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Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.

ABSTRACT: Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in AAs with moderate to severe pruritus, lesional and non-lesional punch biopsies were taken from AA patients along with age-, race-, and sex-matched controls. Histology of lesional skin showed psoriasiform dermatitis and spongiotic dermatitis, suggesting both Th2 and Th17 activity. Gene Set Variation Analysis showed upregulation of Th2 and Th17 pathways in both lesional versus non-lesional and lesional versus control (p < 0.01), while Th1 and Th22 upregulation were observed in lesional versus control (p < 0.05). Evidence for a broad immune signature also was supported by upregulated Th1 and Th22 pathways, and clinically may represent greater severity of AD in AA. Furthermore, population-level analysis of data from TriNetX, a global federated health research network, revealed that AA AD patients had higher values for CRP, ferritin, and blood eosinophils compared to age-, sex-, and race-matched controls as well as white AD patients, suggesting broad systemic inflammation. Therefore, AA AD patients may feature broader immune activation than previously thought and may derive benefit from systemic immunomodulating therapies that modulate key drivers of multiple immune pathways.

SUBMITTER: Wongvibulsin S

PROVIDER: S-EPMC8160001 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.

Wongvibulsin Shannon S Sutaria Nishadh N Kannan Suraj S Alphonse Martin Prince MP Belzberg Micah M Williams Kyle A KA Brown Isabelle D ID Choi Justin J Roh Youkyung Sophie YS Pritchard Thomas T Khanna Raveena R Eseonu Amarachi C AC Jedrych Jaroslaw J Dillen Carly C Kwatra Madan M MM Chien Anna L AL Archer Nathan N Garza Luis A LA Dong Xinzhong X Kang Sewon S Kwatra Shawn G SG

Scientific reports 20210527 1

Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in AAs with moderate to severe pruritus, lesional and non-lesional punch biopsies were taken from AA patients along with age-, race-, and sex-matched controls. Histology of lesional skin showed psoriasiform dermatitis and spongiotic dermatitis, suggesting both Th2 and Th17 activity. Gene Set Variation Analysis showed upregulation of ...[more]

PMID: 34045476

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Project description:Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an "allergic"/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects.We sought to define whether both variants share a common pathogenesis.We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry.A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin).Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.

Project description:In atopic dermatitis (AD), epidermal disease hallmarks are driven by a complex cutaneous inflammatory milieu that varies between patients. How these variable inflammatory signatures translate to patient-specific disease endotypes is poorly understood, which hampers the personalized use of targeted drugs. We here employed primary and immortalized keratinocyte-derived human epidermal equivalents stimulated with T helper (Th)2, -17 and -22 cytokines, to unravel which AD-associated cytokines drive specific epidermal disease hallmarks. Th2 cytokines IL-4 and IL-13 were main inducers of a pro-inflammatory and hyperproliferative response. The presence of IL-17A or IL-22 in the Th2 milieu caused spongiosis, impaired keratinocyte differentiation (loss of FLG, IVL, KRT2) and epidermal barrier defects (altered CLDN1, CLDN4, transepithelial impedance). Transcriptomic analyses revealed upregulation of proliferation genes by Th2 cytokines, and activation of different immune pathways upon Th2 cytokines alone and combination of Th2 and Th17/22 cytokines. Downregulation of epidermis development was most apparent upon combined exposure to Th2 cytokines and IL-22. Single-cell spatial transcriptomics showed expansion of keratinocytes expressing high level of proliferation genes in all epidermal layers, and downregulation of terminal differentiation genes in the upper epidermal layers. Our in vitro AD model using Th2 + IL-22 showed the highest transcriptome resemblance with in vivo AD lesional epidermis and we identified IL-22 specific alteration of epidermis development by lipid mediators like ACER1 and AKR1C3. Finally, we revealed that Aryl Hydrocarbon Receptor (AHR) ligands partially restored the barrier defects caused by Th2 and IL-22, whereas combination of AHR ligand Tapinarof with Janus Kinase (JAK) inhibitor I had an even greater restoring effect. Thus, specific combinations of cytokines upregulated in AD skin drive differential disease hallmarks highlighting the importance of personalized medicine and the need for prediction models in the targeted treatment of AD patients.

Project description:ImportanceFlare is a term commonly used in atopic dermatitis (AD) care settings and clinical research, but little consensus exists on what it means. Meanwhile, flare management is an important unmet research and treatment need. Understanding how various therapies might comparatively improve AD flares as a measure of treatment effectiveness may facilitate shared decision-making and enable assessment of effectiveness within and outside clinical settings.ObjectiveTo identify patient-reported attributes associated with an AD flare to develop a patient-centered, consensus-based working definition.Design, setting, and participantsThis consensus survey study used a modified eDelphi method involving consensus-building focus groups and a survey conducted from January 10 through October 24, 2023. Focus groups were conducted virtually, and the online survey was advertised to National Eczema Association members. US adults aged 18 years or older with AD were recruited via convenience sampling.ExposureLived experience of AD.Main outcomes and measuresThe main outcome was consensus on which attributes of AD to include in a patient-centric definition of flare. Using a rating scale (range, 1-9), consensus for the modified eDelphi statement rating was defined as at least 70% of participants rating a statement as 7 to 9 (critical to a flare definition) and less than 15% rating it as 1 to 3 (not important).ResultsTwenty-six participants with AD who completed focus group activities (24 aged 18-44 years [92.3%] and 2 aged 45-64 years [7.7%]; 18 women [69.2%]) and 631 participants with AD (mean [SD] age, 45.5 [18.1] years; 533 women [84.5%]) who completed the survey were included in the analysis. Fifteen statements reached consensus from the focus groups, and of those, 12 reached consensus from survey participants. More than half (334 of 631 [52.9%]) of survey participants reported alignment with their health care practitioner on what a flare is, and most (478 of 616 [77.6%]) reported that a patient-centered definition would be useful when communicating with their health care practitioner about their condition.Conclusions and relevanceIn this study, participants with AD reached consensus on what an AD flare means from the patient perspective. This understanding may improve research and care by addressing this key patient-centered aspect of evaluating treatment effectiveness.

Dataset Information

Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.

Publications

Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.

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