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Age-related thinning and reduced cell proliferation in the human epidermis are associated with the accumulation of senescent cells and decreases in the number and function of epidermal stem cells.This study examined the expression of INHBA/Activin-A in human epidermis and expression differences with age, and the effect of Activin-A on epidermal stem/progenitor cells.Immunohistochemical staining was used to analyze age-related changes in the expression of INHBA/Activin-A in the epidermal tissue of young and old subjects. Epidermal INHBA/Activin-A expression levels, epidermal morphology, and the number of epidermal stem/progenitor cells or proliferating cells were investigated using older abdominal skin samples. The effects of Activin-A on the development of a three-dimensional (3D) reconstructed epidermis and cell proliferation were also assessed.INHBA/Activin-A expression levels in the human epidermis increased with age, although they varied among individuals. In the epidermis of older abdominal skin samples, INHBA/Activin-A expression levels negatively correlated with epidermal thickness, the rete ridge depth and the interdigitation index. The proportion of epidermal stem/progenitor cells and proliferating cells decreased with increases in INHBA/Activin-A expression levels. Activin-A had no effect on the differentiation of keratinocytes in the 3D-reconstructed epidermis; however, thinning of the 3D epidermis was noted. Moreover, the addition of Activin-A inhibited the proliferation of epidermal stem/progenitor cells in a concentration-dependent manner.Age-related increased in INHBA/Activin-A expression levels were observed in the human epidermis, and may contribute to epidermal thinning and decreases in the number of epidermal stem/progenitor cells and proliferative activity. more...

BACKGROUND Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES We investigated the role of IL36Ra in cutaneous I/R injury. METHODS We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-β, IL-1β, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1β, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1β showed significantly increased CXCL1, TNF-α, IL-6, IL-36β and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells. more...

Syphilis can cause a wide range of systemic manifestations, such as papular rash, malaise, weight loss, muscle aches, generalized lymphadenopathy, and meningitis. However, pulmonary involvement in patients with secondary syphilis is thought to be relatively rare. Moreover, bone involvement in patients with secondary syphilis is also considered rare, and only a few cases of involvement of lung and bone in such patients have been reported. In this paper, we report a case of secondary syphilis with pulmonary involvement in the form of multiple nodules with low attenuation areas, lymphadenopathy and multiple bone lesions detected on computed tomography and 18F fluorodeoxyglucose-positron emission tomography/computed tomography. more...

Background: Infiltrative lesions of the skin caused by unresectable malignant tumors reduce the quality of life of patients significantly due to the presence of bleeding, exudate, pain, and/or malodor. Objective: We compared the efficacy of a modified Mohs' technique and topical application of a starch powder containing zinc oxide as palliative treatments for skin lesions caused by unresectable tumors in our hospital. Design: This is a retrospective study. Settings/Subjects: This study included nine patients who were treated for skin-infiltrating lesions caused by unresectable malignant tumors at our hospital in Japan from April 2008 to December 2019. Measurements: Mohs' paste or zinc oxide powder (50%) was applied to the infiltrative skin lesions. Arterial embolization was performed before the application of the Mohs' paste for patients at risk for arterial hemorrhage. Patients were evaluated for pain, tumor size, bleeding, wound exudate, and malodor. Results: Both treatments were useful for alleviating symptoms, such as tumor size, local bleeding, malodor, and exudate in patients with unresectable malignant tumors. Pain was reduced in patients treated with Mohs' paste for 1 hour as compared with those treated for 24 hours. Conclusions: Effective management of skin infiltrative lesions can be achieved by using a modified Mohs' technique, topical application of starch powder containing zinc oxide, and arterial embolization to reduce the vascularization of the tumors. more...

