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A 24-year-old Japanese female presented to our department complaining of redness of eyes and pain in the mouth and throat. She had no particular medical history. She was treated in dentistry of our hospital, but there was no improvement. Stomatitis was exacerbated, and conjunctival hyperemia and hoarseness appeared, so she was referred to otolaryngology and ophthalmology of our hospital. At that time, she had hyperemia and blistering of the bulbar conjunctiva and pseudomembrane formation in the palpebral conjunctiva, and multiple ulcerative lesions of the oral cavity, pharynx and larynx (Fig.1a-d). Her symptom was suspected pemphigus vulgaris (PV), so she was referred to a dermatologist. Biopsy specimen from the lip revealed blisters and acantholytic cells in the epidermis with the infiltration of lymphocytes and neutrophils (Fig.1e). In the direct fluorescent antibody method, IgG and C3 are weak-positive deposited between epidermal cells (Fig.1f).

Hidradenitis suppurativa (HS) is a chronic relapsing skin disease localized mainly on the apocrine gland‐bearing areas. In Japan, HS is yet to be fully understood, and no criteria have been established for its diagnosis or severity assessment. The purpose of this study was to investigate and characterize HS in Japan. We conducted a nationwide questionnaire‐based study, in which Japanese diagnostic criteria were proposed. Question items included age, sex, disease duration, past history, family history, smoking status, disease severity scores (Hurley stage, modified Sartorius score and Physician Global Assessment [PGA] score), treatments, comorbidities and prognosis. We analyzed 300 patients (219 males and 81 females) diagnosed with HS based on our criteria. Average disease duration was 92.3 ± 6.82 months. Only 12 (4%) patients had a family history of HS. Disease severity was classified by PGA score (mild, 100 [33.3%]; moderate, 133 [44.3%]; severe, 34 [11.3%]; most severe, 29 [9.7%]) and Hurley stage (I, 69 [23%]; II, 109 [36.3%]; III, 121 [40.3%]). Disease severities based on PGA score and Hurley stage were positively correlated to modified Sartorius score using the Kruskal–Wallis test (P

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin‐23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/{"type":"clinical-trial","attrs":{"text":"NCT03000075","term_id":"NCT03000075"}}NCT03000075), a phase 2/3, double‐blinded, placebo‐controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross‐over to 75 mg risankizumab and placebo with cross‐over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross‐over to risankizumab at week 16. The primary end‐point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI‐90) at week 16 for risankizumab versus placebo. Missing data were imputed as non‐response. All primary and psoriasis‐related secondary end‐points were met for both risankizumab doses (P

Interleukin (IL)-21 is regarded as a potent antitumor agent, which increases the cytotoxicity of both natural killer (NK) and CD8(+) T cells. In this study, we investigated the role of IL-21 in mycosis fungoides (MF). IL-21 mRNA expression levels in patch and plaque MF were significantly higher than those in normal skin. IL-21 mRNA expression levels in tumor MF were significantly decreased compared with those in patch and plaque MF. Interestingly, mRNA expression levels of IL-21 in MF lesional skin significantly correlated with those of T-helper type-1 cytokines/chemokines such as CXCL10, CXCL11 and γ-interferon. Immunohistochemistry showed that IL-21 was expressed by keratinocytes in patch and plaque MF. Furthermore, serum IL-21 levels in patients with tumor MF were significantly lower than those of healthy controls and plaque MF. Thus, IL-21 expression was significantly downregulated in skin and blood of patients with tumor MF, which may contribute to progression of MF. Our study suggests that recombinant IL-21 would be a promising therapy for MF.

Some patients with cutaneous T-cell lymphoma (CTCL) show a miserable clinical course and the only option that can induce long-term remission for advanced CTCL may be hematopoietic stem cell transplantation (HSCT). So far, studies on HSCT for CTCL patients have been limited. In this study, we summarized 11 cases with CTCL treated with HSCT, including nine cases in Japan and two cases in Brazil. The patients were five cases with mycosis fungoides (MF), two cases with Sézary syndrome (SS), three cases with anaplastic large cell lymphoma, and one case with primary cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL-NOS). Currently, seven out of 11 cases are alive (at 13-108 months after transplantation) and four died at 15 days to 14 months after transplantation. When focusing on the eight patients who received allogeneic HSCT for MF/SS and PTL-NOS, all four patients at 45 years old or under are alive at present. One case showed relapse in the skin. On the other hand, one out of the other four patients at over 45 years old survived. Engraftment failure was seen in one case and all the other three cases experienced relapse. Although this is only a case series with a small number, our study has suggested that we should be careful about age when treating patients with MF/SS by allogeneic HSCT.

Summary Background Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. Aim To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. Methods Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. Results Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. Conclusions These results suggest that serum IL-33 levels generally reflect increased inflammation in patients with psoriasis.

Loss of consciousness (LOC) in long QT syndrome (LQTS) patients can be caused by torsade de pointes (TdP) or vasovagal syncope (VVS). On genetic testing and head-up tilt testing (HUTT), we diagnosed three young patients with both genotyped LQTS and autonomic dysregulation. According to grade of prolongation of QT interval and LOC status, syncope episodes in two patients were classified as due to VVS, while those of the other patient were due to TdP. We also diagnosed one patient with postural orthostatic tachycardia syndrome. Syncope in LQTS patients should not automatically be labeled TdP. If there is a possibility of VVS, HUTT should be performed, but careful observation is required because TdP cannot be completely ruled out.

Background Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases. Objectives To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL). Methods Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sezary syndrome. Results IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sezary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25. Conclusions Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL-13 by tumour cells.

IL-32 is a pro-inflammatory cytokine expressed by activated natural killer cells, T cells, keratinocytes, and fibroblasts. In this study, we examined the role of IL-32 in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS). IL-32 mRNA expression levels in lesional skin of MF patch, plaque, and tumor were increased compared with those of normal skin, which positively correlated with CCL17 and CCL18 mRNA expression levels. Serum IL-32 levels positively correlated with disease activity within each patient. Immunostaining showed that keratinocytes expressed IL-32 in the lesional skin of MF patch and plaque, whereas in MF tumor, atypical T cells in the dermis strongly expressed IL-32. We also showed that IL-32 dose-dependently accelerated the proliferation of MF and SS cell lines in vitro, which was inhibited by blocking mitogen-activated protein kinase and NF-κB-mediated signaling. The addition of anti-IL-32 antibodies in culture decreased the proliferation of SS cells and the viability of MF cells, suggesting that IL-32 serves as an autocrine growth factor. In conclusion, our results suggest that IL-32 has a role in the formation and maintenance of CTCL lesions, providing a possible therapeutic target for patients with this disease.

Primary cutaneous follicular helper T (TFH)-cell lymphoma has recently been proposed, and is characterized by proliferation of malignant T cells expressing TFH-cell markers, such as CXCL13, accompanied by numerous reactive B cells. We report here a patient whose skin histology showed massive infiltration of both T and B cells, with a proliferation of arborizing high endothelial venules and follicular dendritic cells. Infiltrating T cells were positive for CXCL13, programmed death (PD)-1, inducible T-cell co-stimulator, and BCL-6. Southern blot analyses using DNA from the skin revealed monoclonality of both T and B cells. The patient had marked resistance to treatments, and complete remission was achieved only after allogeneic stem cell transplantation. The present case showed overlapping features with angio-immunoblastic T-cell lymphoma (AITL), although systemic symptoms were not observed. Further study is needed to define the criteria of this provisional entity, representing the cutaneous counterpart of the nodal follicular peripheral T-cell lymphoma or AITL.

Angiogenesis is a crucial process in the growth and progression of cancer, correlating with the metastatic potential of tumour cells. Angiopoietins are ligands for the endothelium-specific tyrosine kinase Tie2 receptor, which comprise 4 structurally related proteins, termed angiopoietin (Ang)-1, Ang-2, Ang-3 and Ang-4. The roles of Ang-1 and Ang-2 have recently been clarified as crucial in angiogenesis. In this report, we measured serum Ang-1 and Ang-2 levels in patients with cutaneous T-cell lymphoma (CTCL). Serum levels of Ang-2, but not Ang-1, in patients with Sézary syndrome were significantly higher than those in patch mycosis fungoides (MF), plaque/tumour MF, and healthy controls. In patients with CTCL, serum Ang-2 correlated with disease activity. Moreover, the numbers of Ang-2+ cells in lesional skin of CTCL were significantly larger than those in normal skin. These results suggest that Ang-2 may have important roles in the development of CTCL.

Many patients with cutaneous T-cell lymphoma (CTCL) experience severe pruritus. This study evaluated serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in patients with CTCL. Although serum NGF and BDNF levels in patients with CTCL were not significantly higher than in healthy controls, serum NGF levels in patients with Sézary syndrome were higher than in those with mycosis fungoides and in healthy controls. Enhanced NGF expression by keratinocytes and increased dermal nerve fibres were detected in lesional skin of subjects with Sézary syndrome. Correlations between pruritus in CTCL and serum levels of NGF, BDNF, chemokine (C-C motif) ligand 1 (CCL1), CCL17, CCL26, CCL27, lactate dehydrogenase (LDH), IgE, and soluble interleukin-2 receptor were analysed. Serum CCL1, CCL26, LDH, and IgE levels correlated with pruritus in patients with CTCL. NGF may be associated with increased dermal nerve fibres and pruritus in Sézary syndrome, and CCL1, CCL26, and IgE may be associated with pruritus in CTCL.

Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances. CD155 is expressed in various types of cancer, and this surface molecule on tumor cells functions either as a co-stimulatory molecule or a co-inhibitory molecule, depending on its receptor. CD226, a CD155 ligand, is mainly expressed on natural killer cells and CD8+ T cells, playing important roles in natural killer cell-mediated cytotoxicity. In this study, we investigated the expression and function of CD155 and CD226 in cutaneous T-cell lymphoma (CTCL). CD155 was strongly expressed on tumor cells and CD155 mRNA expression levels were increased in CTCL lesional skin. CD226 expression on natural killer cells and CD8+ cells in peripheral blood of CTCL patients was decreased. On the other hand, serum CD226 levels were significantly elevated in CTCL patients, strongly reflecting disease activity, suggesting that soluble CD226 in sera was generated by shedding of its membrane form. Recombinant CD226 itself showed cytotoxic activity against CD155-expressing CTCL cells in vitro. These data suggest that soluble CD226 elevated in sera of CTCL patients would be important for tumor immunity by interacting with CD155 on tumor cells.

Syndecan-4 (SDC-4) is a cell surface proteoglycan, which participates in signaling during cell adhesion, migration, proliferation, endocytosis, and mechanotransduction, and is expressed on various cells, including endothelial cells, epithelial cells, T cells, and eosinophils. Emerging evidences have suggested that SDC-4 might contribute to Th2-driven allergic immune responses. Here, we examined the role of SDC-4 in patients with atopic dermatitis (AD). Serum SDC-4 levels in AD patients were significantly higher than in healthy individuals, and they increased according to the disease severity. Importantly, they positively correlated with Eczema Area and Severity Index and itch visual analogue scale scores. Furthermore, serum SDC-4 levels decreased after treatment. We also analyzed SDC-4 expression in AD lesional skin. SDC-4 mRNA levels in AD skin were significantly higher than those of normal skin. Immunohistochemical staining revealed that SDC-4 was highly expressed in the epidermis and endothelial cells in AD lesional skin. Taken together, our study has demonstrated that SDC-4 expression was increased in sera and skin of AD patients, suggesting that SDC-4 may contribute to the development of AD.

Thymic stromal lymphopoietin (TSLP) activates dendritic cells to induce Th2-mediated inflammation. Periostin, an extracellular matrix protein produced by fibroblasts, induces chronic inflammation by stimulating TSLP production. Recently, a reinforcing cycle linking Th2-type immune responses with periostin-induced keratinocyte activation has been proposed in atopic dermatitis pathogenesis. In this study, we investigated the role of TSLP and periostin in the development of cutaneous T-cell lymphoma (CTCL), where Th2 cytokines and chemokines are also dominant. TSLP and periostin mRNA expression levels were elevated in CTCL lesional skin, both of which correlated with IL4 expression levels. In vitro and ex vivo, IL4 or IL13 stimulated periostin expression by dermal fibroblasts, and fibroblasts from CTCL lesional skin expressed higher levels of periostin than those from control skin. Serum periostin levels of CTCL patients were also significantly higher than those of healthy individuals. Hut78 and MJ, CTCL cell lines, and peripheral blood mononuclear cells from leukemic CTCL patients expressed the TSLP receptor. TSLP induced production of IL4 and IL13 by Hut78 and MJ cells through the activation of STAT5. Moreover, TSLP induced proliferation of CTCL cells both in vitro and in vivo. These data suggest that periostin-mediated TSLP production by keratinocytes directly stimulates CTCL tumor cell growth in addition to inducing a Th2-dominant tumor environment in CTCL. Cancer Res; 76(21); 6241–52. ©2016 AACR.

Localized scleroderma is an inflammatory disorder affecting the skin and underlying tissues, a certain subset of which develops other autoimmune diseases on the basis of a prominent autoimmune background. We here report a unique case of linear scleroderma presenting with a sclerotic plaque on the left thigh, multiple lymphadenopathy in bilateral inguinal and para-aortic lymph nodes, and hepatosplenomegaly, who later developed polymyositis. We describe the detailed disease course of our case and discuss the clinical significance of multiple lymphadenopathy in localized scleroderma based on a review of published work.

Angiogenin is a member of the ribonuclease superfamily that is associated with the angiogenic process. Angiogenesis is regarded as an important step to support primary and metastatic tumor growth. In cutaneous T cell lymphoma (CTCL), angiogenesis in lesional skin is increased, suggesting that interaction between tumor cells and their microvasculature are likely to occur during progression of CTCL. Patients with hematological malignancies show increased serum angiogenin levels, which are related with poor overall survival. To investigate possible roles of angiogenin in development of CTCL, we measured serum angiogenin levels in 36 patients with CTCL and 21 healthy controls by enzyme-linked immunosorbent assay. We also investigated angiogenin mRNA and protein expression in lesional skin of CTCL by quantitative RT-PCR and immunohistochemistry. Serum angiogenin levels in patients with CTCL were significantly higher than those in healthy controls. When classified with types of skin lesions, serum angiogenin levels were elevated only in erythrodermic CTCL patients. Angiogenin mRNA expression levels in lesional skin were significantly elevated in erythrodermic CTCL compared to normal skin. Immunohistochemical study revealed that angiogenin was expressed by keratinocytes, endothelial cells, and infiltrating lymphocytes in CTCL. Our results suggest that enhanced angiogenin expression may be related with a poor prognosis of erythrodermic CTCL. As angiogenin acts as an inhibitor of polymorphonuclear leukocyte degranulation, angiogenin may also be linked to impaired host defense in erythrodermic CTCL.

Purpose: Both patients with cutaneous T-cell lymphoma (CTCL) and those with atopic dermatitis (AD) have pruritus, TH2-biased T cells, and a tendency to have bacterial infections, suggesting a common pathologic basis for these two diseases. Recently, interleukin (IL)-22–producing T cells were reported in skin of patients with AD. In this study, we investigated expression levels of TH22- and TH17-related molecules in lesional skin and sera isolated from patients with CTCL. Experimental Design: Skin biopsies and sera were collected from patients with CTCL or psoriasis and from healthy volunteers. Protein and mRNA expression levels of IL-22, IL-17A, IL-17F, IL-23p19, IL-10, IL-4, CCL20, CCR6, IL-8, and IL-20 were examined in lesional tissue and a subset of these molecules in sera. Phosphorylation of STAT3 was also assessed in lesional skin of CTCL and psoriasis by immunohistochemistry. Results: IL-22, IL-10, IL-4, CCL20, and CCR6 mRNA and protein levels, but not IL-17A, IL-17F, IL-23p19, IL-8, or IL-20, were significantly elevated in lesional skin of CTCL. Phosphorylation of STAT3 was detected in epidermis of CTCL skin. Moreover, serum IL-22, IL-10, and CCL20 levels were increased in CTCL and correlated with disease severity. Conclusions: Our results suggest that IL-22 is important in establishing the tumor microenvironment for CTCL. Enhanced expression of CCL20 may explain epidermal hyperplasia and migration of CCR6+ cells, such as Langerhans cells, into lesional skin. Relatively low expression of IL-17 may explain the lack of neutrophils in lesions of CTCL, which correlates with bacterial infections that commonly occur in skin affected by CTCL. Clin Cancer Res; 17(24); 7529–38. ©2011 AACR.

