Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous lesions, intense itch, and type 2 immune responses. Interleukin 31 (IL-31) is a cytokine mainly produced from skin-homing CLA+ T cells.1, 2 Serum IL-31 levels correlate with the disease severity of AD patients,2 and the administration of an anti-IL-31 receptor antibody alleviates pruritus in AD patients.3 Thus, IL-31 plays a major role in AD pathogenesis. Dedicator of cytokinesis 8 (DOCK8) is an evolutionarily conserved guanine nucleotide exchange factor (GEF) for Cdc42.4 Bi-allelic loss-of-function mutations of DOCK8 cause a combined immunodeficiency characterized by AD.5 We have previously shown that knock down of DOCK8 gene in T cells from healthy controls markedly increases T-cell receptor-mediated IL31 gene expression.6 Therefore, DOCK8 acts as a negative regulator for IL-31 induction in human T cells. However, DOCK8 expression is comparable between healthy controls and AD patients,6 and functional significance of DOCK8 in the disease predisposition remains unknown. The aim of this study was to evaluate whether DOCK8 gene polymorphism is associated with AD. We recruited age- and gender-matched 46 AD patients and 46 healthy controls (Table S1). Blood samples were obtained from all participants according to the institutional review board approvals. Gene polymorphisms in all exons of DOCK8 (Exon 1–48) were analyzed by direct DNA sequencing using exon-specific primers (Table S2). The difference of allele and genotype frequencies between patients and control samples was compared using the chi-square test. Among the sequences of all the 48 DOCK8 exons, only the frequency of the DOCK8 allele encoding T instead of C at position 1790 (DOCK8 + 1790 T allele, rs17673268) showed significantly higher frequency in AD patients than that in the controls (Table 1, 50% vs. 34%; odds ratio [OR] = 1.96; p = .025). In addition, the frequency of the TT genotype significantly increased in AD patients (Table 1), suggesting that this genotype contributes to disease susceptibility to AD. Moreover, severe AD (Investigator Global Assessment [IGA] score: 4) was observed only in patients with CT and TT genotypes (Figure S1). When AD patients were subdivided into two populations with IGA scores of 4 or ≤3, the frequency of the TT genotype significantly increased in patients with IGA scores of 4, compared with patients with IGA scores of ≤3 (p = .029; Table S3). We made further comparisons of EASI scores between CT and TT genotypes in moderate-to-severe patients, which indicate that EASI scores were significantly higher in patients with TT genotype than those with CT genotype (p = .005; Figure S2). We previously identified endothelial PAS domain protein 1 (EPAS1) as a master transcriptional factor essential for T-cell receptor-mediated IL-31 induction.6 Although EPAS1 translocates to the nucleus in response to hypoxia to mediate promoter activation of target genes, this process is negatively regulated by DOCK8, independent of its Cdc42 GEF activity.6 To better understand whether DOCK8 + 1790 T allele affects EPAS1 nuclear localization, the fluorescence intensity of intranuclear EPAS1 was analyzed after stably expressing DOCK8 + 1790C allele or + 1790 T allele (NM_203447.3:c.1790C > T; p.Ala597Val) in the human cell line HCT116 lacking endogenous DOCK8 protein (Figure S3). When +1790C allele was expressed in HCT116 cells, hypoxia-induced nuclear translocation of EPAS1 was inhibited (Figure 1). However, such inhibitory effect was not seen for +1790 T allele (Figure 1). Collectively, these results indicates that the TT genotype of DOCK8 gene augments IL-31 production by promoting EPAS1 nuclear localization. In conclusion, we found that DOCK8 polymorphism at position 1790 (rs17673268) is associated with the susceptibility to AD and revealed its underlying molecular basis. Although this study used a relatively small sample size, our findings provide a novel insight into AD pathogenesis. The authors acknowledge technical assistance from Arisa Aosaka, Sawako Sakai, and members of the Laboratory for Research Support of the Medical Institute of Bioregulation in Kyushu University. We thank Chie Kikutake in the Medical Institute of Bioregulation in Kyushu University for statistical consulting. We also thank all study subjects for participation in this study. This project was supported by Medical Research Center Initiative for High Depth Omics. This work was supported by Japan Agency for Medical Research and Development (AMED) under grant number JP19gm0010001, JP20ek0410064, and JP21gm1310005 (to Y.F.). The authors declare that they have no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. AppendixS1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of the anti-IL-4 receptor antibody dupilumab implies that type 2 cytokines IL-4 and IL-13 have pivotal roles in atopic inflammation. The expression of IL-4 and IL-13 as well as type 2 chemokines such as CCL17, CCL22 and CCL26 is increased in the lesional skin of AD. In addition, IL-4 and IL-13 down-regulate the expression of filaggrin in keratinocytes and exacerbate epidermal barrier dysfunction. Keratinocytes in barrier-disrupted epidermis produce large amounts of thymic stromal lymphopoietin, IL-25 and IL-33, conducing to type 2 immune deviation via OX40L/OX40 signaling. IL-31, produced by type 2 T cells, is a cardinal pruritogenic cytokine. IL-4 and IL-13 also amplify the IL-31-mediated sensory nerve signal. These molecules are particularly important targets for future drug development for AD.
