Hui Xu

The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization

BACKGROUND Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17(+)-producing cell counts in Asian patients with AD. OBJECTIVE We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. METHODS We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). RESULTS Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD (P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. TH2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. CONCLUSION The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component. The relative pathogenic contributions of the TH17 and TH2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics.

Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without parallel TH17/TH22 skewing

BACKGROUND Alopecia areata (AA) is a common T cell-mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on TH1/IFN-γ responses, several observations support a shared genetic background between AA and atopy. OBJECTIVE We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. METHODS We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). RESULTS We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs [297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in TH1/interferon markers (IFNG and CXCL10/CXCL9) were those noted in TH2 (IL13, CCL18, CCL26, thymic stromal lymphopoietin, and periostin), TH9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in TH17/TH22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85). CONCLUSIONS Our data associate the AA signature with TH2, TH1, IL-23, and IL-9/TH9 cytokine activation, suggesting consideration of anti-TH2, anti-TH1, and anti-IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways.

Diverse activation and differentiation of multiple B-cell subsets in patients with atopic dermatitis but not in patients with psoriasis

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.

Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling

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 TH1, TH2, and also TH17 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 TH1‐centered reaction, and flaky tail mice demonstrate a strong TH17 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.

Alterations in B-cell subsets in pediatric patients with early atopic dermatitis

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, TH1, TH2, 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.

Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis

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.

Early-onset pediatric atopic dermatitis is characterized by T H 2/T H 17/T H 22-centered inflammation and lipid alterations

Background: Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early‐onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. Objective: We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. Methods: We performed microarray, RT‐PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early‐onset AD (<6 months disease duration) compared with age‐matched control subjects and adults with longstanding AD. Results: Transcriptomic analyses revealed profound differences between pediatric patients with early‐onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored TH2‐centered inflammation, pediatric AD also showed significant TH17/TH22 skewing but lacked the TH1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o‐acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid‐associated mediators (eg, fatty acyl‐CoA reductase 2 and fatty acid 2‐hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Conclusions: Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early‐onset disease.

Dust mite induces multiple polar T cell axes in human skin

House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new‐onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model ADs emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown.

Asian atopic dermatitis serum is characterized by Th2/Th22-activation, highly correlated with non-lesional skin measures.

Asian AD serum is characterized by prominent Th2 and Th22 signatures that correlate with the non-lesional skin profile, suggesting that serum phenotyping can serve as a surrogate for assessing disease extent beyond apparent AD lesions.

Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features

Our data established the molecular fingerprints of AD and psoriasis in Han Chinese patients, and identified tissue biomarkers of disease that correlated with clinical severity.