The Editors' Choice

Abstract

Atopic dermatitis (AD) is associated with intense itch and loss of sleep in early life and with food allergy and asthma, in later life. The early origins of AD are incompletely understood but involve a complex interplay between the skin barrier, immune dysregulation, and the cutaneous microbiome. Eczema has a close relationship with Staphylococcus aureus colonization, which is associated with flares of AD. However, it was not known whether S aureus colonization preceded eczema or eczema followed S aureus colonization. In this issue of the Journal, Kennedy et al (p 166) followed a cohort of patients (the Cork BASELINE Cohort) over their first year of life and regularly sampled their skin microbiome. The authors were able to show that S aureus colonization did not precede development of AD in this cohort, and surprisingly, several commensal staphylococci present at 2 months were associated with reduced incidence of AD at 1 year. This is an important new finding in the complex relationship between the microbiome and skin inflammation, suggesting that some commensal bacteria might be anti-inflammatory or protective against eczema. Atopic dermatitis (AD) is caused by allergic skin inflammation and is the most common chronic inflammatory disease that affects infants and children. IL-4 is a critical factor in mediating AD pathology, and an antibody targeting of IL-4 receptor has shown great promise in the clinic. In this issue Serezani et al (p 142) present data on transcriptome analysis of IL-4–treated human keratinocytes. The authors confirm previously identified decreases in genes that regulate barrier function (allowing greater allergen exposure) and pathogen defense (allowing colonization by pathogenic bacteria and viruses) and increases in expression of proinflammatory genes that facilitate increased inflammation (see Figure). Serezani et al further identify decreases in genes regulating the wound-healing response, specifically diminishing the ability of keratinocytes to mediate re-epithelialization of wounds, as demonstrated in cultured keratinocytes and in a mouse model of AD. Importantly, they identified the extracellular matrix protein fibronectin as a key gene that is lost in response to IL-4 and that topical application of fibronectin restored re-epithelialization potential (see Figure). These observations are particularly relevant in patients with a disease that is exacerbated by the itch-scratch cycle and might highlight new therapeutic approaches for the treatment of AD. Monogenic autoinflammatory syndromes are rare disorders characterized by periodic episodes of fever and chronic sterile inflammation that are generally associated with mutations in genes responsible for the inflammatory response, the inflammasome in particular. Prototypic diseases in this group are cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever. Despite the direct relationship between mutations in inflammasome genes and the appearance of autoinflammatory syndromes, not all patients exhibit (detectable) mutations. In some cases, mutations do not relate to the severity of the disease or allow us to predict the occurrence and intensity of the attacks. Such observations suggest the existence of additional contributing pathogenic mechanisms. Vento-Tormo et al (p 202) report the first description of epigenetic regulation of inflammasome genes in patients with autoinflammatory disorders; a novel regulatory mechanism in controlling IL-1β–mediated inflammation. Specifically, the authors determine that inflammasome-related genes rely on DNA methylation changes to become activated. Monocytes from untreated patients with CAPS display exacerbated demethylation of these genes, providing a novel mechanism that is linked to the aberrant inflammatory response of these patients. These results open up possibilities for novel clinical markers for diagnosis and for evaluation of the response to drugs. Better understanding of the molecular basis of disease leads to pathogenesis-based therapies. The ichthyoses are rare genetic skin disorders characterized by epidermal barrier impairment, inflammation, and scaling. Therapeutic options largely focus on scale reduction. Paller et al (p 152) compared the clinical characteristics and barrier abnormalities with the cellular and molecular immune expression patterns in skin from 21 genotyped patients with ichthyosis spanning the more common subtypes (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome). The inflammation profile in ichthyotic skin was compared with that of skin from healthy control subjects and patients with 2 common immune skin disorders: atopic dermatitis and psoriasis. As in psoriasis but in contrast to atopic dermatitis, ichthyotic skin showed dramatic induction of markers regulated by IL-17 or synergistically by IL-17/TNF-α (IL-17A/C, IL-19, and CCL20: P < .05). The extent of upregulation strongly correlated with severity of the disease (IL-17A: r = 0.74, P < .001). These markers also significantly correlated with transepidermal water loss, possibly linking inflammation with barrier defects in patients with ichthyosis. Given the shared TH17/IL-23 immune fingerprint underlying all studied forms of ichthyosis, the authors suggest that targeting the TH17 pathway could be a new treatment paradigm for managing the ichthyoses. Although a prominent role of TH2 cells in type 2 immune responses is well established, the recently identified type 2 innate lymphoid cells (ILC2s) can also orchestrate allergic and asthmatic responses. Air pollution represents a high environmental risk to human health, leading to increased morbidity and mortality. Several epidemiologic studies reported that exposure to traffic-related particulate matter, including diesel exhaust particles (DEPs), contributes to the onset and aggravation of allergic asthma; however, the mechanisms remain unclear. In this issue De Grove et al (p 246) use a murine model in which combined exposure to DEPs and a clinically relevant allergen (house dust mite) augments the allergen-induced airway hyperresponsiveness and airway inflammation characterized by eosinophilia, mucus metaplasia, and type 2 cytokine production. Using genetically modified mice, the authors demonstrate that a dysregulation of ILC2s and TH2 cells is associated with attenuated DEP-enhanced allergic airway inflammation. Of interest, they show a crucial role for the adaptive immune system in DEP-enhanced airway hyperresponsiveness and allergic airway inflammation, whereas ILC2s seem dispensable during combined DEP plus house dust mite exposure. These findings might have clinical implications because coexposure to multiple environmental factors could modulate the contribution of ILC2s or TH2 cells in patients with airway disease. Tissue eosinophilia implicates poorer prognosis in patients with chronic rhinosinusitis (CRS) with nasal polyps, and thus strategies to inhibit eosinophil recruitment might improve treatment outcomes in these patients. In this issue Min et al (p 130) showed that levels of IL-13 and eotaxin-3, an eosinophil chemoattractant, were positively correlated with tissue eosinophilia in patients with CRS. They further presented novel findings that proton pump inhibitors (PPIs), which classically block the gastric H,K-ATPase (encoded by the ATP4A gene) for gastroesophageal reflux disease treatment, have class-specific and dose-dependent inhibitory effects on IL-13–induced eotaxin-3 expression in human airway epithelial cells in vitro. Concordant with these results, eotaxin-3 levels in nasal tissue were also significantly lower in patients with CRS taking PPIs compared with those not taking PPIs. Furthermore, the authors discovered that IL-13 might require the activity of an ATP4A homolog, the nongastric H,K-ATPase (encoded by the ATP12A gene), to optimally express its proinflammatory effects in epithelial cells. These results raise the possibility that targeting activity of the nongastric H,K-ATPase with PPIs or other more specific drugs might reduce mucosal eosinophilia in patients with CRS with nasal polyps.