Tadashi Terui

Prevalence of dermatological disorders in Japan: A nationwide, cross‐sectional, seasonal, multicenter, hospital‐based study

To clarify the prevalence of skin disorders among dermatology patients in Japan, a nationwide, cross‐sectional, seasonal, multicenter study was conducted in 69 university hospitals, 45 district‐based pivotal hospitals, and 56 private clinics (170 clinics in total). In each clinic, information was collected on the diagnosis, age, and gender of all outpatients and inpatients who visited the clinic on any one day of the second week in each of May, August, and November 2007 and February 2008. Among 67 448 cases, the top twenty skin disorders were, in descending order of incidence, miscellaneous eczema, atopic dermatitis, tinea pedis, urticaria/angioedema, tinea unguium, viral warts, psoriasis, contact dermatitis, acne, seborrheic dermatitis, hand eczema, miscellaneous benign skin tumors, alopecia areata, herpes zoster/postherpetic neuralgia, skin ulcers (nondiabetic), prurigo, epidermal cysts, vitiligo vulgaris, seborrheic keratosis, and drug eruption/toxicoderma. Atopic dermatitis, impetigo, molluscum, warts, acne, and miscellaneous eczema shared their top‐ranking position in the pediatric population, whereas the most common disorders among the geriatric population were tinea pedis, tinea unguium, psoriasis, seborrheic dermatitis, and miscellaneous eczema. For some disorders, such as atopic dermatitis, contact dermatitis, urticaria/angioedema, prurigo, insect bites, and tinea pedis, the number of patients correlated with the average high and low monthly temperatures. Males showed a greater susceptibility to some diseases (psoriasis, erythroderma, diabetic dermatoses, inter alia), whereas females were more susceptible to others (erythema nodosum, collagen diseases, livedo reticularis/racemosa, hand eczema, inter alia). In conclusion, this hospital‐based study highlights the present situation regarding dermatological patients in the early 21st century in Japan.

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.

B Cells Capturing Antigen Conjugated with CpG Oligodeoxynucleotides Induce Th1 Cells by Elaborating IL-12

APCs initiate T cell-mediated immune responses against foreign Ags. Dendritic cells are professional APCs that play unique roles, including Ag-nonspecific capture, priming of naive T cells, and Th1 induction, whereas B cells generally lack these functions. In this study we uncovered novel aspects of murine B cells as APCs using CpG oligodeoxynucleotides (CpG) conjugated with an Ag. B cells served as efficient APCs independently of surface Igs. This characteristic was underlaid by the CpG-mediated Ag uptake and presentation, which were functional only when CpG were covalently conjugated to Ag. The B cells cultured with CpG-conjugated Ag not only enhanced IFN-γ formation by Th1 cells, but also induced Th1 differentiation from unprimed T cells. These effects paralleled with the increase in the expression of CD40, CD86, and class II molecules on B cells and the coordinated production of IL-12 by the cells. To our knowledge this is the first report revealing that B cells share with dendritic cells common intrinsic characteristics, such as the Ag-nonspecific capture and presentation, and the induction of Th1 differentiation from unprimed T cells.

Dehydroepiandrosterone may be one of the regulators of cytokine production in atopic dermatitis.

Previous studies in mice have shown that dehydroepiandrosterone (DHEA) increases the production of Th1-associated lymphokines, and of interleukin-2 (IL-2) and interferon-gamma (IFN-γ), by lymphocytes. However, there are no reports concerning the effect of DHEA on the production of Th2-associated lymphokines, IL-4 and IL-5, by lymphocytes in humans. We examined serum DHEA levels in patients with atopic dermatitis (AD), which is thought to be associated with a higher activity of Th2 cells than of Th1 cells. We also studied the effects of DHEA on the production of IL-4 and IL-5 by human lymphocytes. Serum DHEA concentrations in 47 adult male patients with AD aged 19–30 years were significantly lower than those of 53 age-matched healthy male controls. Preincubation of peripheral blood mononuclear cells (PBMCs) with DHEA reduced the IL-4 production by concanavalin A-stimulated PBMCs. Their IL-5 production also showed a tendency to decrease. These results suggest that DHEA may be one of the regulators of IgE synthesis and eosinophil proliferation in patients with AD and it may act by controlling IL-4, IL-5 and IL-2 production by lymphocytes.

Accelerated Clearance of Escherichia coli in Experimental Peritonitis of Histamine-Deficient Mice

We prepared a model of experimental peritonitis by introducing Escherichia coli into the peritoneal cavity of the histamine-deficient mice generated by a disruption of the gene for histidine decarboxylase (HDC), the unique histamine-synthesizing enzyme. When we inoculated E. coli into the peritoneal cavities of the HDC−/− (histamine-deficient) mice, they eliminated E. coli more efficiently than did the wild-type mice. Histamine was released efficiently from the peritoneal cells after E. coli inoculation in HDC+/+ mice, although only trace amounts were detected in the peritoneal cells of HDC−/− mice. Two histamine agonists (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)hepatanecarboxamide (H1) and dimaprit (H2)) impaired the clearance of E. coli from the peritoneal cavity in HDC−/− mice, suggesting that the activation of both H1 and H2 receptors suppresses the clearance. In contrast, two kinds of H1 and H2 receptor antagonists, cimetidine and pyrilamine, promoted the clearance of E. coli in HDC+/+ mice. Phagocytosis appeared to be enhanced in HDC−/− mice, since the number of neutrophils in the peritoneal cavity of HDC−/− mice was markedly increased. This enhanced recruitment of neutrophils was suppressed in the presence of the histamine agonists, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)hepatanecarboxamide and dimaprit. In this report histamine was first shown to be an important mediator in an E. coli infectious peritonitis model, causing a delay in the elimination of bacteria. This also raised the possibility of the use of antihistamine drugs for bacterial infection.