CC chemokine receptor 3 (CCR3), the sole receptor for eotaxins, is expressed on eosinophils and T helper type 2 (Th2) cells. In Hodgkin's disease, eotaxin-1 secreted by fibroblasts collects Th2 cells and eosinophils within the tissue. Similarly, many Th2 cells infiltrate the lesional skin of cutaneous T-cell lymphoma (CTCL). In this study, we investigated the role of eotaxins in the development of the Th2 environment of CTCL. We revealed that fibroblasts from lesional skin of CTCL expressed higher amounts of eotaxin-3 messenger RNA (mRNA) compared with those from normal skin. Lesional skin of CTCL at advanced stages contained significantly higher levels of eotaxin-3 and CCR3 mRNA, compared with early stages of CTCL. IL-4 mRNA was expressed in some cases at advanced stages. Immunohistochemistry revealed that keratinocytes, endothelial cells, and dermal fibroblasts in lesional skin of CTCL showed a stronger expression of eotaxin-3 than did normal skin. CCR3 + lymphocytes and IL-4 expression were observed in some cases of advanced CTCL. Furthermore, both serum eotaxin-3 and eotaxin-1 levels of CTCL patients at advanced stages were significantly higher than those of healthy individuals. The concentrations of these chemokines correlated with serum soluble IL-2 receptor levels. These results suggest that interaction of eotaxins and CCR3 regulates the Th2-dominant tumor environment, which is closely related to the development of CTCL.

We wanted to clarify the relationships between the degree of acute coronary artery dilation caused by Kawasaki disease and subsequent late calcification. Electron beam computed tomography (EBCT) was used to study 79 patients who had previously undergone selective coronary angiograms less than 100 days after the onset of Kawasaki disease. The EBCT was performed using an Imatron C-150 with a 100-ms exposure time and consecutive images at 6-mm intervals. The interval from the onset of Kawasaki disease to EBCT ranged from 2 to 242 months (median, 103 months). The maximum diameters of the right coronary, the left anterior descending, and the left circumflex arteries, as well as the bifurcation of the left coronary artery were measured in the initial coronary angiograms. A total of 250 branches, including 53 left coronary arteries, were measured, and the relationship between the degree of the initial coronary artery dilation and subsequent calcification in the branches and left coronary artery was analyzed. The coronary arterial diameter of all branches that eventually calcified was 6 mm or greater. The incidence of calcification in branches measuring 6 mm or greater on the initial coronary angiogram was 12% at 5 years, 44% at 10 years, and 94% at 20 years (n = 141). Dilation greater than 6 mm is associated with a high probability of late calcification.

Many of the effects of dioxins, which are potent environmental pollutants and teratogens, are mediated through the aryl hydrocarbon receptor, also known as the dioxin receptor. The purpose of the present study was to characterize dioxin-responsive genes in a comprehensive manner using two complementary approaches: bioinformatic analysis and microarray analysis. First, we characterized the overall distribution of the cis-regulatory element for the dioxin-responsive element sequence (DRE) ‘gcgtg’ within putative promoter regions. We assembled the upstream sequences 10 kb from the transcription start site and evaluated their location and frequency in the human and mouse genomes. Second, we characterized the expression profile of mouse embryonic day 12 fetal brain exposed to 2,3,7,8-tetrarchlorodibenzo-p-dioxin. The distributions of 26 680 DREs among 2843 human genes and 98 711 DREs among 18 541 mouse genes were examined. In both species, the DREs tended to be located close to the transcription start site. Forty genes exhibited significant induction or repression following dioxin exposure in fetal mice. The set of genes exhibited a strong functional coherence, with statistically significant enrichment in organogenesis and the DNA-dependent regulation of transcription, according to Gene Ontology annotations. In both humans and mice, DREs were preferentially distributed close to transcription start sites. Evolutionary conservation of this unique DRE distribution pattern suggests that DREs may be involved in transcriptional regulation. In mice, prenatal dioxin exposure altered the expression of 10 transcription factors, many of which have been documented to play a role in organogenesis. These genes may represent potential mediators of dioxin’s effects in fetal tissues.

Double-stranded RNA (dsRNA) is a viral product recognized by Toll-like receptor 3 (TLR3), and it is a potent activator of dendritic cells (DC). We compared Langerhans cells (LC) and splenic CD11c(+) DC and investigated the responsiveness to dsRNA. We prepared highly purified LC (> 95%) using the panning method. TLR3 mRNA was expressed in LC, splenic DC, and keratinocytes (KC). The expression of IFN-beta mRNA was enhanced in LC and splenic DC by Poly(I:C) stimulation. However, cytokine/chemokine production in response to Poly(I:C) by LC was much lower than that by splenic DC. In addition, Poly(I:C) induced further maturation in splenic DC, but not in LC. Finally, we found that the mouse KC cell line, PAM212, produced a great amount of IL-1alpha by Poly(I:C) stimulation, and that IL-1alpha promoted the maturation of LC. These data altogether indicate that LC exhibit low responsiveness to dsRNA. It is possible that KC may primarily trigger anti-viral immune responses in the skin via cytokine production such as IL-1alpha.

Summary Anaplastic lymphoma kinase (ALK) is frequently observed in systemic anaplastic large cell lymphoma (ALCL), mostly in childhood or adolescence, but only rarely in primary cutaneous cases. We report a case of primary cutaneous ALCL (pcALCL) with cytoplasmic ALK expression. A 54-year-old woman with an ulcerative tumour on her forehead was admitted to our hospital. Histologically, there was an infiltrate consisting of atypical large lymphocytes and small lymphocytes in the dermis and fat tissue. Southern blot analysis showed monoclonal T-cell receptor Cβ1 gene rearrangement. Atypical large lymphocytes were positive for CD30, CD4 and CD25, and negative for CD3 and CD79a. They were also positive for ALK only in the cytoplasm, and neurophosmin (NPM)-ALK fusion transcript was not detected by reverse transcription-polymerase chain reaction. This suggested that the translocation partner of the ALK gene in this case was different from NPM (variant translocation). The tumour on the forehead resolved in 1 month after biopsy. Nodular lesions recurred on the right knee, and were histologically identical with the forehead lesion. Our case suggests the existence of a subgroup with variant ALK translocation in pcALCL; examining NPM-ALK translocation in each case with ALK expression should be useful to characterize the disease further.