Combination therapy with BRAF and MEK inhibitors (BRAFi/MEKi) have dramatically improved prognosis among patients with BRAF-mutant metastatic melanoma compared with traditional treatment, such as chemotherapy. However, resistance to these targeted agents occurs invariably, thereby limiting their clinical efficacy. Recently, it has been reported that the ligand-independent phosphorylation of erythropoietin-producing hepatocellular receptor A2 (EphA2) at Ser-897 signaling is a driver of BRAF inhibitor resistance in melanoma. A melanoma patient with multiple metastases was treated with dabrafenib plus trametinib therapy and maintained complete remission for more than 2 years. As brain metastasis occurred, we had switched to nivolumab plus ipilimumab therapy. However, new lesions were observed after four cycles of nivolumab plus ipilimumab therapy, she was rechallenged with encorafenib plus binimetinib therapy, and she maintained progression-free status for more than 7 months. We performed immunohistochemical staining of EphA2, phospho-EphA2 (p-EphA2; Ser-897), and epidermal growth factor receptor (EGFR) of melanoma cells before and/or after dabrafenib and trametinib therapy. Immunohistochemical examination showed higher expression of EphA2, p-EphA2, and EGFR in the melanoma cells after dabrafenib plus trametinib therapy as compared with that before therapy. Our results may indicate that EphA2, p-EphA2, and EGFR can be critical factors for resistance and reversible response of BRAFi/MEKi in metastases of melanoma. Our case presents a possible treatment that can help overcome BRAFi/MEKi resistance and improve prognosis of melanoma. more...

Solar lentigo (SL) is a hyperpigmented macule that occurs in sun-exposed areas and is characterized by the accumulation of melanin pigment in the epidermis. On the contrary, melanin-incorporated macrophages have also been identified in the dermis, which is thought to be caused by melanin transfer due to disruption of the basement membrane, but the detailed mechanism remains unclear. In this study, we analysed SL lesions by pathological methods and examined the mechanism of melanin accumulation in the dermis using cultured skin models in vitro. First, we observed a significant decrease in type IV collagen (COL4), a major component of the basement membrane, in SL lesions. The basement membrane is known to be formed by the interaction of keratinocytes and dermal cells. Therefore, we constructed skin models containing fibroblasts or dermal stem cells and examined their effects on basement membrane formation. The results showed a markedly enhanced production of COL4 mediated by dermal stem cell-derived exosomes. The analysis of melanin localization in the SL dermis revealed that CD163-positive macrophages and CD271-positive dermal stem cells both took up melanin pigment. Exosomes of dermal stem cells incorporating melanosomes were less effective in promoting COL4 expression. These findings suggest that while the promotion of COL4 production in keratinocytes by dermal stem cell-derived exosomes is important for maintaining basement membrane homeostasis, this mechanism is disrupted in SL lesions, leading to chronic melanin accumulation in the dermis. more...

The self-duplication and differentiation of dermal stem cells are essential for the maintenance of dermal homeostasis. Fibroblasts are derived from dermal stem cells and produce components of connective tissue, such as collagen, which maintains the structure of the dermis. Cell-cell communication is required for the maintenance of tissue homeostasis, and the role of exosomes in this process has recently been attracting increasing attention. Dermal stem cells and fibroblasts have been suggested to communicate with each other in the dermis; however, the underlying mechanisms remain unclear. In the present study, we investigated communication between dermal stem/progenitor cells (DSPCs) and fibroblasts via exosomes. We collected exosomes from DSPCs and added them to a culture of fibroblasts. With the exosomes, COL1A1 mRNA expression was up-regulated and dependent on the Akt phosphorylation. Exosomes collected from fibroblasts did not show the significant up-regulation of COL1A1 mRNA expression. We then performed a proteomic analysis and detected 74 proteins specific to DSPC-derived exosomes, including ANP32B related to Akt phosphorylation. We added exosomes in which ANP32B was knocked down to a fibroblast culture and observed neither Akt phosphorylation nor enhanced type I collagen synthesis. Additionally, an immunohistochemical analysis of skin tissues revealed that ANP32B expression levels in CD271-positive dermal stem cells were lower in old subjects than in young subjects. These results suggest that DSPCs promote type I collagen synthesis in fibroblasts by secreting exosomes containing ANP32B, which may contribute to the maintenance of skin homeostasis; however, this function of DSPCs may decrease with aging. more...

