Explore the vast range of titles available.

Tissue resident memory T (T RM ) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin T RM cells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8 + CD69 + CD103 +  T RM  cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-β are required for the formation of long-lived T RM cell population in skin. Skin T RM  cells engage virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. Secondary T RM  cell populations are derived from pre-existing T RM  cells and newly recruited T RM precursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8 +  T RM  cells at challenged site. Skin T RM cells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these T RM cells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8 + CD103 + CD49a - T RM cells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8 + CD103 + CD49a + T RM  cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin T RM cells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8 + T RM cells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed T RM cells. CD8 + CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8 + T RM cells. This review will discuss the current understanding of skin T RM biology and their contribution to skin homeostasis and diseases.

Tight junction (TJ) dysfunction in the stratum granulosum leads to aberrant barrier function of the stratum corneum (SC) in the epidermis. However, it is unclear whether TJs are perturbed in atopic dermatitis (AD), a representative aberrant SC-related skin disease, and whether some factors related to AD pathogenesis induce TJ dysfunction. To address these issues, we investigated the alterations of TJs in AD skin and the effects of Th2 and Th17 cytokines on TJs in a skin-equivalent model. The levels of TJ proteins were determined in the epidermis of nonlesional and lesional skin sites of AD. Western blot and immunohistochemical analyses revealed that the levels of zonula occludens 1 were decreased in the nonlesional sites of AD, and the levels of zonula occludens 1 and claudin-1 were decreased in the lesional sites relative to the levels in skin from healthy subjects. Next, we examined the effects of interleukin (IL)-4, tumor necrosis factor-α, IL-17, and IL-22 on the TJ barrier in a skin-equivalent model. Only IL-17 impaired the TJ barrier. Furthermore, we observed a defect in filaggrin monomer degradation in the IL-17-treated skin model. Thus, TJs are dysfunctional in AD, at least partly, due to the effect of IL-17, which may result in an aberrant SC barrier.

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.

Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. Kyowa Kirin.

The critical role of IL-17 has recently been reported in a variety of conditions. Since IL-17 deeply participates in the pathogenesis of psoriasis and keratinocyte production of certain cytokines, the involvement of T helper cell 17 (Th17) in atopic dermatitis (AD) is an issue to be elucidated. To evaluate the participation of Th17 cells in AD, we successfully detected circulating lymphocytes intracellularly positive for IL-17 by flow cytometry, and the IL-17+ cell population was found exclusively in CD3+CD4+ T cells. The percentage of Th17 cells was increased in peripheral blood of AD patients and associated with severity of AD. There was a significant correlation between the percentages of IL-17+ and IFN-γ+ cells, although percentage of Th17 cells was not closely related to Th1/Th2 balance. Immunohistochemically, IL-17+ cells infiltrated in the papillary dermis of atopic eczema more markedly in the acute than chronic lesions. Finally, IL-17 stimulated keratinocytes to produce GM-CSF, TNF-α, IL-8, CXCL10, and VEGF. A marked synergistic effect between IL-17 and IL-22 was observed on IL-8 production. The number of Th17 cells is increased in the peripheral blood and acute lesional skin of AD. Th17 cells may exaggerate atopic eczema.

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.

Adult T‐cell leukemia‐lymphoma (ATL) is a T‐cell malignancy that is endemic to Japan. In this latest nationwide study of ATL, we collected the data from 4 nationwide registries of patients diagnosed in 2012‐2013; the Hematology Blood Disease, the Skin Cancer Society, the Hospital‐Based Cancer Registries, and information from the hospitals that participated in the Japanese nationwide survey of ATL in 2010‐2011. In the present study, 2614 patients with ATL were diagnosed based on the registries, and 117 departments registered 1042 patients. Among these patients, 984 were eligible for analysis. The median age at diagnosis was 69 y. A larger proportion of patients with ATL older than 70 y was diagnosed with the lymphoma subtype, and more than half of the patients with ATL in the metropolitan areas were born in the human T‐cell leukemia virus type I (HTLV‐1)‐endemic areas of Kyushu/Okinawa, which are almost identical to the findings in our 2010‐2011 study. Additionally, we identified that patients with ATL migrated from the endemic areas for HTLV‐1 to the non‐endemic metropolitan areas. The present study was able to reduce the burden of searching each hospital and to update the clinico‐epidemiological characteristics of a large number of patients with ATL in Japan, suggesting the usefulness and feasibility of the novel data collection method. The establishment of a more sophisticated database management system for ATL is necessary for future continuous surveys. We identified that ATL patients shifted from areas endemic for HTLV‐1 to non‐endemic metropolitan areas. The median age at diagnosis was 69 y, which was significantly older than that in the 1980s and 1990s. We conducted a nationwide survey of ATL during 2012‐2013 by modifying data acquisition from 4 nationwide registries.

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor‐beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast‐dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery. Secondary lymphedema develops and causes skin fibrosis after cancer surgery. We developed a novel rat hindlimb model that accurately mimics human secondary lymphedema, and investigated disease progression. We found that myofibroblasts and transforming growth factor‐beta 1/Smad signaling play key roles in the skin fibrosis of secondary lymphedema.

Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown. Here, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in human keratinocytes (KCs). Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway. Our findings suggest that the phototoxic moieties of VRCZ metabolites may participate in the initiation phase of VRCZ skin cancer, while VRCZ per se promotes the tumor development. Therefore, during VRCZ therapy, sun exposure protection is essential to prevent photocarcinogenesis caused by VRCZ metabolites plus UV. Chemoprevention with selective COX-2 inhibitors may be helpful to repress the development of skin cancers derived from DNA-damaged KCs.

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.