CCR4, a member of the CC chemokine receptor family, is believed to play an important role in the pathogenesis of atopic dermatitis. To examine whether CCR4 single nucleotide polymorphism (SNP) is associated with susceptibility to atopic dermatitis, we investigated the allele and genotype frequencies of C1014T SNP of CCR4 in 198 Japanese patients with atopic dermatitis and controls by a PCR-restriction fragment length polymorphism method. There was no significant difference in allele or genotype frequencies between patients with atopic dermatitis and controls. Serum IgE levels and peripheral blood eosinophil counts were not significantly different among genotypes. There was also no significant difference in allele or genotype frequencies between the patient subgroup with and without asthma, with mild or moderate disease, with and without family history of atopic dermatitis, or with and without family history of atopic disorders. C1014T SNP of CCR4 does not appear to be associated with susceptibility to atopic dermatitis in Japanese patients.

We examined modulatory effects of lipopolysaccharide (LPS) on IL-6 and IL-12 production by mouse Langerhans cells (LC), spleen-derived CD11c+ dendritic cells (DC), and macrophages (Mphi). Low dose LPS (1 ng/ml) increased IL-6 and IL-12 p40 production by Mphi. LPS slightly augmented IL-6 production but showed no effect on IL-12 p40 production by DC. In contrast, only high dose LPS (1 microg/ml) induced IL-6 but not IL-12 p40 production by LC. CD14 expression was the highest on Mphi and then on DC, but not on LC, which may explain the difference in responsiveness to LPS. We also found that TGF-beta inhibited IL-6 and IL-12 p40 production by LPS-stimulated Mphi. However, TGF-beta did not inhibit IL-6 production and even enhanced IL-12 p40 production by anti-CD40/IFN-gamma-stimulated Mphi. Concerning LC, TGF-beta enhanced IL-6 and IL-12 p40 production when stimulated with anti-CD40/IFN-gamma alone or with anti-CD40/IFN-gamma and LPS. Taken together, these findings indicate diverse effects of LPS and TGF-beta on these antigen presenting cells, which probably represents their differential roles in the innate immunity.

We performed balloon angioplasty in three patients with postoperative coarctation in the transverse arch adjacent to the left common carotid artery. The age at arch reconstruction was 5, 6, and 2 days, while the interval between operation and balloon dilatation was 59 days, 87 days, and 12 months, respectively. Two balloons, one in the stenosis and the other in the left common carotid artery, were introduced over a wire sequentially and inflated simultaneously until the waist of the balloon in the arch disappeared. After balloon dilatation, a significant reduction in the peak-to-peak pressure gradient and an increase in vessel diameters were observed in all patients. Further growth of the transverse arch was documented at follow-up in two patients. No aneurysm has been detected in any patients. We believe that placing a protective balloon in the neck vessel increases safety during balloon dilatation of coarctation in the transverse arch.

Thymus and activation-regulated chemokine (TARC/CCL17) is a Th2-type chemokine and its receptor CC chemokine receptor 4 (CCR4) is preferentially expressed on Th2 cells. Langerhans cells (LC) are immature dendritic cells (DC) in the epidermis of the skin and play vital roles in immune response. In this study, we investigated TARC expression by murine freshly isolated LC and 48 h cultured (mature) LC, and the regulation of TARC production in cultured LC by various cytokines. Murine LC was prepared using a panning method from BALB/c mice. RT-PCR was performed using fresh and cultured LC to evaluate TARC mRNA levels. ELISA was carried out using supernatant of cultured LC to calculate secreted TARC protein levels. TARC mRNA was strongly upregulated during maturation of murine LC. TARC production by murine LC was upregulated by TNF-alpha and IL-4 and downregulated by IFN-gamma, dose-dependently. Th1 and Th2 cytokines reciprocally regulate the production of Th2-type chemokine TARC by murine LC. Th2 cytokine microenvironments in skin may increase TARC production by mature LC, providing attraction of Th2 cells in skin. This may be an amplification circuit in Th2-dominant inflammatory skin disease like atopic dermatitis.

Interleukin (IL)-13 plays an important role in the induction of immunoglobulin E (IgE) and in the pathogenesis of atopic dermatitis (AD). We investigated the allele and genotype frequencies of three IL-13 single nucleotide polymorphisms (SNPs) (A704C and C1103T in the promoter region and G4257A in exon 4) in Japanese patients with AD. For A704C and C1103T SNPs, there were no significant differences in allele or genotype frequencies between AD patients and controls. For G4257A SNP, A allele was significantly increased in AD patients (39.5%) compared with controls (29.4%) (P = 0.016). The same proportion of each genotype and allele was observed in the patient subgroup with and without asthma. Serum IgE levels and peripheral eosinophil counts were not significantly different among genotypes in G4257A SNP. There was also no significant difference in allele or genotype frequencies between AD patients with mild disease and those with severe disease, between those with family history of AD and those without it, or between those with family history of atopic disorders and those without it. This result suggests that 4257A allele is associated with susceptibility to AD and that it may function in the pathogenesis of AD itself, presumably by other mechanisms than inducing IgE production.

