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Background: Vitiligo is an acquired pigmentary disorder characterized by depigmented patches on the skin that majorly impact patients' quality of life. Although its etiology involves genetic and environmental factors, the role of microorganisms as environmental factors in vitiligo pathology remains under-researched., Objectives: Our study explored the presence of characteristic bacterial and fungal flora in vitiligo-affected skin and investigated their potential roles in vitiligo pathogenesis., Methods: We sequenced bacterial 16S rRNA and the fungal ITS1 region from skin swabs collected at frequently affected sites, namely the forehead and back, of patients with vitiligo. We analyzed bacterial and fungal flora in lesional and non-lesional areas of patients with vitiligo compared with corresponding sites in age- and sex-matched healthy subjects., Results: Our findings revealed elevated α-diversity in both bacterial and fungal flora within vitiligo lesions compared with healthy controls. Notably, bacterial flora exhibited a distinctive composition in patients with vitiligo, and the proportional representation of Enterococcus was inversely correlated with the degree of vitiligo progression. Gammaproteobacteria, Staphylococcus spp., and Corynebacterium spp. were more abundant in vitiligo patients, with notable Staphylococcus spp. prevalence during the stable phase on the forehead. Conversely, the proportion of Malassezia sympodialis was lower and that of Malassezia globosa was higher in the progressive phase on the back of vitiligo patients., Conclusion: Our study identified some characteristic bacterial and fungal groups associated with vitiligo activity and prognosis, highlighting the potential roles of microorganisms in pathogenesis and offering insights into personalized disease-management approaches., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as topical treatments. Recently, novel topical agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, have emerged. Ruxolitinib is the first approved in vitiligo therapy. Furthermore, ritlecitinib is currently under clinical trials for oral treatment of active vitiligo. In this review, we discuss the possibility of topical JAK inhibitors as promising options for the treatment of vitiligo with regard to their mechanism of action, efficacy and safety., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain., Methods: We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation., Results: There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93)., Conclusions: We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Exosomes are nanosized extracellular vesicles that originate from endosomes and are secreted by most cells into the extracellular space. They serve as mediators of intercellular communication and have been implicated in the regulation of several physiological and pathological processes. Vitiligo is a depigmentation skin disease caused by progressive destruction of autologous epidermal melanocytes. Autoimmune intolerance is one of the leading theories proposed for melanocyte destruction in vitiligo via CD8 + , regulatory T (Treg) and T helper 17 (Th17) cell imbalance in adaptive immunity. In this review, we investigate the association of exosomes with vitiligo and emphasize the role of exosomes in immune regulation, melanocyte-keratinocyte interactions, and melanogenesis. The exosomal pathway is necessary for the regulation of CD8 + , Treg and Th17 cells in both pathological and physiological conditions. Exosomes derived under pathological conditions can influence CD8 + , Treg and Th17 cell balance in the disease microenvironment, which may contribute to disruption of autoimmune tolerance in vitiligo. In addition, exosomes serve as mediators of communication between keratinocytes and melanocytes in the melanogenesis pathway and may also be involved in melanosome transport. They also regulate melanocyte survival and the protein expression of enzymes such as tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), tyrosinase-related protein-2 (TYRP2) and microphthalmia-associated transcription factor (MITF) in melanogenesis, which suggests that melanin production is associated with exosomes. An improved understanding of the role of exosomes in immune regulation and melanogenesis may help to elucidate the pathogenesis of vitiligo and lead to the development of potential diagnostic markers and therapeutic options., (Copyright © 2020. Published by Elsevier B.V.)

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein., Methods: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants., Results: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.)., Conclusions: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Neurofibromas in von Recklinghausen's disease (vRD) can develop in the dermis. Therefore, we hypothesized that a dermal niche exists that promotes the development of these neurofibromas in subjects with vRD., Objective: The purpose of this study is to examine the function of polydom, known as a ligand for integrin, mediating cell adhesion, and expressed in mouse nerve tissue, in promotion of neurofibroma., Methods: Molecular, transcriptome and immunohistochemical analysis were performed to investigate the association between polydom expression and neurofibroma development., Results: Polydom mRNA levels were significantly higher in neurofibroma tissue than in control tissue. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis of RNA purified from primary cultured dermal neurofibroma cells demonstrated significantly higher polydom mRNA expression in cells derived from the surrounding dermis of neurofibromas compared to those from normal human dermal fibroblasts. RNA sequencing was used to compare gene expression between cultured cells derived from dermal neurofibroma-surrounding tissue with or without polydom knockdown. Subsequent gene ontology assays revealed that expression of integrinβ8 (ITGB8), a factor that releases transforming growth factor-β (TGF-β) from pro-TGF-β, was downregulated following polydom knockdown, suggesting upregulation of polydom-mediated TGF-β production. Furthermore, we observed a strong association between polydom expression and the increase in platelet-derived growth factor B (PDGFB) expression in primary cultured cells from the surrounding dermis of neurofibromas exposed to TGF-β1., Conclusion: Our results suggest that increased polydom expression in the dermis surrounding neurofibromas may promote dermal neurofibroma development by activating the TGF-β signaling pathway., (Copyright © 2019. Published by Elsevier B.V.)

We have reported characteristic cutaneous manifestations of Sjögren syndrome (SS) with special references to autoimmune anhidrosis or hypoidrosis and related mucocutaenous manifestations in addition to annular erythema or cutaneous vasculitis. Although significance of cutaneous manifestations of SS has been gradually recognized in rheumatologists, sudomotor function has not been fully evaluated and recognized in the diagnosis of SS except for dermatologists. SS is a relatively underestimated collagen disease in contrast to SLE, systemic sclerosis, or dermatomyositis, special care should be needed not to make misdiagnosis of SS when we see the patients with common skin disease such as, drug eruption, infections skin disease or xerosis in the daily practice. In contrast to pathomechanisms of dry skin observed in SS, we recently reported that reduced sweating function and dry skin seen in atopic dermatitis (AD) are mediated by histamine or substance P, those are usually restored to normal levels after improvement of the dermatitis by topical corticosteroid ointment with or without oral anti-histamine. Therefore, xerotic skin lesions seen in SS and AD might be attributable to different pathomechanisms with similar dry skin manifestations. We recently reported that SS promotes dry skin when complicated with AD possibly due to acceleration of hypoidrosis. In this review, we would like to summarize our recent understanding of regulatory mechanism of impaired sweating function in allergic inflammatory skin diseases by introducing clinical presentations of AD/SS overlap cases as the model of hypoidrotic inflammatory skin diseases., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Sweat is a transparent hypotonic body fluid made from eccrine sweat glands. Various ingredients contained in sweat are involved in a broad sense in skin homeostasis including temperature regulation, skin moisture, and immune functions. Thus, sweat plays a major role in maintaining skin homeostasis. Therefore, abnormal sweating easily compromises human health. For example, in atopic dermatitis (AD), perspiration stagnation accompanying sweat tube or sweat pore blockage, leakage of perspiration from the sweat gland to the outside tissue, and impaired secretion of sweat from the sweat gland are confirmed. In recent years, the hypothesis that atopic dermatitis is a sweat stasis syndrome has been clarified by the establishment of a sweat and sweat gland dynamic analysis technique. Secretion of sweat and leakage into tissues is caused by dermatitis and is thought to promote itching. Furthermore, from the metabolomic analysis of sweat of patients with atopic dermatitis, it was confirmed that the glucose concentration in AD sweat increased according to severity and skin phenotype, suggesting that elevated glucose affected the homeostasis of the skin. Multifaceted analyses of sweat from subjects with AD have revealed new aspects of the pathology, and appropriate measures to treat sweat can be expected to contribute to long-term control of AD., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Intense chronic itch significantly reduces quality of life for atopic dermatitis patients, impairing daily activity. Although abnormal itch sensation can be induced by innocuous stimuli, known as alloknesis, the mechanisms driving this process remain obscure. Psychological and environmental stimuli are known to aggravate atopic dermatitis symptoms. Recently, the enzyme 11β-hydroxysteroid dehydrogenase-1 (HSD11β1), which is expressed in keratinocytes, has been implicated in maintaining homeostasis against environmental stimuli by activating endogenous glucocorticoids. To investigate the role of HSD11β1 in keratinocytes, we generated keratinocyte-specific Hsd11b1-knockout (Hsd11b1 KC-/- ) mice and analyzed skin phenotype. Hsd11b1 KC-/- mice exhibited abnormal cutaneous innervation and skin sensitivity, including light mechanical stimulus-evoked itch (i.e., alloknesis). Attenuated endogenous glucocorticoid activation induced by aberrant artemin production in keratinocytes was involved in alloknesis in Hsd11b1 KC-/- mice. Finally, we observed a significant negative correlation between expression of HSD11β1 and artemin in human skin with and without AD. These results suggest that endogenous glucocorticoids that maintain skin homeostasis in the epidermis affect both skin innervation and cutaneous sensation. Modulation of HSD11β1 activation could be a therapeutic target for sensitive or itchy skin., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The transfer of sweat to the skin surface without leakage is important for the homeostatic regulation of skin and is impaired in atopic dermatitis. Although the precise composition of the leakage barrier remains obscure, there is a large contribution from claudins, the major components of tight junctions. In humans, claudin-1, -3, and -15 are expressed on sweat ducts, and claudin-3 and -10 are expressed on secretory coils. Although only two claudins are expressed in murine sweat glands, we found that the expression of claudin-3 is conserved. Atopic dermatitis lesional skin had decreased claudin-3 expression in sweat glands, which was accompanied by sweat leakage. This critical role in water barrier function was confirmed in Cldn3 -/- and Cldn3 +/- mice and those with experimentally decreased claudin-3. Our results show the crucial role of claudin-3 in preventing sweat gland leakage and suggest that the pathogenesis of dermatoses accompanied by hypohidrosis involves abnormally decreased claudin-3., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Accumulating evidence has described the involvement of mTORC1 signaling in pigmentation regulation; however, the precise mechanism is not fully understood. Here, we generated mice with conditional deletion of the mTORC1 suppressor Tsc2 in melanocytes. It resulted in constitutive hyperactivation of mTORC1 and reduced skin pigmentation. Mechanistically, neither the number of melanocytes nor the expression of melanogenesis-related enzymes was decreased; however, endoplasmic reticulum and mitochondrial oxidative stress and lower melanization in melanosomes were observed. By contrast, abrogation of mTORC1 by rapamycin completely reversed the reduced pigmentation, and alleviation of endoplasmic reticulum stress by SMER28 or 4-phenylbutyrate (PBA) or alleviation of mitochondrial oxidative stress by administration of adenosine triphosphate partially reversed the reduced pigmentation in these mice. In addition, we showed that these mechanisms were involved in reduced pigmentation of TSC2 small interfering RNA-transfected cultured human primary melanocytes and skin lesions of patients with the TSC gene mutation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tuberous sclerosis complex (TSC) gene mutations lead to constitutive activation of the mammalian target of rapamycin (mTOR) pathway, resulting in a broad range of symptoms. Hypopigmented macules are the earliest sign. Although we have already confirmed that topical rapamycin treatment (an mTOR inhibitor) protects patients with TSC against macular hypopigmentation, the pathogenesis of such lesions remains poorly understood., Objective: Recently emerging evidence supports a role for autophagy in skin pigmentation. Herein, we investigated the impact of autophagic dysregulation on TSC-associated hypopigmentation., Methods: Skin samples from 10 patients with TSC, each bearing characteristic hypopigmented macules, and 6 healthy donors were subjected to immunohistochemical and electron microscopic analyses. In addition, TSC2-knockdown (KD) was investigated in human epidermal melanocytes by melanin content examination, real-time PCR, western blotting analyses, and intracellular immunofluorescence staining., Results: Activation of the mTOR signaling pathway decreased melanocytic pigmentation in hypopigmented macules of patients with TSC and in TSC2-KD melanocytes. In addition, LC3 expression (a marker of autophagy) and autophagosome counts increased, whereas, intracellular accumulation of autophagic degradative substrates (p62 and ubiquitinated proteins) was evident in TSC2-KD melanocytes. Furthermore, depigmentation in TSC2-KD melanocytes was accelerated by inhibiting autophagy (ATG7-KD or bafilomycin A1-pretreatment) and was completely reversed by induction of autophagy via mTOR-dependent (rapamycin) or mTOR-independent (SMER28) exposure. Finally, dysregulation of autophagy, marked by increased LC3 expression and accumulation of ubiquitinated proteins, was also observed in melanocytes of TSC-related hypopigmented macules., Conclusion: Our data demonstrate that melanocytes of patients with TSC display autophagic dysregulation, which thereby reduced pigmentation, serving as the basis for the hypomelanotic macules characteristic of TSC., (Copyright © 2017. Published by Elsevier B.V.)