Impetigo herpetiformis (IH) is a rare pustular dermatosis. It can be life-threatening for both the mother and fetus and often causes therapeutic problems. However, there is no specific guideline for the treatment of IH and the evidence regarding the efficacy of treatments for IH has not been established. Herein, we report two cases of IH, which were successfully treated with anti-tumor necrosis factor (TNF)-α drugs. The serum levels of the drugs in the infants and mothers were examined using enzyme-linked immunosorbent assay (ELISA). Case 1 was a 35-year-old, gravida 2, para 1, female patient in week 20 of pregnancy; she was treated with adalimumab (ADA) until delivery. Case 2 was a 26-year-old, gravida 1, para 0, female patient in week 30 of pregnancy; she was treated with certolizumab pegol (CZP) until delivery. In both cases, the skin lesions started regressing considerably after administration of the biologic agents. We examined the serum levels of the biologic agents in the mothers and infants using ELISA. In case 1, the ADA serum level in the infant was as high as that in the mother at birth; it then decreased below the lower limit of quantification at week 12 post-delivery. In case 2, the CZP serum level in the infant was below the lower limit of quantification at birth. In this report, we revealed that biologic agents could be an effective treatment for severe IH and that CZP treatment can be considered safe for the mothers and fetuses. more...

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition. more...

Previous studies have demonstrated that the numbers of interfollicular epidermal stem cells (IFE-SCs) and dermal stem cells (DSCs) decrease with age and that this decrease is attributed to the age-related deterioration of skin homeostatic functions and the delay in wound healing. Meanwhile, functional decline in the stem cells is also considered to be responsible for the deteriorated skin homeostatic functions and the delayed wound healing associated with ageing. In the present study, we focused on epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signalling and fibroblast growth factor-2/fibroblast growth factor receptor (FGF2/FGFR) signalling to analyse the age-related changes. Immunohistological analysis revealed that the expressions of EGFR and FGFR1 declined in IFE-SCs and DSCs with age, respectively. Additionally, IFE-SCs and DSCs isolated from the skin samples of elderly subjects exhibited lowered responsiveness to EGF and FGF2, respectively. These results suggest that the lowered responsiveness of the skin stem cells to growth factors may be a factor involved in the age-related deterioration of skin regenerative functions during wound healing and skin homeostatic functions. We hope that homeostatic and wound healing functions in the skin could be maintained if the decreased expressions of EGFR and FGFR1 in IFE-SCs and DSCs, respectively, can be suppressed. more...

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS. more...

Wnt/β-catenin signalling promotes melanogenesis in melanocytes and also induces melanocytogenesis from melanocyte stem cells (McSCs). Previous study reported that WNT1, a ligand which activates Wnt/β-catenin signalling pathway, was more highly expressed in the epidermis at SLs than in normal skin areas, suggesting that WNT1 causes hyperpigmentation. To elucidate the mechanism by which WNT1 expression is increased in SLs, we examined the methylation of 5-carbon of cytosine (5mC), that is 5-methylcytosine (5mC) level, in a region within the WNT1 promoter; the methylation of the region was known to negatively regulate WNT1 gene expression. We used an immortalized cell line of human interfollicular epidermal stem cells to analyse the effect of UVB irradiation on DNA methylation level of WNT1 promoter and found that UVB irradiation caused demethylation of WNT1 promoter and promoted WNT1 mRNA expression. It was also found that UVB irradiation reduced the expression of DNA methyltransferase 1 (DNMT1), an enzyme responsible for maintaining methylation patterns during cell division. Pathological analysis of SLs and non-SL regions in the human skin revealed that both DNMT1 expression and 5mC level were decreased at SLs compared to non-SL skins. Furthermore, bisulphite sequencing showed that the methylated CpG level in WNT1 promoter was also lower at SLs than in non-SL skins. Thus, in the skin exposed to a high amount of UV rays, excessive expression of WNT1 is thought to be caused by the demethylation of WNT1 promoter, and the upregulated WNT1 promotes melanocytogenesis and melanogenesis, then resulting in SL formation. more...

