Background Several studies have suggested that asthma is associated with an increased risk of stroke. However, the results are inconsistent. The aim of this study is to investigate the relation of ...asthma and the risk of stroke through a systematic review and meta-analysis of published research. Methods Pertinent studies were identified by a search of the PubMed and the Web of Science databases to June 2015. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using fixed-effect or random-effect models when appropriate. Associations were tested in subgroups representing different participants and study characteristics. Publication bias was assessed with Egger's test. Results Five articles comprising 524,637 participants and 6031 stroke cases were eligible for inclusion. Asthma was associated significantly with increased risk of stroke, and the pooled HR was 1.32 (95% CI: 1.13, 1.54, I2 = 80.4%). Subgroup analyses revealed that the association between asthma and stroke risk was stronger among female patients (HR = 1.42, 95% CI: 1.15-1.76) and prospective cohort study design (HR = 1.52, 95% CI: 1.21-1.91). Conclusion Asthma is associated with a significantly increased risk of stroke. This finding may have clinical and public health importance.
Background Genomic profiling of lesional and nonlesional skin of patients with atopic dermatitis (AD) using microarrays has led to increased understanding of AD and identification of novel ...therapeutic targets. However, the limitations of microarrays might decrease detection of AD genes. These limitations might be lessened with next-generation RNA sequencing (RNA-seq). Objective We sought to define the lesional AD transcriptome using RNA-seq and compare it using microarrays performed on the same cohort. Methods RNA-seq and microarrays were performed to identify differentially expressed genes (criteria: fold change, ≥2.0; false discovery rate ≤0.05) in lesional versus nonlesional skin from 18 patients with moderate-to-severe AD, with real-time PCR (RT-PCR) and immunohistochemistry used for validation. Results Both platforms showed robust disease transcriptomes and correlated well with RT-PCR. The common AD transcriptome identified by using both techniques contained 217 genes, including inflammatory ( S100A8/A9/A12, CXCL1 , and 2′-5′-oligoadenylate synthetase-like OASL ) and barrier ( MKi67 , keratin 16 K16 , and claudin 8 CLDN8 ) AD-related genes. Although fold change estimates determined by using RNA-seq showed somewhat better agreement with RT-PCR (intraclass correlation coefficient, 0.57 and 0.70 for microarrays and RNA-seq vs RT-PCR, respectively), bias was not eliminated. Among genes uniquely identified by using RNA-seq were triggering receptor expressed on myeloid cells 1 (TREM-1) signaling (eg, CCL2 , CCL3 , and single immunoglobulin domain IL1R1 related SIGIRR ) and IL-36 isoform genes. TREM-1 is a surface receptor implicated in innate and adaptive immunity that amplifies infection-related inflammation. Conclusions This is the first report of a lesional AD phenotype using RNA-seq and the first direct comparison between platforms in this disease. Both platforms robustly characterize the AD transcriptome. Through RNA-seq, we unraveled novel disease pathology, including increased expression of the novel TREM-1 pathway and the IL-36 cytokine in patients with AD.
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.
Background The molecular signature of atopic dermatitis (AD) lesions is associated with TH 2 and TH 22 activation and epidermal alterations. However, the epidermal and dermal AD transcriptomes and ...their respective contributions to abnormalities in respective immune and barrier phenotypes are unknown. Objective We sought to establish the genomic profile of the epidermal and dermal compartments of lesional and nonlesional AD skin compared with normal skin. Methods Laser capture microdissection was performed to separate the epidermis and dermis of lesional and nonlesional skin from patients with AD and normal skin from healthy volunteers, followed by gene expression (microarrays and real-time PCR) and immunostaining studies. Results Our study identified novel immune and barrier genes, including the IL-34 cytokine and claudins 4 and 8, and showed increased detection of key AD genes usually undetectable on arrays (ie, IL22 , thymic stromal lymphopoietin TSLP , CCL22 , and CCL26 ). Overall, the combined epidermal and dermal transcriptomes enlarged the AD transcriptome, adding 674 upregulated and 405 downregulated differentially expressed genes between lesional and nonlesional skin to the AD transcriptome. We were also able to localize individual transcripts as primarily epidermal (defensin, beta 4A DEFB4A ) or dermal ( IL22 , cytotoxic T-lymphocyte antigen 4 CTLA4 , and CCR7 ) and link their expressions to possible cellular sources. Conclusions This is the first report that establishes robust epidermal and dermal genomic signatures of lesional and nonlesional AD skin and normal skin compared with whole tissues. These data establish the utility of laser capture microdissection to separate different compartments and cellular subsets in patients with AD, allowing localization of key barrier or immune molecules and enabling detection of gene products usually not detected on arrays.
Background Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although ...many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. Objective We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin. Methods Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg -mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23–injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays. Results IL-23–injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysis–derived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust TH 1, TH 2, and also TH 17 activation are seen in IL-23–injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a TH 1-centered reaction, and flaky tail mice demonstrate a strong TH 17 polarization. Flg -mutated mice display filaggrin downregulation without significant inflammation. Conclusion No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23–injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.
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.
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 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.
Background Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for ...assessing different formulations and concentrations. The “plaque model” has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis. Objective We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics. Methods We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated. Results TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss ( P < .05). Significant differences versus vehicle values were limited to steroids ( P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus ( P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids ( P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers. Conclusion We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.
Background B cells undergo maturation and class-switching in response to antigen exposure and T-cell help. Early B-cell differentiation has not been defined in patients with early-onset atopic ...dermatitis (AD). Objective We sought to define the frequency of B-cell subsets associated with progressive B-cell maturation and IgE class-switching. Methods We studied 27 children and 34 adults with moderate-to-severe AD (mean SCORAD score, 55 and 65, respectively) and age-matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometric panel were used to determine the frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgE) levels were measured by using ImmunoCAP. Results Compared with adults, children showed T-cell predominance in the skin. Circulating CD19+ CD20+ B-cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T-cell counts were higher (62% vs 52%, P = .05). A decreased B-cell/T-cell lymphocyte ratio with age was observed only in pediatric control subjects ( r = −0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B-cell/T-cell ratio and nonswitched memory B-cell counts ( r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD ( P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD ( P < .01). Positive correlations were observed between activated B-cell and memory T-cell counts ( P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH 1, TH 2, total IgE levels, and B-cell memory subsets. Conclusions Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions.