Koremasa Hayama

Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria.

BACKGROUND Wheal reactions to intradermally injected neuropeptides, such as substance P (SP) and vasoactive intestinal peptide, are significantly larger and longer lasting in patients with chronic urticaria (CU) than in nonatopic control (NC) subjects. Mas-related gene X2 (MrgX2) has been identified as a receptor for basic neuropeptides, such as SP and vasoactive intestinal peptide. Mast cell (MC) responsiveness to eosinophil mediators contributes to the late-phase reaction of allergy. OBJECTIVE We sought to compare the frequency of MrgX2 expression in skin MCs from patients with CU and NC subjects and to identify the receptor for basic eosinophil granule proteins on human skin MCs. METHODS MrgX2 expression was investigated by using immunofluorescence in skin tissues from NC subjects and patients with severe CU and on skin-derived cultured MCs. MrgX2 expression in human MCs was reduced by using a lentiviral small hairpin RNA silencing technique. Ca(2+) influx was measured in CHO cells transfected with MrgX2 in response to eosinophil granule proteins. Histamine and prostaglandin D2 levels were measured by using enzyme immunoassays. RESULTS The number of MrgX2(+) skin MCs and the percentage of MrgX2(+) MCs in all MCs in patients with CU were significantly greater than those in NC subjects. Eosinophil infiltration in urticarial lesions was observed in 7 of 9 patients with CU. SP, major basic protein, and eosinophil peroxidase, but not eosinophil-derived neurotoxin, induced histamine release from human skin MCs through MrgX2. CONCLUSION MrgX2 might be a new target molecule for the treatment of wheal reactions in patients with severe CU.

Significantly High Levels of Anti-dsDNA Immunoglobulin E in Sera and the Ability of dsDNA to Induce the Degranulation of Basophils from Chronic Urticaria Patients

Background: Chronic urticaria (CU) appears to be of autoimmune origin in about half of all patients, since several autoreactive immunoglobulin Gs (IgGs), such as anti-FcεRIα and anti-IgE, are detected in the sera of such patients. However, whether autoreactive IgE is associated with CU remains unclear. In this study, we attempted to identify autoreactive IgE antibodies in sera from patients with CU. Methods: Sera were collected from 67 normal subjects, 85 patients with CU and 28 patients with atopic dermatitis (AD). An autologous serum skin test (ASST) was performed on 27 of the CU patients. Autoreactive IgE and IgG levels against self-antigens were measured using enzyme-linked immunosorbent assays. The basophils were activated with dsDNA, and the CD63 expression level was examined using a fluorescence-activated cell sorter. Results: The anti-dsDNA IgE levels were significantly higher in patients with CU and AD than in normal subjects, but no differences in the anti-dsDNA IgG levels were seen. The levels of thioredoxin-, peroxiredoxin- and thyroglobulin-reactive IgE and IgG were not significantly higher in the CU patients than in the other 2 groups. There was no significant difference in the levels of anti-dsDNA IgE between ASST-positive and ASST-negative patients. The basophils from 2 out of 9 CU patients exhibited degranulation in response to dsDNA. Conclusions: Our data suggest that anti-dsDNA IgE is involved in the pathogenesis of some cases of CU.

Effectiveness of a heparinoid-containing moisturiser to treat senile xerosis

With the increasing elderly population in Japan, skin problems have become a greater concern. A heparinoid‐containing moisturiser is frequently used in Japan, but there is a lack of evidence for its efficacy in treating senile xerosis. To determine whether there is a correlation between age and the hydration state of the stratum corneum (SC) assessed by skin capacitance, and to evaluate the efficiency of a heparinoid‐containing moisturiser and a bed bath to treat senile xerosis.

Gold activates mast cells via calcium influx through multiple H2O2-sensitive pathways including L-type calcium channels

Heavy metals, including gold, induce severe contact hypersensitivity and autoimmune disorders, which develop through an initial Th2-independent process followed by a Th2-dependent process. It has been shown that mast cell activation plays a role in the Th2-independent process and that gold stimulates histamine release in vitro. However, the mechanisms of the gold-induced mast cell activation remain largely unclear. Here we report that gold directly activates mast cells in a Ca2+-dependent manner. HAuCl4 [Au(III)] at nontoxic concentrations (≤50 μM) induced substantial degranulation and leukotriene C4 secretion in an extracellular Ca2+-dependent manner. Au(III) induced a robust Ca2+ influx but not Ca2+ mobilization from internal stores. Au(III) also stimulated intracellular production of reactive oxygen species, including H2O2, and blockade of the production abolished the mediator release and Ca2+ influx. Au(III) induced Ca2+ influx through multiple store-independent Ca2+ channels, including Cav1.2 L-type Ca2+ channels (LTCCs) and 2-aminoethoxydiphenyl borate (2-APB)-sensitive Ca2+ channels. The 2-APB-sensitive channel seemed to mediate Au(III)-induced degranulation. Our results indicate that gold stimulates Ca2+ influx and mediator release in mast cells through multiple H2O2-sensitive Ca2+ channels including LTCCs and 2-APB-sensitive Ca2+ channels. These findings provide insight into the roles of these Ca2+ channels in the Th2-independent process of gold-induced immunological disorders.

A Case of Sporotrichosis Caused by Sporothrix globosa in Japan

Dear Editor: Sporotrichosis is the most common subcutaneous mycosis. Sporothrix schenckii was once considered a single species, but a recent study has demonstrated that S. schenckii is actually a complex of distinct species with similar morphological features, called the S. schenckii complex1. To our knowledge, this is the first case report of sporotrichosis caused by S. globosa, a member of the S. schenckii complex, in Japan. A 77-year-old Japanese man presented to our department with a three month history of crusted erythematous nodules on the dorsum of his right hand and forearm, in a linear arrangement (Fig. 1A). The right hand was scratched by a cat two weeks before the onset. Because sporotrichosis was suspected, a skin biopsy was performed. Histopathological examination demonstrated a mixed granulomatous reaction with focal neutrophilic microabscesses. Spores were identified in the tissue sections using periodic acid-Schiff stains (Fig. 1B). The biopsy specimen was also submitted for culturing, using enriched glucose-containing media and Sabourauds agar, at two different conditions, 25℃~27℃ and 35℃~37℃. Microscopic morphology obtained from the 25℃ culture showed septate hyphae and hyaline or slightly pigmented conidia that grouped in rosettes at the tips of the conidiophores (Fig. 1C). Interestingly, there was no conversion to the yeast form in the 37℃ culture. Because the features was atypical of classical S. schenckii, we considered the causative microorganism as another member of S. schenckii complex. Genetic analysis of DNA by polymerase chain reaction identified this agent as S. globosa with 99% homology compared to the known genetic sequence. Thus, we diagnosed this case as sporotrichosis caused by S. globosa. Three months of oral potassium iodide (1,200 mg/day) and two months of oral itraconazol (200 mg/day) achieved the resolution of the symptom. Fig. 1 (A) Skin lesion on the dorsum of right hand and forearm with multiple erythematous crusted nodules along lymphatics. (B) Periodic acid-Schiff stain (×200)

Electron microscopic observation of cholesterotic fibrous histiocytoma of the finger.

1 Enzinger FM, Harvey DA. Spindle cell lipoma. Cancer 1975; 36: 1852–1859. 2 Billings SD, Folpe AL. Diagnostically challenging spindle cell lipomas: a report of 34 “low-fat” and “fat-free” variants. Am J Dermatopathol 2007; 29: 437–442. 3 Chen BJ, Mari~ no-Enr ıquez A, Fletcher CD, Hornick JL. Loss of retinoblastoma protein expression in spindle cell/pleomorphic lipomas and cytogenetically related tumors: an immunohistochemcal study with diagnostic implications. Am J Surg Pathol 2012; 36: 1119– 1128.

