BACKGROUND:The increased susceptibility of patients with atopic dermatitis (AD) to disseminated viral skin infections such as eczema herpeticum (ADEH+) is poorly understood. OBJECTIVES:The primary goal of the current study was to determine whether ADEH+ subjects have identifiable defects in cell-mediated immunity that reduce their ability to control viral infections. MATERIALS AND METHODS:In this study, we evaluated cytokine expression by various subsets of peripheral blood mononuclear cells from ADEH+ (n = 24) compared with AD without a history of viral infections (ADEH-) (n = 20) before and after treatment with herpes simplex virus (HSV). RESULTS:We found that interferon (IFN)-γ expression after HSV treatment was lower in the CD8+ T cells and monocytes from patients with ADEH+ compared with patients who are ADEH- or nonatopic. Given the induction of CD8+ T cells as the result of antigen presentation by human leucocyte antigen (HLA) class I, consistent with the findings described above we also found that the HLA B7 allele was significantly associated with risk of the ADEH+ phenotype (odds ratio = 1·91, P = 0·02, 125 ADEH+ and 161 ADEH- subjects). CONCLUSIONS:These data suggest that defects in viral-induced IFN-γ from CD8+ T cells contribute to the ADEH+ phenotype.

The high co-morbidity of food allergy (FA) and sensitization (FS) with other IgE-mediated diseases such as asthma, suggests common genetic determinants. We tested this hypothesis for a set of GWAS-identified candidate genes for asthma/atopy in FA/FS. 359 single nucleotide polymorphisms (SNPs) representing 46 asthma/total IgE GWAS-identified genes were genotyped (Illumina BeadExpress) in a discovery cohort (Consortium of Food Allergy Research, CoFAR:NIAID) of 317 European-American (EA) and 70 African-American (AA) children with atopic dermatitis (AD) and clinical and/or serologic evidence of FA (milk/egg/peanut) and 270 EA and 332 AA non-FA-non-AD controls. Replication was sought in Atopic Dermatitis Research Network (ADRN:NIAID) participants:139 EA and 84 AA AD cases characterized for FS using a multiallergenspecific Phadia ImmunoCAP tests (FX5E) and compared to 114 EA and 107 AA AD cases without FS, respectively. Association tests were conducted within a logistic framework including relevant covariates. In CoFAR, 7 SNPs were significantly associated with FA risk in EA (Bonferonni-corrected-P-values≤2.9x10-5). Six of these mapped to GPR126, PDE4D, PTCH1, GSTCD and IL13. Another 17 SNPs representing 7 genes (DENND1B, IL1R1, SMAD3, IL-10, ADAM33, RAD50 and ADCY2) were associated at P=0.0005-0.041 in EA and AA, but failed Bonferonni corrections. A gene-based-replication for FS was observed for PDE4D in EA and AA of the AD ADRN cohort with lower statistical evidence (uncorrected P=0.002). Genetic variants in genes associated with asthma and high total IgE levels (i.e., PDE4D) may be risk factors for FA/FS in AD individuals.

Atopic dermatitis (AD) is characterized by disseminated viral skin infections, particularly eczema herpeticum (ADEH). Previously, we genotyped 8 common (>1% minor allele frequency) non-synonymous coding single nucleotide polymorphisms in FLG2, a gene on the epidermal differentiation complex locus associated with ADEH, at the conclusion of the 2011 AAAAI meeting. Currently we are sequencing the entire gene to discover additional rare and novel variants that may be associated with ADEH. We are currently sequencing 15kb of the FLG2 gene using Agilent's targeted deep-resequencing platform on 112 ADEH- and 125 ADEH+ European ancestry patients. To date a subset (100 ADEH-, 100 ADEH+) has been sequenced on exon 2 and 600 base pairs of exon 3 nearest exon 2, using Sanger sequencing. Genetic associations for risk of ADEH and associated traits were determined by the Cochran-Armitage trend test. Sequencing so far has uncovered three previously known SNPs, and two novel variants in exon 3 not previously documented in dbSNP or the Thousand Genomes Project. Tests for association on single SNPs and a collapsed test on all rare variants did not reveal any associations with ADEH. We also performed analyses adjusting for FLG mutations R501X and 2282del4, but did not observe significant associations with ADEH. Interim sequence data on FLG2 has not yielded novel associations with ADEH; however, we anticipate additional novel variants to be identified by targeted deep-resequencing of the entire gene, and will perform additional burden tests collapsing on all newly identified rare functional variants previously un-captured by any tagging genotyping strategy.

Helminth infections have been associated with protection against immune-mediated diseases, such as allergies and autoimmunity. It is postulated that induction of IL-10, suppression of IgE and increased IgG4 are some of the possible mechanisms related to that protection. We hypothesized that IL10 polymorphisms are associated with helminth infection, asthma and allergy.