Capillary structural abnormalities cause skin disorders. Mottled redness, i.e., skin redness unevenness, may appear on the sun-exposed skin, suggesting capillary structural abnormalities, although its mechanism remains unclear.To observe the capillary structures in the sun-exposed skin where skin redness unevenness is likely to occur, and clarify the mechanism of capillary structural abnormalities.The tissue structures in the skin with skin redness unevenness were observed by LC-OCT. Subsequently, immunostaining of the sun-exposed skin where skin redness unevenness is often observed, was performed. Vascular endothelial cells were UV-irradiated to analyze the expression and functions of genes involved in the capillary structures and morphogenesis.The skin with skin redness unevenness exhibited scattering of dilated tubular tissue and disturbance of distribution uniformity. Immunostaining of the sun-exposed skin that were more likely to be exposed to UV rays also revealed similarly disorder of capillary structures. In addition, UVA-irradiated vascular endothelial cells exhibited increased expression of ETBR, involved in telangiectasia, decreased expression of BMPR2, involved in the morphogenesis and maintenance of the blood vessels, and reduced migration of the capillaries.UV rays alter ETBR and BMPR2 expression in the skin capillaries, and cause partial dilation and decreased migration, resulting in capillary structural abnormalities and causing skin redness unevenness. more...

Emerging evidence has pointed to the noxious effects of senescent cells in various tissues, and senescent cells in the epidermis are known to accumulate with age. We hypothesized that there is a mechanism by which senescent cells in the epidermis are preferentially removed and that the function of such removal mechanism declines as age increases. In this study, we investigated whether Notch signalling is involved in such senescent cell removal. We found that Notch1 receptor was expressed more highly in p16INK4a-positive senescent cells than in surrounding cells in human epidermis both in young and old subjects. On the other hand, the expression of its ligand JAG1 was decreased in the epidermis of aged subjects. When normal epidermal cells and UVB-irradiated senescent cells were mixed and three-dimensional reconstructed epidermis was developed in vitro, the senescent cells were preferentially removed from the basal layer and located in the upper layer. We also found that the depletion of senescent cells from the basal layer was suppressed by JAG1 knockdown in normal cells or using a Notch signalling inhibitor. From these results, Notch signalling may be involved in senescent cell removal in the epidermis and the age-related decrease of JAG1 expression in the basal layer may lead to accumulation of senescent cells owing to reduced activation of Notch signalling. more...

Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of various skin disorders. Previous findings showed that IL-36γ promoted wound healing in mice; however, the pathogenic role of IL-36Ra in wound healing remains unclear. We elucidated the role of IL-36Ra, a regulator of IL-36 in tissue repair by investigating the recruitment of inflammatory cells and cytokine production in the absence of IL-36Ra. Full-thickness excisional wounds were made on the back of Il36rn−/− mice and healing was assessed by monitoring macroscopic wound sizes, numbers of infiltrated cells, and gene expression of inflammatory cytokines. Macroscopic wound healing, re-epithelialization, and granulation tissue formation were delayed by 3 days post-injury in Il36rn−/− mice. This delay was associated with increased infiltrations of neutrophils and macrophages, and increased expression of cytokines, such as IL-36γ, C-X-C motif chemokine ligand 1 (CXCL1), and transforming growth factor (TGF)-β. Importantly, administration of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, caused normalization of wound healing in Il36rn−/− mice, abrogating the initial delay in tissue repair. These results showed that targeting TLR4- mediated infiltrations of immune cells and cytokine production could be beneficial in regulating wound healing in IL-36Ra-deficient skin disorders. more...

Recently, increasing attention has been paid to senescence-associated secretory phenotype (SASP), a phenomenon that senescent cells secrete molecules such as inflammatory cytokines and matrix metalloproteinases (MMPs), due to its noxious effects on the surrounding tissue. Senescent cells in the blood and liver are known to be properly depleted by macrophages. In the dermis, accumulation of senescent cells has been reported and is thought to be involved with skin ageing. In this study, to elucidate the clearance mechanism of senescent cells in the dermis, we focused on macrophage functions. Our co-culture experiments of senescent fibroblasts and macrophages revealed a two-step clearance mechanism: first, TNF-α secreted from macrophages induces apoptosis in senescent fibroblasts, and then, dead cells are phagocytosed by macrophages. Furthermore, it was suggested that SASP factors suppress both of the two steps of the senescent cell clearance by macrophages. From these findings, normally senescent cells in the dermis are thought to be removed by macrophages, but when senescent cells are excessively accumulated owing to oxidative stress, ultraviolet (UV) ray or other reasons, SASP was suggested to suppress the macrophage-dependent clearance functions and thereby cause further accumulation of senescent cells. more...

Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn−/− mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn−/− mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn−/− mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA. more...

