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Background <p>Atopic dermatitis (AD) occurs across all ages but presents distinct clinical and immunologic features between children, adults, and older adults. The molecular programs underlying these age-specific immune differences remain poorly understood.</p> Methods <p>We performed single-cell multi-omics profiling of peripheral blood mononuclear cells (PBMCs) from 29 AD patients and 29 matched healthy controls (HC), spanning pediatric (0–17 years), adult (18–59 years), and geriatric (≥60 years) groups. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we simultaneously quantified transcriptomic (RNA) and surface proteomic (ADT) profiles across ~280,000 immune cells. Integrated analyses identified 30 immune subsets for cell-type proportion and differential expression analyses. Machine-learning classifiers were trained on significant gene and protein features to distinguish AD subgroups by age.</p> Results <p>Compared with HC, AD blood showed enrichment of CD14+ monocytes, plasmacytoid dendritic cells, and CD4+ proliferating T cells, and differential gene expression analysis of AD vs HC revealed downstream Th2-associated signatures shared across all age groups. Within AD, pediatric patients had increased γδ T cells, naïve CD4+, and naïve CD8+ T cells, while geriatric patients exhibited more CD4+ cytotoxic and CD8+ central memory T cells, indicating a shift from naive to effector predominance with aging. Transcriptomic and proteomic analyses revealed distinct programs: pediatric AD was enriched for IL-10 and cytokine–cytokine receptor signaling; adult AD demonstrated activation of metabolic and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Th1/Th17 pathways; and geriatric AD exhibited reduced adaptive immune activity but increased innate signaling. Machine-learning models based on differentially expressed genes and proteins accurately classified AD age groups (transcript-based F1 = 0.70, AUC = 0.79), identifying stable markers such as IRF2, PDK4, ZFP90, CD21, CD94, and CD122.</p> Conclusions <p>Single-cell multi-omics profiling revealed age-specific transcriptional and immunological programs overlaid on a shared Th2-driven inflammatory foundation in AD. Rather than discrete disease states, pediatric, adult, and geriatric AD each exhibited distinct molecular signatures: developmental and cytoskeletal in children, stress-response and chronic inflammatory in adults, and innate and metabolic in geriatric individuals. These findings support age-group molecular subtyping and age-tailored therapeutic strategies across the AD lifespan.</p>

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Immunological differences in atopic dermatitis across age groups: insights from single-cell multi-omics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月1日

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  • Gian Carlo L. Baldonado,
  • Sugandh Kumar,
  • Joy Jin,
  • Xiaohui Fang,
  • Alexander Ildardashty,
  • Mitchell Braun,
  • Isaac M. Neuhaus,
  • Erin Mathes,
  • Tina Bhutani,
  • Wilson Liao

摘要

Background

Atopic dermatitis (AD) occurs across all ages but presents distinct clinical and immunologic features between children, adults, and older adults. The molecular programs underlying these age-specific immune differences remain poorly understood.

Methods

We performed single-cell multi-omics profiling of peripheral blood mononuclear cells (PBMCs) from 29 AD patients and 29 matched healthy controls (HC), spanning pediatric (0–17 years), adult (18–59 years), and geriatric (≥60 years) groups. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we simultaneously quantified transcriptomic (RNA) and surface proteomic (ADT) profiles across ~280,000 immune cells. Integrated analyses identified 30 immune subsets for cell-type proportion and differential expression analyses. Machine-learning classifiers were trained on significant gene and protein features to distinguish AD subgroups by age.

Results

Compared with HC, AD blood showed enrichment of CD14+ monocytes, plasmacytoid dendritic cells, and CD4+ proliferating T cells, and differential gene expression analysis of AD vs HC revealed downstream Th2-associated signatures shared across all age groups. Within AD, pediatric patients had increased γδ T cells, naïve CD4+, and naïve CD8+ T cells, while geriatric patients exhibited more CD4+ cytotoxic and CD8+ central memory T cells, indicating a shift from naive to effector predominance with aging. Transcriptomic and proteomic analyses revealed distinct programs: pediatric AD was enriched for IL-10 and cytokine–cytokine receptor signaling; adult AD demonstrated activation of metabolic and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Th1/Th17 pathways; and geriatric AD exhibited reduced adaptive immune activity but increased innate signaling. Machine-learning models based on differentially expressed genes and proteins accurately classified AD age groups (transcript-based F1 = 0.70, AUC = 0.79), identifying stable markers such as IRF2, PDK4, ZFP90, CD21, CD94, and CD122.

Conclusions

Single-cell multi-omics profiling revealed age-specific transcriptional and immunological programs overlaid on a shared Th2-driven inflammatory foundation in AD. Rather than discrete disease states, pediatric, adult, and geriatric AD each exhibited distinct molecular signatures: developmental and cytoskeletal in children, stress-response and chronic inflammatory in adults, and innate and metabolic in geriatric individuals. These findings support age-group molecular subtyping and age-tailored therapeutic strategies across the AD lifespan.