Background: The drug-induced lymphocyte stimulation test (DLST), also referred to as lymphocyte transformation test (LTT), is used to identify the culprit drug in cases of cutaneous adverse drug reactions (cADR). Although DLST is a widely used in vitro test, its sensitivity and specificity are unsatisfactory. Recent reports suggest that the detection of drug-induced interferon (IFN)-γ production using enzyme-linked immunoSpot (ELISpot) assay (conventional IFN-γ ELISpot) is useful for identifying culprit drugs in cADR cases., Objective: The aim of this study was to establish a novel method for identifying culprit drugs in patients with cADR by efficiently detecting drug-specific IFN-γ production using activated cells., Methods: Sixteen patients with cADR, including drug-induced hypersensitivity syndrome, erythema multiforme-like eruption, maculopapular exanthema, Stevens-Johnson syndrome, and toxic epidermal necrolysis, caused by clinically convincing culprit drugs were enrolled in this study. In some cases, the blood samples were obtained at two or three different time points. Peripheral blood mononuclear cells (PBMCs) from total 20 samples were analyzed using both the DLST and drug-induced conventional IFN-γ ELISpot. In addition, drug-induced IFN-γ ELISpot was performed using PBMCs, which were stimulated with anti-cluster of differentiation (CD)-3/CD28 antibody-coated microbeads and interleukin (IL)-2 for 7 days before exposure to the culprit drugs (modified IFN-γ ELISpot)., Results: Among the culprit drugs tested in each patient, the modified IFN-γ ELISpot was positive in 17 samples (13 patients) while DLST and conventional IFN-γ ELISpot were positive in eight and four samples (six and three patients), respectively., Conclusion: The modified IFN-γ ELISpot using activated PBMCs was more sensitive than the conventional IFN-γ ELISpot was for detecting drug-induced IFN-γ production, which could be a useful in vitro tool for identifying culprit drugs in cADR cases., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is an inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the "Guidelines for the Treatment of Atopic Dermatitis 2008" prepared by the Health and Labour Sciences Research and the "Guidelines for the Management of Atopic Dermatitis 2015 (ADGL2015)" prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2016" together with those for other allergic diseases., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) displays different clinical symptoms, progress, and response to treatment during early infancy and after childhood. After the childhood period, itch appears first, followed by formation of well-circumscribed plaque or polymorphous dermatoses at the same site. When accompanied with dermatitis and dry skin, treatment of skin lesions should be prioritized. When itch appears first, disease history, such as causes and time of appearance of itch should be obtained by history taking. In many cases, itch increases in the evening when the sympathetic nerve activity decreased. Treatment is provided considering that hypersensitivity to various external stimulations can cause itch. Heat and sweating are thought to especially exacerbate itch. Factors causing itch, such as cytokines and chemical messengers, also induce itch mainly by stimulating the nerve. Scratching further aggravates dermatitis. Skin hypersensibility, where other non-itch senses, such as pain and heat, are felt as itch, sometimes occurs in AD. Abnormal elongation of the sensory nerve into the epidermis, as well as sensitizing of the peripheral/central nerve, are possible causes of hypersensitivity, leading to itch. To control itch induced by environmental factors such as heat, treatment for dermatitis is given priority. In the background of itch exacerbated by sweating, attention should be given to the negative impact of sweat on skin homeostasis due to 1) leaving excess sweat on the skin, and 2) heat retention due to insufficient sweating. Excess sweat on the skin should be properly wiped off, and dermatitis should be controlled so that appropriate amount of sweat can be produced. Not only stimulation from the skin surface, but also visual and auditory stimulation can induce new itch. This "contagious itch" can be notably observed in patients with AD. This article reviews and introduces