Hair follicle stem cells (HFSC) are localized in the bulge region of the hair follicle and play a role in producing hair. Recently, it has been shown that the number of HFSC decreases with age, which is thought to be a cause of senile alopecia. Therefore, maintaining HFSC may be key for the prevention of age-related hair loss, but the regulatory mechanisms of HFSC and the effects of aging on them are largely unknown. In general, stem cells are known to require regulatory factors in the pericellular microenvironment, termed the stem cell niche, to maintain their cell function. In this study, we focused on the extracellular matrix proteoglycan decorin (DCN) as a candidate factor for maintaining the human HFSC niche. Gene expression analysis showed that DCN was highly expressed in the bulge region. We observed decreases in DCN expression as well as the number of KRT15-positive HFSC with age. In vitro experiments with human plucked hair-derived HFSC revealed that HFSC lost their undifferentiated state with increasing passages, and prior to this change a decrease in DCN expression was observed. Furthermore, knockdown of DCN promoted HFSC differentiation. In contrast, when HFSC were cultured on DCN-coated plates, they showed an even more undifferentiated state. From these results, as a novel mechanism for maintaining HFSC, it was suggested that DCN functions as a stem cell niche component, and that the deficit of HFSC maintenance caused by a reduction in DCN expression could be a cause of age-related hair loss. more...

Summary Here we report a rare case of neutrophilic dermatoses related to a granulocyte colony-stimulating factor (G-CSF)-producing solid pseudopapillary tumour (SPT). The patient was a 39-year-old woman presenting with scattered pustules and crusts of the palms, heels and thighs and plaques of the bilateral lower legs. The skin biopsy revealed dense neutrophil infiltration in the epidermis to the dermis. A pancreatic head tumour was detected using computed tomography. A pathological examination of the resected specimen suggested an SPT. As the skin eruption promptly disappeared after SPT resection, we hypothesized that SPT secretes growth factors including epidermal growth factor (EGF) and G-CSF. The SPT cells stained positive for both EGF and G-CSF tumour cells. The serum levels of interleukin (IL)-6 and IL-10 and tumour necrosis factor-α were within normal limits before and after the SPT resection. In contrast, the serum IL-8, EGF and G-CSF levels decreased after the SPT resection. This is a rare case of neutrophilic dermatoses related to a G-CSF-producing SPT. The present case suggests that physicians should be aware that a G-CSF-producing tumour is a differential diagnosis to consider in patients with unusual aseptic pustulosis. more...

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created. more...

Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36Ra) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn−/− mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn−/− mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn−/− mice. These data indicate that Il36rn−/− mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response. more...

In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behcet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behcet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long-term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behcet's disease. more...

L-type amino acid transporter 1 (LAT1), a transporter of large neutral amino acids, is rarely expressed in resting T cells, whereas its expression is remarkably upregulated upon activation. We have proven the essential role of T cells in the development of allergic inflammation in various target organs, though the contribution of LAT1 to T cell function in allergic diseases has not been clarified. Here, we investigated the effect of a LAT1 inhibitor, JPH203, on antigen-induced inflammatory responses in the skin, lungs, and nasal mucosa of immunized mice or mice transferred with in vitro-differentiated antigen-specific Th2 cells. Consistent with the augmented expression of LAT1 in skin-accumulated CD4+ T cells of atopic dermatitis patients, antigen-induced skin inflammation with eosinophil infiltration and Th2 cytokine production developed in immunized and Th2 cell-transferred mice was suppressed by JPH203 treatment. Essentially the same efficacy of JPH203 was seen in antigen-induced nasal eosinophilic inflammation accompanied by nasal hyperresponsiveness evoked in both mice. Remarkably, antigen-induced bronchial hyperresponsiveness was suppressed, whereas lung accumulation of eosinophils or antigen-specific T cells was not affected, by JPH203 in Th2 cell-transferred mice. The blockade of LAT1-mediated glycolysis, oxidative phosphorylation, and activating transcription factor 4-regulated amino acid starving responses in cytokine production and proliferation of Th2 was suggested to be involved in the efficacy of JPH203. LAT1 is essential for the pathogenesis of activated Th2 cell-mediated allergic inflammation and would be a promising target for the development of new means to treat allergic diseases. more...

