Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE ...status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional “one-size-fits-all” therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation.
Skin barrier abnormalities have been suggested to play an essential role in initiation of early atopic dermatitis (AD). Antigen penetration through a compromised barrier likely leads to increased ...innate immune responses, antigen-presenting cell stimulation, and priming of overt cutaneous disease. In a TH 2-promoting environment, T-cell/B-cell interactions occurring in regional lymph nodes lead to excessive IgE switch. Concurrent redistribution of memory T cells into the circulation not only leads to exacerbation of AD through T-cell skin infiltration but also spreads beyond the skin to initiate the atopic march, which includes food allergy, asthma, and allergic rhinitis. Possible primary interventions to prevent AD are focusing on improving skin barrier integrity, including supplementing barrier function with moisturizers. As for secondary prophylaxis in children with established AD, this can be stratified into prevention of disease exacerbations by using proactive approaches (with either topical corticosteroids or topical calcineurin inhibitors) in mild AD cases or the prevention of other atopic disorders that will probably mandate systemic immunosuppression in severe AD cases.
Background Allergic contact dermatitis (ACD) is the most common occupational disease. Although murine contact hypersensitivity provides a framework for understanding ACD, it carries important ...differences from its human counterpart. Unlike the contact hypersensitivity model, which is induced by potent sensitizers (ie, dinitrofluorobenzene), human ACD is induced by weak-to-moderate sensitizers (ie, nickel), which cannot induce reactions in mice. Distinct hapten-specific immune-polarizing responses to potent inducers were suggested in mice, with unclear relevance to human ACD. Objective We explored the possibility of distinct T-cell polarization responses in skin to common clinically relevant ACD allergens. Methods Gene-expression and cellular studies were performed on common allergens (ie, nickel, fragrance, and rubber) compared with petrolatum-occluded skin, using RT-PCR, gene arrays, and immunohistochemistry. Results Despite similar clinical reactions in all allergen groups, distinct immune polarizations characterized different allergens. Although the common ACD transcriptome consisted of 149 differentially expressed genes across all allergens versus petrolatum, a much larger gene set was uniquely altered by individual allergens. Nickel demonstrated the highest immune activation, with potent inductions of innate immunity, TH 1/TH 17 and a TH 22 component. Fragrance, and to a lesser extent rubber, demonstrated a strong TH 2 bias, some TH 22 polarization, and smaller TH 1/TH 17 contributions. Conclusions Our study offers new insights into the pathogenesis of ACD, expanding the understanding of T-cell activation and associated cytokines in allergen-reactive tissues. It is the first study that defines the common transcriptome of clinically relevant sensitizers in human skin and identifies unique pathways preferentially activated by different allergens, suggesting that ACD cannot be considered a single entity.
Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease activity, ...although 85% of cases begin by 5 years. Blood phenotyping shows only TH2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies.
We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD.
Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects.
In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3+, CD11c+, and FcεRI+) than adults with AD. Similar to adults, strong activation of the TH2 (IL-13, IL-31, and CCL17) and TH22 (IL-22 and S100As) axes and some TH1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of TH17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), TH9/IL-9, IL-33, and innate markers (IL-8) than adults (P < .02). Despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children. Nonlesional skin in pediatric patients with AD showed higher levels of inflammation (particularly IL-17A and the related molecules IL-19 and LL37) and epidermal proliferation (keratin 16 and S100As) markers (P < .001).
The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess TH2 activation characterizes both, TH9 and TH17 are highly activated at disease initiation. Increases in IL-19 levels might link TH2 and TH17 activation.
Atopic dermatitis (AD) is increasingly recognized as a complex, inflammatory skin disease involving interplay of multiple elements. This article notes key advances in understanding of immune ...dysregulation, skin barrier dysfunction, environmental, genetic, and microbial influences orchestrating disease pathogenesis, and the relevance of therapeutic interventions in each area. Accumulating evidence and the discovery of new T-cell subsets has matured AD as a multiple-cytokine-axes-driven disorder, evolved from the widely held belief of it being a biphasic Th1/Th2 disease. These new insights have led to active trials testing multiple, targeted therapeutics with better efficacy and safety-profiles.
Identifying differences and similarities between cutaneous lymphocyte antigen (CLA)+ polarized T-cell subsets in children versus adults with atopic dermatitis (AD) is critical for directing new ...treatments toward children.