causes of aggravation of itch and information regarding how to cope with such causes., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Cortisol and corticosterone are the endogenous glucocorticoids (GCs) in humans and rodents, respectively. Systemic GC is released through the hypothalamic-pituitary-adrenal (HPA) axis in response to various stressors. Over the last decade, extra-adrenal production/activation of cortisol/corticosterone has been reported in many tissues. The enzyme that catalyzes the conversion of hormonally inactive cortisone/11-dehydrocorticosterone (11-DHC) into active cortisol/corticosterone in cells is 11β-hydroxysteroid dehydrogenase (11β-HSD). The 11β-HSD1 isoform is predominantly a reductase, which catalyzes nicotinamide adenine dinucleotide phosphate hydrogen-dependent conversion of cortisone/11-DHC to cortisol/corticosterone, and is widely expressed and present at the highest levels in the liver, lungs, adipose tissues, ovaries, and central nervous system. The 11β-HSD2 isoform, which catalyzes nicotinamide adenine dinucleotide + -dependent inactivation of cortisol/corticosterone to cortisone/11-DHC, is highly expressed in distal nephrons, the colon, sweat glands, and the placenta. In healthy skin, 11β-HSD1 is expressed in the epidermis and in dermal fibroblasts. On the other hand, 11β-HSD2 is expressed in sweat glands but not in the epidermis. The role of 11β-HSD in skin physiology and pathology has been reported recently. In this review, we summarize the recently reported role of 11β-HSD in the skin, focusing on its function in cell proliferation, wound healing, inflammation, and aging., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Over the past decade, extra-adrenal cortisol production was reported in various tissues. The enzyme that catalyzes the conversion of hormonally inactive cortisone into active cortisol in cells is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is also expressed in keratinocytes and regulates inflammation and keratinocyte proliferation. To investigate the function of 11β-HSD1 in keratinocytes during inflammation in vivo, we created keratinocyte-specific 11β-HSD1 knockout (K5-Hsd11b1-KO) mice and analyzed the inflammatory response in models of hapten-induced contact irritant dermatitis. K5-Hsd11b1-KO mice showed enhanced ear swelling in low-dose oxazolone-, 2,4,6-trinitro-1-chlorobenzene (TNCB)-, and 2,4-dinitrofluorobenzene-induced irritant dermatitis associated with increased inflammatory cell infiltration. Topical application of corticosterone dose dependently suppressed TNCB-induced ear swelling and cytokine expression. Similarly in mouse keratinocytes in vitro, corticosterone dose dependently suppressed 2,4,6-trinitrobenzenesulfonic acid-induced IL-1α and IL-1β expression. The effect of 11-dehydrocorticosterone was attenuated in TNCB-induced irritant dermatitis in K5-Hsd11b1-KO mice compared with wild-type mice. In human samples, 11β-HSD1 expression was decreased in epidermis of psoriasis vulgaris compared with healthy skin. Taken together, these data suggest that corticosterone activation by 11β-HSD1 in keratinocytes suppresses hapten-induced irritant dermatitis through suppression of expression of cytokines, such as IL-1α and IL-1β, in keratinocytes., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Keratin 5 (K5) is a cytoskeletal tissue-specific protein expressed in the epithelial cells of skin and esophagus and ectopic K5 expression in lymphocytes has never been reported., Objective: Here we demonstrate an ectopic epidermal self-protein expression in B-1 B cell by fate mapping of K5-expressing cells., Methods: K5-Cre×CAG-CAT-loxP-EGFP double Tg (K5×GFP) mice that express enhanced GFP under the control of the K5 promoter were employed., Results: Unexpectedly, B220(+)GFP(+) cells were found in LN, spleen, peripheral blood and peritoneal cavity. These cells were IgM(+)IgD(low)CD23(-)CD43(+)CD19(+)CD93(-), indicating that they were B-1 B cells. The number of B220(+)GFP(+) cells was significantly larger in spleen than in the other tissues tested. Although GFP(+) B-1 cells did not express K5 in the periphery, Lin(-)CD93(+)B220(low-neg)CD19(+) B-1 B cell progenitors expressed GFP and B220(+)CD93(+) progenitor cells expressed K5 and MHC-class II in BM, indicating that GFP(+) B-1 cells