Japanese guidance for use of biologics for psoriasis (the 2013 version)

The clinical use of adalimumab and infliximab, human anti‐tumor necrosis factor (TNF)‐α monoclonal antibodies, for psoriasis began in January 2010. In January 2011, ustekinumab, a human anti‐interleukin‐12/23p40 (IL‐12/23p40) monoclonal antibody, was newly approved as the third biologic with an indication for psoriasis. While all of these biologics are expected to exhibit excellent therapeutic effect for psoriasis and to contribute to the improvement of quality of life in patients, these drugs require careful safety measures to prevent adverse drug reactions, such as serious infections. The new guidance, an English version prepared by revising the Japanese Guidance/Safety Manual for Use of Biologics for Psoriasis 2011 (in Japanese), is intended to provide up‐to‐date, evidence‐based recommendations and safety measures on the use of biologics, and describes the optimal use of the three biologics, medical requirements for facilities for using biologics, details of safety measures against reactivation of tuberculosis and hepatitis B virus infection, and recommendable combination therapies with biologics.

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.

Aspirin and salicylates modulate IgE-mediated leukotriene secretion in mast cells through a dihydropyridine receptor-mediated Ca2+ influx

Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that may potentiate some acute allergies and causes adverse immunological reactions collectively referred to as aspirin intolerance. Aspirin intolerance is accompanied by increased leukotriene (LT) synthesis, and high levels of serum IgE are a risk factor for NSAID sensitivity. Here we demonstrate that aspirin modulates LTC(4) secretion in mast cells. Therapeutic levels of aspirin and salicylates (<or=0.3 mM, i.e., the concentrations observed in vivo in the use of antipyretic analgesic) increased IgE-mediated LTC(4) secretion. Aspirin-induced stimulation was accompanied by increased Ser-505 phosphorylation of cytosolic phospholipase A(2), which occurred independently of extracellular signal-regulated protein kinase-1/2 and p38 mitogen-activated protein kinase pathways. Aspirin also increased IgE-mediated Ca(2+) influx, whereas aspirin at concentrations of >or=0.3 mM dose-dependently reduced Ca(2+) store emptying and Ca(2+) release-activated Ca(2+) channel activation. Instead, aspirin facilitated a dihydropyridine receptor-mediated Ca(2+) influx, resulting in increased LTC(4) secretion. This novel action of aspirin may play roles in exacerbation of immediate allergy and aspirin intolerance.

Identification and analysis of an early diagnostic marker for malignant melanoma: ZAR1 intra-genic differential methylation

BACKGROUND Epigenetic changes such as aberrant DNA methylation and histone modification have been shown to play an important role in the tumorigenesis of malignant melanoma. OBJECTIVE To identify novel tumor-specific differentially methylated regions (DMRs) in human malignant melanoma. METHODS The aberrant methylation at 14 candidate human genomic regions identified through a mouse model study with quantitative DNA methylation analysis using the Sequenom MassARRAY system was performed. RESULTS The CpG island Exon 1 region of the Zygote arrest 1 (ZAR1) gene, which is responsible for oocyte-to-embryo transition, showed frequent aberrant methylation of 28 out of 30 (93%) melanoma surgical specimens, 16 of 17 (94%) melanoma cell lines, 0% of 4 normal human epidermal melanocyte (NHEM) cell lines, 0% of 10 melanocytic nevi and 100% of 51 various cancer cell lines. According to the real-time RT-PCR, the ZAR1 gene was overexpressed in part of the hypermethylated cell lines, while its low expression with bivalent histone methylation status was seen in unmethylated cell lines. CONCLUSION Our findings suggest that the ZAR1 intra-genic differentially methylated region would be a useful tumor marker for malignant melanoma and may be other type of cancers. The involvement of ZAR1 in the carcinogenesis of melanoma, still remains unclear, although we have examined tumorigenic capacities by exogenous full-length ZAR1 over-expression and siRNA knock-down experiments.

TGF-β-Producing CD4+ Mediastinal Lymph Node Cells Obtained from Mice Tracheally Tolerized to Ovalbumin (OVA) Suppress Both Th1- and Th2-Induced Cutaneous Inflammatory Responses to OVA by Different Mechanisms

Advances in the treatment of allergic disorders require elucidation of the autoregulatory immune systems induced in averting detrimental inflammatory responses against invading foreign Ags. We previously reported that excessive Ags intruding through the airway mucosa induce a subset of regulatory CD4+ T cells secreting TGF-β in the regional mediastinal lymph nodes (MLNs), which inhibits Th2 cells and subsequent eosinophilic inflammation in the trachea. In the present experiments we examined whether and in what mechanisms TGF-β-secreting CD4+ T cells in the MLNs regulate Th cell-mediated skin inflammation using a previously established murine model. Th1 or Th2 cells injected s.c. into ear lobes of naive mice induced swelling, whereas the concomitant local injection of MLN cells suppressed the inflammation. The suppressor activities of MLN cells were markedly neutralized by anti-TGF-β mAb and were mimicked by rTGF-β. The MLN cell- and rTGF-β-induced inhibition was reversed by anti-IL-10 mAb significantly in Th1-induced inflammation and only partially in Th2-induced inflammation. rIL-10 reduced Th-induced ear swelling, although higher doses of rIL-10 were required in Th2-induced one. Thus, allergen-specific TGF-β-producing CD4+ T cells induced in the respiratory tract controlled cutaneous inflammatory responses by Th1 or Th2 cells either directly by TGF-β or indirectly through IL-10 induction. From a clinical standpoint, these observations might explain the mechanism of spontaneous regression in some patients with atopic dermatitis, which exhibits both Th1- and Th2-mediated skin inflammation in response to airborne protein Ags.