Cleft lip/palate-ectodermal dysplasia syndrome is a rare, autosomal recessive disorder caused by homozygous loss-of-function mutations of the poliovirus receptor-like 1 (PVRL1) gene encoding nectin-1. Nectin-1 is a cell-cell adhesion molecule that is important for the initial step in the formation of adherens junctions and tight junctions; it is expressed in keratinocytes, neurons, and the developing face and palate. Clinical manifestations comprise a unique facial appearance with cleft lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers and/or toes, and in some cases, mental retardation. We present the first report, to our knowledge, of an Asian individual with cleft lip/palate-ectodermal dysplasia syndrome with a novel PVRL1 mutation. A 7-year-old Japanese boy, the first child of a consanguineous marriage, showed hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair and hypodontia, the unique facial appearance with cleft lip/palate, cutaneous syndactyly of the fingers and mild mental retardation. Scanning electron microscopic examination of the hair demonstrated pili torti and pili trianguli et canaliculi. Mutation analysis of exon 2 of PVRL1 revealed a novel homozygous nonsense mutation, c.400C>T (p.Arg134*). His parents were heterozygous for the mutant alleles. All four PVRL1 mutations identified in cleft lip/palate-ectodermal dysplasia syndrome to date, including this study, resulted in truncated proteins that lack the transmembrane domain and intracellular domain of nectin-1, which is necessary to initiate the cell-cell adhesion process.

Predicting the short-term healing progress of pressure ulcers is important for providing timely and appropriate intervention. Although there are some prediction methods available, these are unsuitable for ulcers with abundant necrotic tissue. We aimed to elucidate the relationship between necrotic tissue alteration and protein distributions on ulcers to establish a new prediction method. Thirty-eight pressure ulcers were retrospectively analyzed. Protein distributions on necrotic tissue were evaluated by the wound blotting at three levels: marker protein positivity, signal patterns (speckled, heterogeneous, or homogeneous), and the occupation of heterogeneous pattern. Peroxidase, alkaline phosphatase, tumor necrosis factor α, and matrix metalloproteinase-2 were used as marker proteins. One-week necrotic tissue alteration was classified as liquefaction or nonliquefaction, and associations with protein distributions were analyzed. The peroxidase positivity was significantly higher in the liquefaction than in the nonliquefaction (p = 0.031). In peroxidase-positive samples, the proportion of nonliquefaction samples was significantly higher in the heterogeneous pattern (p = 0.029). In the heterogeneous-patterned samples, the proportion of samples with an occupation values greater than the median value tended to be higher in the nonliquefaction (p = 0.087). There was no significant relationship between liquefaction and other markers. Peroxidase positivity predicts 1-week liquefaction of necrotic tissue, while a heterogeneous pattern indicates nonliquefaction.

Purpose: Atopic dermatitis is characterized by decreased expression of filaggrin and loricrin. Patients with atopic dermatitis often suffer from skin infections, which are also frequently seen in patients with cutaneous T-cell lymphoma (CTCL). In this study, we aimed to investigate the skin barrier in CTCL. Experimental Design: We assessed skin moisture and transepidermal water loss (TEWL) in patients with CTCL. We next examined mRNA expression levels of filaggrin, loricrin, and antimicrobial peptides (AMP) in skin samples of CTCL, using skin from healthy volunteers and patients with atopic dermatitis or psoriasis as controls. Immunostainings for filaggrin, loricrin, and S100 proteins were also performed. Results: Lower levels of skin moisture accompanied by higher levels of TEWL were seen in lesional skin of CTCL than in normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with atopic dermatitis and psoriatic skin. mRNA expression levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and atopic dermatitis were significantly lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, atopic dermatitis, and psoriatic skin and enhanced expression of S100 proteins in psoriatic skin. Conclusions: Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with atopic dermatitis skin. In addition, low AMP expression in CTCL skin was documented when compared with psoriatic skin, which may explain frequent infections that can occur in patients with CTCL. Clin Cancer Res; 20(16); 4339–48. ©2014 AACR.

Early cutaneous T cell lymphoma clinically and histologically resembles benign inflammatory skin diseases, which sometimes makes it difficult to reach a correct diagnosis. It is recently reported that thymocyte selection-associated high mobility group box factor (TOX) serves as a molecular marker for histological diagnosis of early-stage mycosis fungoides (MF). To examine whether TOX could be a marker of tumour cells in different types of cutaneous lymphoma, we investigated immunohistochemical staining for TOX with the lesional skin of patch, plaque, and tumour MF, Sézary syndrome (SS), lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PCALCL), adult T cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), atopic dermatitis (AD), and normal skin. TOX and CCR4 messenger RNA (mRNA) levels in lesional skin of MF/SS were also examined. Immunohistological staining showed that a high specific nuclear staining of TOX was observed at a high frequency in MF, SS, and PTCL, NOS. Tumour cells in LyP, PCALCL, and ATLL showed a slightly dim nuclear staining of TOX. TOX(+) cells in MF and LyP expressed surface molecules characteristics of tumour cells in these diseases. Lesional skin of SS expressed higher levels of TOX mRNA, compared to normal skin or MF lesional skin. Moreover, TOX expression significantly correlated with CCR4 expression. TOX may be a specific marker for tumour cells in some types of cutaneous lymphoma.