transiently expressed K5 and the progenitor cells were potential APC. GFP(+) B-1 cells in the periphery continued expressing MHC class II and had exogenous antigen-presenting capacity comparable to non-follicular B cells. GFP(+) B-1 cells spontaneously secreted more IgM than GFP(-) B-1 cells in vitro., Conclusion: These results indicate that B-1 B cells transiently and partially express K5 in BM and are potent for both natural antibody production and antigen presentation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary involvement in tuberous sclerosis complex (TSC) includes lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). This retrospective study investigated pulmonary involvement in Japanese TSC patients and pulmonary function testing in TSC-LAM., Methods: The study subjects included 59 TSC patients (age range: 13-66, 15 males and 44 females). Female patients were divided into 3 groups (Group 1: symptomatic LAM, Group 2: asymptomatic LAM, Group 3: without LAM) and 3 cystic grades according to increasing cyst numbers on computed tomography images (patients without LAM, Grade 1 patients, and Grade 2+Grade 3 patients). The results of pulmonary function tests were compared among the groups and the grades., Results: One male (6.7%) patient and 19 female (43.2%) patients were diagnosed with LAM and 7 male (43.2%) and 23 female (52.3%) patients were diagnosed with MMPH. Patients with multiple pulmonary nodules had higher rates of renal angiomyolipoma and history of seizures than patients without nodules. Although all 6 adolescent patients displayed no pulmonary symptoms, MMPH was found in 3 patients and LAM was found in a 13-year-old girl. Carbon monoxide diffusing capacity (DLco) differed significantly among the 3 groups and DLco and carbon monoxide diffusing capacity divided by the alveolar volume (DLco/VA) differed significantly among the 3 cystic grades., Conclusions: There was no difference in the prevalence of pulmonary involvement in TSC patients among countries. LAM and MMPH occur even during adolescence in TSC patients. DLco and the number of cysts are useful predictors of onset and progression of TSC-LAM., (Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

An aortic arch aneurysm rarely perforates the pulmonary artery, but once this occurs symptoms of heart failure may develop rapidly and result in a serious course. Here, we report such a case that was treated with life-saving emergency surgery. The patient was an 86-year-old man in whom aortic arch aneurysm had been pointed out 8 years earlier, but left untreated. In January 2014, dyspnea developed and he visited the emergency unit of our hospital. Continuous murmur was heard on auscultation, and aorta-pulmonary artery shunt was noted on transthoracic echocardiography. Chest computed tomography revealed a giant aortic arch aneurysm of size 106 mm that had perforated the left pulmonary artery (LPA). Emergency surgery was performed for a diagnosis of acute heart failure associated with perforation of the LPA by a giant aortic arch aneurysm. The postoperative course was favorable, and the patient was discharged with independent walking on postoperative day 28., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Nerve growth factor (NGF), a neurotrophin that plays a critical role in developmental neurobiology, is released by proliferating keratinocytes and induces proliferation., Objective: The aim of this study was to investigate the role of tyrosine kinase receptor A (TrkA), a high-affinity receptor of NGF, in human keratinocytes., Methods: Expression of TrkA and NGF in skin diseases was investigated by immunohistochemistry. Expression of TrkA in cells was examined by Western blotting and RT-PCR. Cell proliferation was assessed by BrdU assay., Results: We first determined the expression of TrkA and NGF in skin samples from patients with atopic dermatitis, prurigo nodularis, psoriasis vulgaris, and seborrheic keratosis. TrkA was only expressed in proliferating basal cells, and its expression was enhanced in atopic dermatitis samples. NGF expression was enhanced in atopic dermatitis and prurigo nodularis samples and in some samples from seborrheic keratosis patients. Investigation of the role of TrkA in vitro using normal human epidermal keratinocytes (NHEK) revealed that TrkA was