The skin is the human body's largest organ, colonized by a diverse milieu of microorganisms, most of which are harmless or even beneficial to their host. Colonization is driven by the ecology of the skin surface, which is highly variable depending on topographical location, endogenous host factors and exogenous environmental factors. The cutaneous innate and adaptive immune responses can modulate the skin microbiota, but the microbiota also functions in educating the immune system. The development of molecular methods to identify microorganisms has led to an emerging view of the resident skin bacteria as highly diverse and variable. An enhanced understanding of the skin microbiome is necessary to gain insight into microbial involvement in human skin disorders and to enable novel promicrobial and antimicrobial therapeutic approaches for their treatment.

The skin microbiome

Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.

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The development of allergic inflammation

Atopic dermatitis is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental triggers and is often the first step in the atopic march that results in asthma and allergic rhinitis. The clinical phenotype that characterizes atopic dermatitis is the product of interactions between susceptibility genes, the environment, defective skin barrier function, and immunologic responses. This review summarizes recent progress in our understanding of the pathophysiology of atopic dermatitis and the implications for new management strategies.

New insights into atopic dermatitis

BackgroundDupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. MethodsIn two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. ResultsWe enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who...

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Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis

Defensins are peptidic components of the innate immune system of plants and animals. In mammals, defensins have evolved to have a central function in the host defense properties of granulocytic leukocytes, mucosal surfaces, skin and other epithelia. This review focuses on the biological functions of three structural subgroups of mammalian defensins and the evidence for their involvement as effectors of antimicrobial innate immunity.

Mammalian defensins in the antimicrobial immune response

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced (P Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.

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Cytokine modulation of atopic dermatitis filaggrin skin expression

Atopic dermatitis (AD) and psoriasis are the two most common chronic skin diseases. However patients with AD, but not psoriasis, suffer from frequent skin infections. To understand the molecular basis for this phenomenon, skin biopsies from AD and psoriasis patients were analyzed using GeneChip microarrays. The expression of innate immune response genes, human beta defensin (HBD)-2, IL-8, and inducible NO synthetase (iNOS) was found to be decreased in AD, as compared with psoriasis, skin (HBD-2, p = 0.00021; IL-8, p = 0.044; iNOS, p = 0.016). Decreased expression of the novel antimicrobial peptide, HBD-3, was demonstrated at the mRNA level by real-time PCR (p = 0.0002) and at the protein level by immunohistochemistry (p = 0.0005). By real-time PCR, our data confirmed that AD, as compared with psoriasis, is associated with elevated skin production of Th2 cytokines and low levels of proinflammatory cytokines such as TNF-alpha, IFN-gamma, and IL-1beta. Because HBD-2, IL-8, and iNOS are known to be inhibited by Th2 cytokines, we examined the effects of IL-4 and IL-13 on HBD-3 expression in keratinocyte culture in vitro. We found that IL-13 and IL-4 inhibited TNF-alpha- and IFN-gamma-induced HBD-3 production. These studies indicate that decreased expression of a constellation of antimicrobial genes occurs as the result of local up-regulation of Th2 cytokines and the lack of elevated amounts of TNF-alpha and IFN-gamma under inflammatory conditions in AD skin. These observations could explain the increased susceptibility of AD skin to microorganisms, and suggest a new fundamental rule that may explain the mechanism for frequent infection in other Th2 cytokine-mediated diseases.

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Cytokine Milieu of Atopic Dermatitis, as Compared to Psoriasis, Skin Prevents Induction of Innate Immune Response Genes

Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

Background IL-31 is a newly discovered T-cell cytokine that, when overexpressed in mice, results in pruritus and skin dermatitis resembling human atopic dermatitis (AD). Objective We sought to investigate the expression of IL-31 and IL-31 receptor A (IL-31RA) in skin biopsy specimens and peripheral blood cells from patients with AD and healthy individuals. Methods Expression of IL-31 and IL-31RA was evaluated in skin biopsy specimens from patients with AD and healthy individuals by means of immunohistochemistry and RT-PCR. IL-31 protein production by skin-homing cutaneous lymphocyte antigen (CLA)–positive T cells was also assessed. Results IL-31RA protein was expressed by keratinocytes and infiltrating macrophages in skin biopsy specimens from patients with AD. Comparisons between skin from patients with AD and healthy skin showed IL-31RA expression at higher levels on epidermal keratinocytes in AD samples. Infiltrating cells, more numerous in skin from patients with AD compared with that of healthy individuals, expressed IL31 mRNA. Histomorphometric analysis of these cells indicated they were of the lymphocytic lineage, with the majority of cells staining positive for CLA and CD3. IL31 mRNA and protein expression is largely restricted to CD45RO + (memory) CLA + T cells in peripheral blood of patients with AD and healthy volunteers. Moreover, circulating CLA + T cells from patients with AD, but not from patients with psoriasis, are capable of producing higher levels of IL-31 compared with CLA + T cells from healthy individuals. However, the average levels of IL-31 were not significantly different between patients with AD and healthy individuals. Conclusion We provide evidence that IL-31 expression is associated with CLA + T cells and might contribute to the development of AD-induced skin inflammation and pruritus.

https://www.jacionline.org/article/S0091-6749(05)02530-3/pdf

Michael D. Howell

Papers

New insights into atopic dermatitis

Cytokine modulation of atopic dermatitis filaggrin skin expression

Cytokine Milieu of Atopic Dermatitis, as Compared to Psoriasis, Skin Prevents Induction of Innate Immune Response Genes

Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.