Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation

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Abstract

Background

African Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population.

Objective

We sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls.

Methods

We performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls.

Results

African American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1β), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA.

Conclusion

The molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting all ethnic populations with varying rates of prevalence associated with disproportionate degrees of impact on health care.[1], [2] The AD disease phenotype is characterized by T-cell and dendritic cell (DC) infiltrates,[3], [4] up-regulation of inflammatory mediators,4 epidermal hyperplasia,5 and epidermal barrier defects with down-regulation of differentiation proteins, lipids, and claudins.[6], [7], [8] Currently AD is considered to be a TH2/TH22-centric disease, largely based on molecular profiling in European American (EA) adults.[4], [9] However, AD is increasingly recognized as a heterogeneous disease with significant variation in molecular phenotypes across different populations.[10], [11] For instance, Asian and pediatric AD show increased TH17 activation in addition to TH2 skewing.[10], [11], [12], [13] This heterogeneity has important implications for future development and selection of targeted therapeutics, which thus far has been based primarily on pathogenic insights derived from the EA AD adult phenotype.[4], [7],8

African Americans (AA) are disproportionately impacted by AD, with a prevalence of 19.3% vs 16.1% in EA in the United States,[14], [15] comparable with AD prevalence rates reported in African countries of up to 23%.16 Additionally, a US-based study comparing health care utilization for atopic dermatitis in different ethnic groups found that although white patients had a greater number of per capita visits for all medical conditions and skin conditions, black patients had higher per capita numbers of visits for AD and were 3 times more likely than whites to have an office visit at which AD was diagnosed.2 This disproportionate impact is exacerbated by unique treatment challenges in this population, such as higher required doses of cyclosporine A17 and narrow-band ultraviolet B,18 increased incidence of corticosteroid-induced hypopigmentation,19 and greater risk of dryness because of increased transepidermal water loss20 and decreased ceramide-to-cholesterol ratio.21 The paucity of safe and effective treatments for moderate-to-severe AD in AA further highlights the need for biomarker research and identification of therapeutic targets in this population, thus allowing for accurate prediction of phenotype-specific responses to available targeted therapeutics, in addition to development of novel treatment strategies.

Still, molecular mechanisms of AD are profoundly understudied in this population.[22], [23] Prior research in AA is limited to genome-wide association studies (GWAS), which have detected some polymorphisms in risk loci within AD-associated genes, including IL-7R,24 TSLP,[24], [25] IL-18R1,26 FLG,[26], [27], [28], [29] and FLG2,28 without molecular phenotypic correlation. We thus set out to conduct the first global molecular profiling study of AA AD using RNA-seq. Our study identified significant variations in immune polarization and expression of epidermal barrier markers in AA AD as compared with an EA AD cohort.

Section snippets

Sample Collection

Biopsy specimens were collected from lesional and nonlesional (>10 cm from active lesions) skin in 30 patients with chronic AD since childhood (15 AA, 15 EA), and from healthy skin in 16 control subjects (9 AA, 7 EA), under an institutional review board–approved protocol. Of the 12 AA patients studied, a heterozygous FLG mutation in the 2282del41 allele was found in 1 patient, and no mutations were found in R501X, R2447X, and S3247X. No heterozygous FLG mutations (R501X and 2282del4 allele)

Results

This study included 15 AA and 15 EA patients with moderate-to-severe AD (AA ages 18-59 [mean 40.6], Scoring of Atopic Dermatitis (SCORAD) 38-94 [mean 56.9]; EA ages 23-69 [mean 47.8], SCORAD 44-77 [mean 58]), as well as 9 AA and 7 EA healthy control subjects (AA ages 23-56 [mean 41.3]; EA ages 31-56 [mean 46.4]). All AA patients had Fitzpatrick skin types V or VI. There were no significant differences in demographic parameters, including age and sex distribution, between AA and EA cohorts, or

Discussion

This is the first global molecular profiling study of AD skin in African American patients, characterizing phenotypic variations among African American and European American AD cohorts. Despite similar severity and chronicity of AD in both cohorts (long-standing disease since childhood in all patients, lesions present more than 72 hours before biopsy, and no significant differences in epidermal acanthosis between groups), our data revealed significant variations in cellular infiltration as well

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    Disclosures: E.G.Y. is an employee of Mount Sinai and has received research funds (grants paid to the institution) from: Abbvie, Celgene, Eli Lilly, Janssen, Medimmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB. E.G.Y. is also a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. J.G.K. has received research support (grants paid to his institution) or personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. The rest of the authors declare that they have no relevant conflicts of interest.

    Funding Sources: R.D.S. was supported by TL1 grant #TR001434 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health.

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