Japanese guidelines for the management and treatment of generalized pustular psoriasis: The new pathogenesis and treatment of GPP

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.

Identification of biomarkers for predicting the response to cyclosporine A therapy in patients with chronic spontaneous urticaria

Cyclosporine A (CsA) is recommended as a third-line treatment for patients with chronic urticaria (CU) in the guideline of the European Academy of Allergy and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA2 LEN), the European Dermatology Forum (EDF), and theWorld Allergy Organization (WAO); i.e., CsA is recommended for use in patients with severe disease refractory to treatment with not only antihistamines, but also omalizumab.1 However, no useful biomarkers for predicting the therapeutic response to CsA in patients with chronic spontaneous urticaria (CSU) presently exist. This letter describes efforts to identify biomarkers for predicting the response to CsA therapy in patients with CSU. Thirty-four patients with CSU whose symptoms could not be controlled with second-generation H1-antihistamines at a dose of up to 2-fold of the recommended dose were treated with 3 mg/kg/day of CsA2 for 4 weeks in the Department of Dermatology, Nihon University School of Medicine, Japan. Their median age was 47 years (range, 18e82 years), and the median duration of their CSU was 18 months (range, 2e480 months, Table 1). Subjects were excluded if steroids had been used within 3 weeks. Blood tests, which included the serum IgE level, basophil counts, IgG anti-nuclear Abs, IgG anti-thyroglobulin Abs, and IgG antithyroid microsomal Abs, were performed. IgG autoantibodies (AAbs) to FcεRI a-chain (FcεRIa) and IgE were measured using ELISAs (see Supplementary Methods). The autologous serum skin test (ASST) was performed as described previously3 (see Supplementary Methods). The UAS7 is used to quantify the severity of pruritus and the number of hives appearing during a 1-week period.4 Five CSU health states were defined according to the UAS7: urticaria-free (UAS7 1⁄4 0); well-controlled urticaria (UAS7 1⁄4 1e6); mild urticaria (UAS7 1⁄4 7e15); moderate urticaria (UAS7 1⁄4 16e27); severe urticaria (UAS7 1⁄4 28e42).5 This study was approved by the Ethics Committee of the Nihon University School of Medicine, Japan. All the subjects provided written informed consent in accordance with the Helsinki Declaration of the World Medical Association. To identify variables associated with the response to CsA, we compared continuous variables between patients with a positive ASST and those with a negative ASST and between patients whose UAS7 was 6 and those whose UAS7 was >6 after treatment with CsA for 4 weeks using the Mann-Whitney-U test; to compare categorical variables, a 2-

Verrucous nevoid melanoma with satellite lesions on the scalp of a young man

A 32-year-old man presented to our outpatient clinic with a 1-month history of a gradually enlarging painful nodule on his left parietal region. Physical examination revealed a 3.0 9 3.5 cm papillomatous and slightly elevated tumor, which was gray–brown in the center and red– brown at the margin. Several small red papules were disseminated away from the tumor within the range of 1.5 cm (Fig. 1). The lymph nodes in his neck were not swollen. The patient had no pigmented macules or alopecia since birth. Levels of 5-S-cysteinyl DOPA were within normal limits. Systemic metastases were not found by computed tomography. An incisional biopsy was carried out and was histologically diagnosed as nevoid malignant melanoma (NMM). Three weeks later, the tumor was excised surgically, and a split-thickness skin graft was implanted under general anesthesia. The excised specimen showed hyperkeratosis with partial parakeratosis, papillomatosis of the epidermis, and an irregular proliferation of the tumor cells with strong nuclear atypia, mitoses, and hyperchromatism in the dermis. No pagetoid melanocytes Figure 1 A 3.0 9 3.5 cm papillomatous and slightly elevated tumor, which was gray–brown in the center and red–brown at the margin. Several small red papules were disseminated away from the tumor within the range of 1.5 cm