Alopecia areata has basically been understood as a type 1 inflammatory disease. Activated NKG2D+CD8+ cells produce the Th1 cytokine interferon‐γ, which leads to the disruption of immune tolerance of hair follicles and the exposure of self‐antigens. This results in dense inflammatory cell infiltration and apoptosis around hair follicles, inducing hair loss. A well‐known complication of alopecia areata is atopic dermatitis, a typical type 2 inflammatory disease. Hair scientists have shied away from confronting and understanding how alopecia areata, a type 1 inflammatory disease, and atopic dermatitis, a type 2 inflammatory disease, can occur together. This review summarizes the research on the cytokine balance in alopecia areata and then focuses on the classification of the cytokine balance in alopecia areata, including the classification of atopic dermatitis into extrinsic and intrinsic types. Dupilumab reportedly showed dual efficacy in a patient with concomitant atopic dermatitis and alopecia areata, supporting our own experience. Elevated Th2 cytokine levels have also been reported in patients with alopecia areata, with increased serum IL‐4, IL‐5, IL‐6 levels, high IgE levels and elevated eosinophil levels. Because local immunotherapy is a treatment that induces Th2‐type inflammation, it may worsen the condition of alopecia areata patients with extrinsic atopic dermatitis. It is desirable to select appropriate treatments with consideration of the cytokine balance.

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.

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Background Atopic dermatitis (AD) patients have a barrier disorder in association with Th2 dominant skin inflammation. Galectin‐7 (Gal‐7), a soluble unglycosylated lectin, is highly expressed in the stratum corneum of AD patients. However, the biological significance of increased Gal‐7 expression in AD skin lesions remains unclear. Objective We aimed to investigate the production mechanism and functional role of Gal‐7 in AD patients and IL‐4/IL‐13–stimulated epidermal keratinocytes. Methods We assessed the Gal‐7 expression levels in skin lesions and sera from AD patients. Gal‐7 levels were also measured in monolayered normal human epidermal keratinocytes (NHEKs) and 3‐dimensional (3D)–reconstructed epidermis in the presence or absence of IL‐4/IL‐13 with or without Stat3, Stat6 or Gal‐7 gene silencing. Results Gal‐7 was highly expressed in the stratum corneum or intercellular space of AD lesional epidermis as assessed by the stratum corneum proteome analysis and immunohistochemistry. A positive correlation was noted between serum Gal‐7 level and transepidermal water loss in patients with AD. These clinical findings were corroborated by our in vitro data, which showed that IL‐4/IL‐13 facilitated the extracellular release of endogenous Gal‐7 in both monolayered NHEKs and 3D‐reconstructed epidermis. This machinery was caused by IL‐4/IL‐13–induced cell damage and inhibited by knockdown of Stat6 but not Stat3 in NHEKs. Moreover, we performed Gal‐7 knockdown experiment on 3D‐reconstructed epidermis and the result suggested that endogenous Gal‐7 serves as a protector from IL‐4/IL‐13–induced disruption of cell‐to‐cell adhesion and/or cell‐to‐extracellular matrix adhesion. Conclusion and Clinical Relevance Our study unveils the characteristic of Gal‐7 and its possible role as an alarmin that reflects the IL‐4/IL‐13–induced skin barrier impairment in AD.

Suprabasin (SBSn) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSn level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSn-null (Sbsn-/-) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn-/mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn-/mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (cHS) responses to haptens than did Wt mice. the blood nickel level after oral feeding of nickel was significantly higher in Sbsn-/mice than in Wt mice, and cHS to nickel was elevated in Sbsn-/mice under nickel-loading condition. our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high cHS to nickel, sharing the features of intrinsic AD.