We sought to compare activation markers and frequencies of skin-homing (CLA+) versus systemic (CLA−) “polar” CD4 and CD8 T-cell subsets in patients with early pediatric AD, adults with AD, and control subjects.
Flow cytometry was used to measure CD69/inducible costimulator/HLA-DR frequency in memory cell subsets, as well as IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines, defining TH1/cytotoxic T (TC) 1, TH2/TC2, TH9/TC9, TH17/TC17, and TH22/TC22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children less than 5 years old and 42 adults with well-characterized moderate-to-severe AD, as well as age-matched control subjects (17 children and 25 adults).
Selective inducible costimulator activation (P < .001) was seen in children. CLA+ TH2 T cells were markedly expanded in both children and adults with AD compared with those in control subjects, but decreases in CLA+ TH1 T-cell numbers were greater in children with AD (17% vs 7.4%, P = .007). Unlike in adults, no imbalances were detected in CLA− T cells from pediatric patients with AD nor were there altered frequencies of TH22 T cells within the CLA+ or CLA− compartments. Adults with AD had increased frequencies of IL-22–producing CD4 and CD8 T cells within the skin-homing population, compared with controls (9.5% vs 4.5% and 8.6% vs 2.4%, respectively; P < .001), as well as increased HLA-DR activation (P < .01).
These data suggest that TH2 activation within skin-homing T cells might drive AD in children and that reduced counterregulation by TH1 T cells might contribute to excess TH2 activation. TH22 “spreading” of AD is not seen in young children and might be influenced by immune development, disease chronicity, or recurrent skin infections.
Background Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular ...responses induced by petrolatum in the skin have never been assessed. Objective We sought to define the cutaneous molecular and structural effects induced by petrolatum. Methods Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. Results Significant upregulations of antimicrobial peptides (S100A8/fold change FCH, 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 elafin/FCH, 15.40; lipocalin 2/FCH, 6.94, human β-defensin 2 DEFB4A/FCH, 4.96; P < .001 for all) and innate immune genes ( IL6 , IL8 , and IL1B ; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of “normal-appearing” or nonlesional AD skin, which is known to harbor barrier and immune defects. Conclusions Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.
The immune abnormalities underlying the ichthyoses are poorly understood.
To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of ...desmoplakin gene (DSP) and target therapy on the basis of molecular pathogenesis.
Immunophenotyping was performed by using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy.
On the basis of the discovery of T helper 1 and T helper 17/interleukin 23 skewing in the skin and T helper 17/interleukin 22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded despite previous poor responses to immunosuppressants and retinoids.
Small number of patients and immunophenotyping in only 1 patient.
An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants.
Background Atopic dermatitis (AD) and psoriasis pathogeneses involve skin barrier impairment and immune dysregulation; however, the contribution of B-cell imbalances to these diseases has not yet ...been determined. Objective We sought to quantify B-cell populations and antibody-secreting cells in the blood of patients with AD, patients with psoriasis, and control subjects. Methods We studied 34 adults with moderate-to-severe AD (mean SCORAD score, 65), 24 patients with psoriasis (mean Psoriasis Area and Severity Index score, 16), and 27 healthy subjects using an 11-color flow cytometric antibody panel. IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies of plasmablasts and naive, memory, transitional, and activated B cells. Results We measured increased CD19+ CD20+ B-cell counts in the skin and blood of patients with AD ( P < .01). Significantly higher frequencies of chronically activated CD27+ memory and nonswitched memory B cells were observed in patients with AD ( P < .05), with lower values of double-negative populations (4% for patients with AD vs 7% for patients with psoriasis P = .001 and 6% for control subjects P = .02). CD23 expression was highest in patients with AD and correlated with IgE levels ( P < .01) and disease severity ( r = 0.6, P = .0002). Plasmablast frequencies and IgE expression were highest in all memory subsets of patients with AD ( P < .01). Finally, CD19+ CD24++ CD38++ transitional and CD19+ CD24− CD38− new memory B-cell counts were higher in patients with AD versus those in patients with psoriasis (2.8% vs 1.4% P = .001 and 9.2% vs 5.7% P = .02, respectively). Conclusions AD is accompanied by systemic expansion of transitional and chronically activated CD27+ memory, plasmablast, and IgE-expressing memory subsets. These data create a critical basis for the future understanding of this debilitating skin disease.
Background Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to TH 2/TH 22 cytokine activation. However, ...these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. Methods CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of TH 2-, TH 22-, and some TH 17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.
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