In atopic dermatitis (AD), recent research advances have portrayed a complex disease profile based on different subtypes/ phenotypes and underlying molecular mechanisms/endotypes. Extrinsic and intrinsic subdivision is one of the most common types, defined in terms of total serum immune globulin E (IgE) and/or specific IgE to food and environmental allergens. Extrinsic AD is the most common type (80%), with high IgE, impaired skin barrier, as well as high incidence of comorbid atopic diseases, whereas intrinsic AD accounted for 20% of AD, with normal IgE and intact barrier function. Clinical studies have shown that extrinsic AD was a classic Th2-based inflammatory dermatitis, while the intrinsic subtype presented increased Th1/Th17/Th22 but normal Th2 cytokines. Protein sensitization, a classic Th2 response, has been clearly characterized in extrinsic AD, while metal hapten induces intrinsic AD's sensitization, which may be associated with suprabasin deficiency. In this review, we aimed to further expand our knowledge about similarities and differences between these two subtypes, which will expand our capability to further dissect pathophysiology of AD and enable us to develop personalized medicine approaches.

BackgroundAtopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease characterized by severe pruritus and eczematous lesions. Heterogeneity of AD has been reported among different racial groups according to clinical, molecular and genetic differences.ObjectiveThis study aimed to conduct an in‐depth transcriptome analysis of AD in Chinese population.MethodsWe performed single‐cell RNA sequencing (scRNA‐seq) analysis of skin biopsies from five Chinese adult patients with chronic AD and from four healthy controls, combined with multiplexed immunohistochemical analysis in whole‐tissue skin biopsies. We explored the functions of IL19 in vitro.ResultsScRNA‐seq analysis was able to profile a total of 87,853 cells, with keratinocytes (KCs) in AD manifesting highly expressed keratinocyte activation and pro‐inflammatory genes. KCs demonstrated a novel IL19+IGFL1+ subpopulation that increased in AD lesions. Inflammatory cytokines IFNG, IL13, IL26 and IL22 were highly expressed in AD lesions. In vitro, IL19 directly downregulated KRT10 and LOR in HaCaT cells and activated HaCaT cells to produce TSLP.ConclusionAbnormal proliferation and differentiation of keratinocytes contribute immensely to the pathogenesis of AD, whereas AD chronic lesions have witnessed significant presence of IL19+IGFL1+KCs, which may be involved in the disruption of the skin barrier, the connection and magnification of Th2 and Th17 inflammatory responses, and mediation of skin pruritus. Furthermore, progressive activation of multiple immune axes dominated by Type 2 inflammatory reaction occur in AD chronic lesions.