significantly enhanced by the T helper type 2 (Th2) cytokines interleukin (IL)-4 and IL-13 but not by other inflammatory cytokines, such as IL-1β, tumor necrosis factor α, interferon γ, or epidermal growth factor. On the other hand, expression of NGF was not altered by Th2 cytokines. Notably, inhibition of TrkA significantly reversed the effects of IL-4 on proliferation and differentiation. Furthermore, overexpression of TrkA enhanced proliferation of NHEK. These results indicate that IL-4-induced TrkA expression in keratinocytes modulates proliferation and differentiation of these cells., Conclusion: Increased TrkA expression in keratinocytes in atopic dermatitis may contribute to the observed epidermal hyperproliferation in these patients., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. β2-glycoprotein I (β2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact β2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA class II complexes in the absence of phospholipids. In situ association between β2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against β2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that β2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis., (© 2015 by The American Society of Hematology.)

The various symptoms associated with excessive or insufficient perspiration can significantly reduce a patient's quality of life. If a versatile and minimally invasive method could be established for returning sweat activity to normalcy, there is no question that it could be used in the treatment of many diseases that are believed to involve perspiration. For this reason, based on an understanding of the sweat-gland control function and sweat activity, it was necessary to conduct a comprehensive search for the factors that control sweating, such as the central and peripheral nerves that control sweat-gland function, the microenvironment surrounding the sweat glands, and lifestyle. We focused on the mechanism by which atopic dermatitis leads to hypohidrosis and confirmed that histamine inhibits acetylcholinergic sweating. Acetylcholine promotes the phosphorylation of glycogen synthesis kinase 3β (GSK3β) in the sweat-gland secretory cells and leads to sensible perspiration. By suppressing the phosphorylation of GSK3β, histamine inhibits the movement of sweat from the sweat-gland secretory cells through the sweat ducts, which could presumably be demonstrated by dynamic observations of the sweat glands using two-photon microscopy. It is expected that the discovery of new factors that control sweat-gland function can contribute to the treatment of diseases associated with dyshidrosis., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the "Guidelines for the Treatment of Atopic Dermatitis 2008" prepared by the Health and Labour Sciences Research and the "Guidelines for the Management of Atopic Dermatitis 2012 (ADGL2012)" prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2013" together with those for other allergic diseases.

Histamine is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases. Recent studies revealed that periostin, a matricelluar protein, contributed to tissue remodeling; however, a link between periostin and histamine remains unproven. We investigated whether periostin was involved in histamine-induced collagen production. Cultured dermal fibroblasts derived from wild-type (WT) or periostin knockout (PN(-/-)) mice were stimulated with histamine, and then collagen and periostin production was evaluated. Histamine induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase, whereas no effect on collagen expression was observed in histamine-stimulated PN(-/-) fibroblasts. In WT fibroblasts, histamine directly induced periostin expression in a dose-dependent manner, and an H1 receptor antagonist blocked both periostin and collagen expression. Histamine activated extracellular signal-regulated kinase 1/2 (ERK1/2) through the H1 receptor. Periostin induction was inhibited by either H1 antagonist or ERK1/2 inhibitor treatment in vitro and was attenuated in H1R(-/-) mice. Elevated expression of periostin was found in lesional skin from atopic dermatitis patients. These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor-mediated ERK1/2 pathway; furthermore, histamine may accelerate the chronicity of atopic dermatitis.

