特应性皮炎（AD）前沿文献精读特辑（J Eur Acad Dermatol Venereol / J Allergy Clin Immunol / Allergy / Proc Natl Acad Sci U S A）

Atopic dermatitis (AD) is increasingly understood as a biologically heterogeneous disease in which barrier dysfunction, type 2 inflammation, neuroimmune dysregulation, and intracellular signaling abnormalities interact in dynamic and context-dependent ways. This review highlights three concepts that have advanced the field in recent years. First, studies in early life suggest that AD harbors measurable preclinical abnormalities, developmental trajectories, and potential opportunities for targeted intervention. Second, recent work has refined the cytokine architecture of AD beyond interleukin (IL)-4 and IL-13 by identifying noncanonical cytokine circuits that shape distinct aspects of the disease phenotype, including upstream pathogenic T helper type 2 (TH2) cell activation, epidermal dysfunction, and itch. Third, rare gain-of-function (GOF) disorders involving signal transducer and activator of transcription 6 (STAT6) and Janus kinase 1 (JAK1) have consolidated the relevance of the IL-4/IL-13-JAK-STAT signaling axis in AD, providing insight into how specific alterations within this axis can drive severe allergic skin disease and associated systemic phenotypes. Considered together, these developments support a more differentiated view of AD pathophysiology, in which disease onset, tissue inflammation, barrier impairment, pruritus, and therapeutic response are governed by partially overlapping but nonidentical pathways.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition that often portends the development of allergic comorbidities. Despite evidence supporting the role of the skin microbiome in AD, its temporal patterns and associations with risk or protection for allergic co-morbidity remain unclear. Our objective is to characterize core species of the pediatric AD bacterial microbiome, assess microbial networks and clusters, and identify global microbial changes relevant to AD and the atopic march. METHODS: We performed metagenomic shotgun sequencing on 353 non-lesional skin samples from children in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort across 5 annual visits. We assessed taxonomic composition and analyzed longitudinal skin microbial patterns with progression to allergic co-morbidities. RESULTS: We identified 436 distinct species. Shannon diversity and richness declined with age, and socioeconomic factors explained the variance in species composition. Staphylococcus aureus (SA) was more abundant in severe AD. Cluster 5, comprised of typically gut-associated microbes, was more abundant in non-sensitized children who did not develop allergic co-morbidities over time. CONCLUSIONS: Our analyses revealed key patterns in core taxa, diversity and abundance of the skin microbiome over time in early life and highlighted previously unexplored factors such as socioeconomic status as key contributors to the variability in species composition. Abundance of SA confers risk, while gut-associated microbes may offer protection, influencing the clinical trajectory of AD and the atopic march. Thus, these results provide a novel and comprehensive understanding of the temporal dynamics of the skin microbiota in pediatric AD.

Skin colonization by Staphylococcus aureus has emerged as a common feature of atopic dermatitis and other allergic diseases, yet it remains unclear how this bacterium contributes to inflammation and pathology. Our S. aureus secretome analysis and bioactivity-guided fractionation uncover that the serine protease SspA destroys keratinocyte junctions, increases epidermal permeability, and activates an epithelial inflammatory program linked to barrier dysfunction. SspA and house dust mite extract (HDM), when epicutaneously applied in combination, cause interleukin (IL)-22-dependent atopic dermatitis-like skin disease in mice. Spatial single-cell analysis and immunophenotyping of lesional skin of these mice reveal massive elongation and branching of epidermal nerve fibers and the formation of T cells simultaneously producing IL-13 and IL-22. Chemical denervation and the resultant dismantling of the neuroimmune signaling network reverse the pathology driven by SspA-HDM combination. These findings link S. aureus colonization to barrier perturbation, allergen sensitization, and neurogenic dermatitis.