Atopic dermatitis (AD) is a chronic or relapsing inflam-matory skin disease. Scratching in AD patients results in proinflammatory cytokine and chemokine production. Thus, serum levels of monocyte chemotactic protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES ), macrophage inflammatory pro-tein (MIP)-1β, eotaxin, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) were increased in AD patients, compared with normal controls (1–4). With regards to Th1 chemokines such as interferon (IFN)-γ-inducible protein 10 (IP-10), IFN-γ-inducible T-cell α-chemoattractant (I-TAC), and monokine induced by IFN-γ (MIG), their expression in le-sional AD skin was confirmed by immunohistochemistry ±(5). They may negatively contribute to the development of AD because macrophages from AD patients produced lower levels of IP-10 compared to cells from healthy con -trols in response to α-toxin (6) and the expression of MIG and IP-10 was lower in Langerhans cells from patients with AD than from patients with psoriasis, whereas the opposite was observed for TARC and MDC (7).Visual analogue scale (VAS) is a valuable method to assess pruritus intensity in patients with pruritic der-matoses (8). In this study , we focus on temporal variation of pruritus in each patient and compare serum samples taken at different time points when there were only slight, if any, changes in disease activity. The aim of this study was to highlight the most sensitive chemokine associated with changes in pruritus in AD patients. MATERIALS AND METHODS

Visfatin, a novel adipocytokine, is related with chronic inflammatory diseases, especially those characterized by T helper (Th)1-type immune responses. In this study, we examined serum visfatin levels in patients with atopic dermatitis (AD) or cutaneous T-cell lymphoma (CTCL), both of which are Th2-dominant diseases. Serum visfatin levels in patients with AD or advanced stage CTCL were significantly elevated compared to healthy controls. In CTCL patients, serum visfatin levels significantly decreased after treatment. Serum visfatin levels correlated with eosinophil counts in AD patients, whereas they correlated with the visual analogue scale itch scores and serum C-C motif ligand (CCL) 11 and CCL26 levels in CTCL patients. Visfatin expression by adipose tissue in lesional skin of AD and advanced stage CTCL was enhanced compared to that of healthy controls. These results suggest that visfatin may also be important in the development of Th2-dominant diseases as well as in Th1-type diseases.

The purpose of the present study is to assess the effect of nicorandil, a coronary vasodilator with a mechanism of potassium channel opening, on the abnormal myocardial 201Tl perfusion evoked by exercise. Eleven patients who had a history of typical angina, positive exercise electrocardiograms, positive 201Tl scintigraphy, nearly normal coronary arteriograms, and negative coronary vasospasm underwent exercise 201Tl scintigraphies under no medication (baseline test) and administration of nicorandil (nicorandil test). 201Tl was injected at a matched workload in both tests. Nicorandil did not alter heart rate, blood pressure, or the rate-pressure product at the end of the exercise, but it significantly improved the extent score from 0.37 +/- 0.22 to 0.20 +/- 0.15 (p0.05) and the severity score from 33.9 +/- 32.2 to 13.5 +/- 16.4 (p0.05), and also significantly hastened the 201Tl mean washout rate from 30.5 +/- 14.8% to 37.4 +/- 13.1% (p0.05). Anginal symptoms disappeared in 3 of 5 cases and ST depression improved in 5 of 7 cases after nicorandil. We conclude that nicorandil augments coronary flow reserve, possibly due to a reduction of vasotone in the small coronary arteries.

Cutaneous involvement is frequent in adult T-cell leukaemia/lymphoma (ATLL), a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus type I (HTLV-I). Patients with ATLL manifest different types of skin lesions, including nodules, plaques, ulcers, erythroderma and purpura. It has been reported that this type of skin eruption is an independent prognostic factor for ATLL. We report here a rare case of a 62-year-old Japanese woman with smouldering-type ATLL, first manifested by lichen planus-like skin lesions on the lower leg. This case report highlights the multiplicity of skin manifestations in ATLL.

Because wound exudate includes secreted proteins that affect wound healing, its biochemical analysis is useful for objective assessment of chronic wounds. Wound blotting allows for collection of fresh exudate by attaching a nitrocellulose membrane onto the wound surface. To determine its applicability for several analysis methods and its executability in clinical wound assessment, this study comprised an animal experiment and clinical case reports. In the animal experiment, full-thickness wounds were created on the dorsal skin of mice, and exudate samples were collected daily by a conventional method and by wound blotting. Extremely small but adequate volumes of exudate were collected by wound blotting for subsequent analysis in the animal experiments. Immunostaining showed the concentration and distribution of tumor necrosis factor (TNF) α. The activity of alkaline phosphatase was visualized by reaction with chemiluminescent substrate. The TNF distribution analysis indicated three different patterns: wound edge distribution, wound bed distribution, and a mostly negative pattern in both the animal and clinical studies, suggesting association between the TNF distribution pattern and wound healing. Our results indicate that wound blotting is a convenient method for biochemical analysis of exudate and a candidate tool with which to predict the healing/deterioration of chronic ulcers.

LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a ligand for HVEM. LIGHT–HVEM interactions are important in T helper type 1 (Th1) immune responses. In some cases with early stages of cutaneous T cell lymphoma (CTCL), IL-2, IFN-γ, and Th1 chemokines are expressed in lesional skin, while IL-4, IL-5, and Th2 chemokines are dominant in advanced CTCL. In this study, we investigated roles of LIGHT and HVEM in the microenvironment of CTCL. LIGHT enhanced production of Th1 chemokines, such as CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, from IFN-γ-treated dermal fibroblasts via phosphorylation of inhibitor κBα. Messenger RNA levels of these chemokines were increased in lesional skin of early CTCL. Interestingly, while LIGHT expression in CTCL skin correlated with disease progression, HVEM expression was significantly decreased in advanced CTCL skin. HVEM was detected in dermal fibroblasts in early CTCL skin, but not in advanced CTCL skin in situ. These results suggest that low HVEM expression on dermal fibroblasts in advanced CTCL skin attenuates expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment as disease progresses.