Stem cells have recently been shown to play important roles in wound healing. The aim of this study was to investigate the role of dermal CD271+ cells in wound healing. Full-thickness wounds were produced on the backs of 5-year-old and 24-week-old mice, and time-course of wound closure, CD271+ cell counts, and gene expression levels were compared. Delayed wound healing was observed in 24-week-old mice. The peak of CD271+ cell increase was delayed in 24-week-old mice, and gene expression levels of growth factors in wounded tissue were significantly increased in 5-year-old mice. Dermal CD271+ cells purified by fluorescence-activated cell sorting (FACS) expressed higher growth factors than CD271- cells, suggesting that CD271+ cells play important roles by producing growth factors. This study also investigated dermal CD271+ cells in patients with chronic skin ulcers. Dermal CD271+ cells in patients were significantly reduced compared with in healthy controls. Thus, dermal CD271+ cells are closely associated with wound healing. more...

Hintergrund: Seit einigen Jahren wird perkutane Sensibilisierung als Hauptmechanismus der Entstehung von Nahrungsmittelallergien diskutiert. In Japan ist seit 2010 bei Personen, die Seife mit hydrolysiertem Weizen verwenden, die Inzidenz von Weizenallergien vom Soforttyp gegen hydrolysiertes Weizenprotein drastisch gestiegen. Dies spricht für die Hypothese, dass Nahrungsmittelallergien durch perkutane Sensibilisierung entstehen. Klinische Zusammenfassung: Ein 25-jähriger Patient (Fall 1) und eine 18-jährige Patientin (Fall 2) mit atopischer Dermatitis stellten sich mit Nahrungsmittelallergie und Handekzem in unserem Hause vor. Nach Aufnahme einer beruflichen Tätigkeit, bei der sie mit Fisch in Kontakt kamen, entwickelte sich ein ausgeprägtes juckendes Ekzem auf den Händen. Im weiteren Verlauf manifestierten sich nach dem Verzehr von Fisch orale Allergiesymptome, intraoraler Pruritus und Dyspnoe. In beiden Fällen wurden spezifische IgE-Antikörper gegen zahlreiche Fischarten nachgewiesen, und auch im Haut-Prick-Test zeigten beide Patienten positive Reaktionen gegen eine Vielzahl von Fischarten. Auch die Microarray-Immunoassay-Analyse ergab positive Reaktionen für die Fluoreszenzstärke spezifischer IgE-Antikörper gegen Parvalbumin verschiedener Fischarten. Wir stellten in beiden Fällen die Diagnose einer Kontakturtikaria infolge perkutaner Sensibilisierung gegen Parvalbumin durch beruflich bedingten körperlichen Kontakt mit Fisch. Schlussfolgerung: Die Vorgeschichten und Untersuchungsergebnisse der Patienten deuten darauf hin, dass eine perkutane Sensibilisierung durch berufsbedingte Exposition gegenüber Parvalbumin zur Entwicklung einer Nahrungsmittelallergie führen könnte. Übersetzung aus Case Rep Dermatol 2015;7:227-232 (DOI:10.1159/000439080) more...

A 72-year-old male visited a nearby hospital with a large tumor in his occipital region, which had existed since 20 years. Since malignant tumor was suspected, he was referred to our department. At the initial consultation, an elastic-hard, yellow-brown, sessile tumor, measuring 8 × 7 × 5 cm and with a flat surface, was observed in the occipital region. The tumor was resected and covered with artificial dermis. Histopathologically, the lesion was composed of basal-cell-like cells with nest formation in the dermis. A rippled pattern, or the single-line arrangement of tumor cells involving the stroma, was present. In addition, some tumor clusters revealed the differentiation to sebaceous glands, and these cells were positive for cytokeratin (AE1/AE3) and epithelial membrane antigen, which is consistent with the staining of sebaceous glands. On the contrary, tumor cells were negative for epithelial antigen (Ber-EP4), and Ki67 (MIB1) index was 5% or lower. Therefore, we diagnosed the tumor as rippled-pattern sebaceoma and not as basal cell carcinoma. Although this case was quite unique in its large size, immunostaining was useful for the definite diagnosis. more...

ファイル公開：2019-02-01