-like disease, and Carvajal syndrome. DP must be indispensable, because DP-/- mice are early abortive. Here, we report a patient with severe fragility of skin and mucous membranes caused by genetic truncation of the DP tail. The new phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. The phenotype also comprised universal alopecia, neonatal teeth, and nail loss. Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes. Immunofluorescence staining of DP showed a distinct punctate intercellular pattern in the patient's skin. Protein analysis revealed expression of truncated DP polypeptides. Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively. Aberrant mRNA transcripts that predict premature termination of translation with loss of the three intermediate filament-binding subdomains in the DP tail were detected by RT-PCR. The new dramatic phenotype, which we named "lethal acantholytic epidermolysis bullosa," underscores the paramount role of DP in epidermal integrity.
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