Abstract Background Endothelin‐1 (EDN1) can evoke histamine‐independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL‐25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. Methods We analyzed the mite‐induced AD‐like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. Results Topical application of bosentan significantly attenuated the development of mite‐induced AD‐like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation‐regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13 , Il17 , and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose‐ and time‐dependent manner, bosentan treatment attenuated this. Conclusions EDN1 plays a significant role in mite‐induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and in AM cell lines. To investigate function of HER3, effects of HER3 inhibition on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients' AM tissues with various intensities and HER3 expression was significantly correlated with patient's disease-free survival. In vitro analyses revealed that HER3 is more highly expressed in AM cells than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells likely through affecting the nuclear translocation of Yes-associated protein. It is implied that HER3 may serve as a novel therapeutic target for AM.
BackgroundAtopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti–IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult.ObjectiveOur aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab.MethodsA multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated.ResultsThe achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab.ConclusionBaseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.
We report a case of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia diagnosed with facial lesions in a 60-year-old Japanese male. The patient had noticed indurated erythema on his face 8 months previously. He was first diagnosed with chronic actinic dermatitis and treated with topical tacrolimus ointment, which showed partial improvement. However, the symptoms persisted, and he was referred to our department. Physical examination showed erythema and swelling localized to the face (Figure 1a–c). Laboratory tests revealed no major abnormalities except an increase in total protein (8.8 g/dL), with no elevation in serum soluble interleukin-2 receptor and IgG4 levels. A skin biopsy from the left cheek showed diffuse lymphoplasmacytic cell infiltration in the dermis (Figure 1e,f). Immunohistochemical studies revealed that these cells expressed CD20 (Figure 1g), CD79a (Figure 1h), and bcl-2 (Figure 1i), but lacked CD10. Kappa light chain restriction was observed (Figure 1j), and the sample tested negative for Epstein–Barr virus. The Ki-67 proliferation index was 5%. Further blood tests indicated elevated IgM (3421 mg/dL), and serum protein electrophoresis confirmed an IgM-kappa monoclonal protein. In addition, the lymphoplasmacytic cells were positive for IgM (Figure 1k). Whole-body computed tomography (CT) and positron emission tomography/CT scans showed involvement only in the nose, cheeks, and ears (Figure 1d), with no evidence in the stomach, spleen, or liver. A bone marrow biopsy confirmed lymphoplasmacytic cell infiltration (Figure 1l) with an MYD88 (L265P) gene mutation, establishing the diagnosis of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.1 Since the patient is classified as being at low risk by the Modified Staging System for Waldenström Macroglobulinemia with a 93% likelihood of surviving 5 years,2 he is under observation without treatment. Primary macroglobulinemia/lymphoplasmacytic lymphoma is a rare lymphoproliferative disorder characterized by the proliferation of lymphoplasmacytic cells producing monoclonal IgM. The MYD88 L265P mutation is found in approximately 90% of cases.3 Cutaneous involvement in this disease is rare, but Stein et al.4 reported that 50% of patients had facial lesions, with four cases presenting purplish, bilateral, and symmetrical infiltration of the cheekbones and ears. To our knowledge, similar symptoms have not been reported in Japanese patients. This case highlights the need for a broader differential diagnosis in patients with persistent facial swelling. Dermatologists should recognize this rare manifestation and consider further hematological evaluation for unexplained facial indurated erythema. We sincerely thank Dr. Takeshi Iwasaki for his advice on the histological examinations. None declared. The authors have obtained patient consent.