Sweating has been associated with the exacerbation of atopic dermatitis (AD) in diverse ways. Acetylcholine (ACh)-mediated sweating is known to be attenuated in AD, but its cause remains obscure. To address this issue, the impact of histamine on ACh-induced sweating was evaluated. Sweating was measured by counting the number of active sweat pores by the starch-iodine reaction and dynamic optical coherence tomography; sweat was visualized using two-photon excitation fluorescence microscopy in mice and the quantitative sudomotor axon reflex test in humans. Both histamine receptor antagonists and H1 receptor (H1R)-knockout (KO) mice were used to determine methodological specificity. Histamine demonstrably inhibited ACh-induced sweating in both mice and humans via H1R-mediated signaling. In sweat glands, ACh inactivated glycogen synthase kinase 3β (GSK3β), a kinase involved in endocytosis and secretion, whereas simultaneous stimulation with histamine activated GSK3β. Results of two-photon excitation fluorescence microscopy confirmed the dynamic motion of sweat and sweat glands after ACh treatment, showing that simultaneous stimulation with histamine altered their dynamic properties. These results indicate that histamine inhibits sweat gland secretions by blocking ACh-induced inactivation of GSK3β. Histamine-mediated hypohidrosis might be involved in the mechanism of abnormal skin dryness in patients with AD.

Background: Eczema in the cubital fossa, which is susceptible to sweat, is frequently observed in atopic dermatitis (AD). However, there has been no direct evidence that sweating causes eczema in the cubital fossa., Methods: To investigate this issue, axon reflex-mediated sweating volume (AXR) and skin barrier function in the cubital fossa were measured in subjects with AD and in healthy volunteers, and were applied to clinical feature of the cubital fossa., Results: AXR in the cubital fossa decreased in AD subjects; it positively correlated only with water-holding capacity in healthy subjects but not in patients with in AD. Furthermore, AD subjects with lichenoid eczema and either prurigo or papules over the cubital fossa showed extremely decreased AXR., Conclusions: These results suggest that decreased sweating is a major source of water in the stratum corneum, and decreased sudomotor function may be involved in both the cause and aggravation of representative atopic eczema in the cubital fossa.

It has been recognized that ceramides are decreased in the epidermis of patients with psoriasis and atopic dermatitis. Here, we generated Sptlc2 (serine palmitoyltransferase long-chain base subunit 2)-targeted mice (SPT-cKO mice), thereby knocking out serine palmitoyltransferase (SPT), the critical enzyme for ceramide biosynthesis, in keratinocytes. SPT-cKO mice showed decreased ceramide levels in the epidermis, which impaired water-holding capacity and barrier function. From 2 weeks of age, they developed skin lesions with histological aberrations including hyperkeratosis, acanthosis, loss of the granular layer, and inflammatory cell infiltrates. Epidermal Langerhans cells showed persistent activation and enhanced migration to lymph nodes. Skin lesions showed upregulation of psoriasis-associated genes, such as IL-17A, IL-17F, IL-22, S100A8, S100A9, and β-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of γδ T cells that produced IL-17 (γδ-17 cells), most of which also produced IL-22, as do Th17 cells. Furthermore, IL-23-producing CD11c(+) cells were observed in the lesions. In vivo treatment of SPT-cKO mice with an anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the numbers of γδ-17 cells. Therefore, we conclude that a ceramide deficiency in the epidermis leads to psoriasis-like lesions in mice, probably mediated by IL-23-dependent IL-22-producing γδ-17 cells.

The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10(-13) M cortisol, whereas 1 × 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11β-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students., Methods: First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires., Results: The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P < 0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P < 0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P < 0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence., Conclusions: These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.