© 2014 The Authors. doi: 10.2340/00015555-1675 Journal Compilation © 2014 Acta Dermato-Venereologica. ISSN 0001-5555 Patients with mycosis fungoides (MF) typically have a prolonged clinical course. A small proportion of cases progress over years through patch, plaque and tumour stages, followed by lymph node and visceral involvement (1). Some cases of MF are difficult to distinguish from other skin diseases, such as psoriasis and atopic dermatitis. Currently, tumour necrosis factor (TNF)-α inhibitors, such as infliximab, adalimumab, and etanercept, are widely used for treating patients with moderate to severe psoriasis (2). Blockade of TNF-α, however, is profoundly immuno suppressive, resulting in reactivation of tuberculosis and histoplasmosis, as well as the emergence of malignant lymphomas (3). In fact, some cases with MF manifested by treatment with TNF-α inhibitors have been reported (4–7). We describe here a 60-year-old woman diagnosed with psoriasis who showed exacerbation of MF with large cell transformation during treatment with infliximab.

The concept of the Down syndrome critical region implies the existence of several dosage-sensitive genes that result in an abnormal phenotype when duplicated. Among the genes in the presumed Down syndrome critical region, DYRK1A and SIM2 are thought to be particularly important because of their critical roles in the development of the central nervous system in model organisms. Considering that regulatory imbalances resulting in an altered amount of expression from crucial target genes tend to produce phenotypic effects in both monosomics and trisomics, haploinsufficiency for the Down syndrome critical region is expected to be associated with an abnormal phenotype. We report on a patient with severe microcephaly, a developmental delay, hypospadias, and corneal opacity who had a microdeletion spanning the Down syndrome critical region, including DYRK1A and SIM2. He presented with intrauterine growth retardation, hypospadias, corneal clouding, arched eyebrows, upslanting and narrow palpebral fissures, bifid uvula, prominent nasal root, short columella, prominent central incisors, pegged shaped teeth, retrognathia, hypoplastic nipples, and severe developmental delay. His G-banded karyotype was normal, but array comparative genomic hybridization showed a de novo deletion of 3.97 Mb at chromosome 21q22. The extreme degree of microcephaly in this patient may be ascribed to the haploinsufficiency of DYRK1A, since brain size is severely reduced in heterozygotes for the Dyrk1a null mutation in mice.

We report the postoperative course of native and graft flow after coronary artery bypass grafting (CABG) in two patients with giant aneurysms and localized stenosis due to Kawasaki disease (KD). Although both patients had undergone CABG to the left anterior descending artery (LAD) with the left internal thoracic artery (ITA), at 5 and 10 years old, respectively, the ITA grafts were occluded 1 month postsurgery. However, when the two patients suffered complete occlusion of the native LAD more than 10 years after surgery, angiograms showed that the ITA grafts had reopened. We believe that this postoperative course reflects competition between the native artery flow and graft flow after CABG. CABG in patients with severely delayed coronary flows or recurrence of thrombus in giant aneurysms was ineffective in preventing myocardial infarction or damage. We conclude that CABG in giant aneurysm without significant localized stenosis should be avoided.

The action of vitamin D 3 on Langerhans cells (LCs) is not well understood. Using highly purified murine LCs (>95%), we investigated the direct action of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) on their functions. 1,25(OH) 2 D 3 inhibited the expression of cell surface molecules including I-A d , CD40, CD80, and CD86, leading to impaired ability of LCs to stimulate allogenic T cells in the mixed leukocyte reaction. Furthermore, this reagent inhibited chemotaxis of LCs to CCL21 and their survival. Interestingly, 1,25(OH) 2 D 3 reduced the IL-10 production by LCs, whereas the production of IL-6 and IL-12p40 upon activation by CD40 ligation was enhanced. With regard to inflammatory cytokines and chemokines, 1,25(OH) 2 D 3 upregulated the production of IL-1β, CCL3, CCL4, and CCL5. The production of Th2-type chemokines, represented by CL17 and CCL22, was inhibited, whereas IFN-γ-triggered production of Th1-type chemokines, represented by CXCL9, CXCL10, and CXCL11, was augmented. These data indicate that the mode of regulation of cytokine and chemokine production in association with 1,25(OH) 2 D 3 treatment seems to be another characteristic discriminating LCs from classical myeloid dendritic cells.

Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare clinical entity of unknown cause. It often coexists with various autoimmune or immunoreactive systemic diseases, and thus it has been reported under multiple names. We describe a patient with quiescent ulcerative colitis, who presented with recurrent small tender papules, nodules and erythematous plaques, located mainly on her hands, together with finger swelling and polyarthralgia. The histopathologic picture indicated an early stage of PNGD with focal degeneration of collagen fibers but without distinct granuloma formation. The differentiation from neutrophilic dermatoses was necessary because of dense and diffuse infiltration of neutrophils with leukocytoclastic debris throughout the dermis, and the association of ulcerative colitis. Dapsone monotherapy was effective in improving the clinical symptoms. PNGD is only rarely associated with ulcerative colitis, and this case suggests that the concept of PNGD, especially in its early stages, might be considered in the wide spectrum of neutrophilic dermatoses.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is thought to play an important role in the pathogenesis of atopic dermatitis. To examine whether GM-CSF single nucleotide polymorphisms (SNPs) are associated with susceptibility to atopic dermatitis, we investigated the genotype and allele frequencies of the SNPs 3606T/C and 3928C/T of the GM-CSF gene in 181 Japanese patients with atopic dermatitis and 100 controls, using a PCR restriction fragment length polymorphism method. A strong linkage disequilibrium existed between the polymorphisms 3606 and 3928, suggesting two common GM-CSF haplotypes, 3606*T-3928*C and 3606*C-3928*T. However, there was no significant difference in genotype or allele frequencies between patients with atopic dermatitis and controls for either of the two polymorphisms, thus GM-CSF SNPs do not appear to be associated with susceptibility to atopic dermatitis in Japanese patients. A large-scale study is necessary to confirm these findings.