Developmental cell programs are co-opted in inflammatory skin disease.

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder.

Epidemiological data indicate that atopic eczema (AE) in infancy significantly increases the risk for attention deficit/hyperactivity disorder (ADHD) in later life. The underlying pathophysiological mechanisms of this comorbidity are unknown. We propose that the release of inflammatory cytokines caused by the allergic inflammation and/or elevated levels of psychological stress as a result of the chronic disease interfere with the maturation of prefrontal cortex regions and neurotransmitter systems involved ADHD pathology. Alternatively, increased stress levels in ADHD patients may trigger AE via neuroimmunological mechanisms. In a third model, AE and ADHD may be viewed as two separate disorders with one or more shared risk factors (e.g., genetics, prenatal stress) that increase the susceptibility for both disorders leading to the co-occurrence of AE and ADHD. Future investigation of these three models may lead to a better understanding of the mechanisms underlying the observed comorbidity between AE and ADHD and further, to targeted interdisciplinary primary prevention and treatment strategies.

A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis.

Two common inflammatory skin disorders with impaired barrier, atopic dermatitis (AD) and psoriasis, share distinct genetic linkage to the Epidermal Differentiation Complex (EDC) locus on 1q21. The EDC is comprised of tandemly arrayed gene families encoding proteins involved in skin cell differentiation. Discovery of semi-dominant mutations in filaggrin (FLG) associated with AD and a copy number variation within the LCE genes associated with psoriasis provide compelling evidence for the role of EDC genes in the pathogenesis of these diseases. To date, little is known about the potentially complex regulatory landscape within the EDC. Here, we report a computational approach to identify conserved non-coding elements (CNEs) in the EDC queried for regulatory function. Coordinate expression of EDC genes during mouse embryonic skin development and a striking degree of synteny and linearity in the EDC locus across a wide range of mammalian (placental and marsupial) genomes suggests an evolutionary conserved regulatory milieu in the EDC. CNEs identified by comparative genomics exhibit dynamic regulatory activity (enhancer or repressor) in differentiating or proliferating conditions. We further demonstrate epidermal-specific, developmental in vivo enhancer activities (DNaseI and transgenic mouse assays) in CNEs, including one within the psoriasis-associated deletion, LCE3C_LCE3B-del. Together, our multidisciplinary study features a network of regulatory elements coordinating developmental EDC gene expression as an unexplored resource for genetic variants in skin diseases.

The relation of markers of fetal growth with asthma, allergies and serum immunoglobulin E levels in children at age 5-7 years.

BACKGROUND: It has been suggested that fetal growth and maturation have an impact on the development of allergic diseases later in life. OBJECTIVE: To examine the association between measures of fetal growth and allergic disease in children at age 5-7 years. METHODS: As part of the German International Study of Asthma and Allergies in Childhood phase II surveys, a random sample of school beginners (n=1138) was examined in 1995. Data on anthropometric measures at birth and gestational age were obtained from maternal copies of birth records. Data on symptoms and doctor-diagnosed asthma, atopic dermatitis and hayfever were gathered by parental questionnaires. Atopic sensitization was assessed by serum IgE and skin prick tests to common aeroallergens. Children (741) had complete data for the explanatory variables of interest and were thus eligible for this analysis. Confounder-adjusted prevalence odds ratios (PORs) and means ratios with 95% confidence intervals (CI) were calculated using multiple logistic and linear regression. RESULTS: Birth weight and gestational age were positively associated with atopic sensitization (Ptrend=0.025 and 0.035, respectively). Children with a low birth weight relative to head circumference had a decreased risk of sensitization (POR 0.44, 95% CI 0.21-0.91; Ptrend=0.020). Moreover, total serum IgE increased with increasing birth weight (Ptrend=0.042). No consistent relationship was observed between markers of fetal growth and wheezing, doctor-diagnosed asthma, atopic dermatitis and hayfever. CONCLUSION: These data suggest that fetal growth and maturity are associated with atopic sensitization and total serum IgE levels in childhood.