Shigeki Ikeya

Biochemical, cytological, and immunological mechanisms of rhododendrol-induced leukoderma

Recently, an unexpected outbreak of patients with leukoderma occurred in Japan with the use of brightening/lightening cosmetics containing rhododendrol (RD). Patients developed leukoderma mostly on the skin sites repeatedly applied with RD, but some patients also had vitiligo-like lesions on the non-applied sites. RD is a tyrosinase-competitive inhibiting substance, thereby serving as an inhibitor of melanin synthesis. Upon inhibition of tyrosinase, RD is converted to new products such as tyrosinase-catalyzed hydroxyl-metabolite, which damage melanocytes. The melanocyte cell lysates seem to induce T-cell response. The frequencies of CD8+ T cells in both lesional skin and peripheral blood are significantly higher in the RD leukoderma as well as non-segmental vitiligo patients than in normal controls. In HLA-A*02:01 positive cases, circulating Melan-A-specific cytotoxic T cells can be detected at a high frequency. It is thus suggested that RD-induced leukoderma is induced by not only cytolysis of melanocytes but also subsequent immune reactions toward melanocytes.

Proteome analysis of stratum corneum from atopic dermatitis patients by hybrid quadrupole-orbitrap mass spectrometer

may also be anti-inflammatory by reducing nuclear factor kappa B gene expression. Similarly, in addition to their inflammatory role, Langerhans cells are thought to have immunoregulatory functions. Indeed, we see that langerin cells are largely reduced in lesional than in nonlesional AD skin at baseline, and significantly increase on clinical reversal after 12 weeks of CsA treatment (Fig 1, E, and Table E3). In addition to the RDGP, other possible mechanisms for disease recurrence in the same areas need to be considered, including (1) regional differences (increased humidity/friction, transepidermal water loss, pH, and lipids) that allow increased antigen penetration, (2) epigenetic modifications, and (3) microbiome differences. In summary, we have demonstrated that although the CsA RDGP is much smaller than the NB-UVB RDGP, important structural defects and residual inflammation remain and the overall size of the RDGP does not predict relapse kinetics. Given that NB-UVB and CsA have different courses of disease maintenance on discontinuing therapy, some elements in the RDGP of each treatment might explain relevant treatmentand disease-specific mechanisms. Mariya Rozenblit, BA Mayte Suarez-Farinas, PhD Avner Shemer, MD Saakshi Khattri, MD Patricia Gilleaudeau, NP Mary Sullivan-Whalen, NP Xiuzhong Zheng, MSc Hui Xu, MSc Irma Cardinale, MSc James G. Krueger, MD, PhD Emma Guttman-Yassky, MD, PhD

Linear IgA bullous dermatosis following human papillomavirus vaccination

ejd.2012.1851 Auteur(s) : Shigeki Ikeya1 shigeki450@yahoo.co.jp, Shoko Urano1, Yoshiki Tokura2 1 Section of Dermatology, JA Shizuoka Koseiren Enshu Hospital, Hamamatsu 430-0929, Japan 2 Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan Linear IgA bullous dermatosis (LABD) is characterized by linear deposits of IgA at the basement membrane zone (BMZ) with IgA autoantibodies directed against several different antigens in the BMZ. Most cases are idiopathic, but medications, [...]

Voriconazole-induced photocarcinogenesis is promoted by aryl hydrocarbon receptor-dependent COX-2 upregulation

Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown. Here, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in human keratinocytes (KCs). Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway. Our findings suggest that the phototoxic moieties of VRCZ metabolites may participate in the initiation phase of VRCZ skin cancer, while VRCZ per se promotes the tumor development. Therefore, during VRCZ therapy, sun exposure protection is essential to prevent photocarcinogenesis caused by VRCZ metabolites plus UV. Chemoprevention with selective COX-2 inhibitors may be helpful to repress the development of skin cancers derived from DNA-damaged KCs.

Successful differentiation of herpes zoster-associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis.

The polymerase chain reaction (PCR) assay for varicella zoster virus (VZV), herpes simplex virus (HSV)‐1 and HSV‐2 is available for use. Sometimes the differential diagnosis of the generalized herpes zoster (HZ), HSV1/2, and drug eruption is difficult. We report a case of HZ followed by the vesicular erythema multiforme (EM)‐like lesion. In this case the use of PCR was of great assistance. A 78‐year‐old Japanese man without any significant previous history of disease was admitted to our hospital complaining of zosteriform vesicle on an erythematous base from his right shoulder to the upper arm. We diagnosed him with HZ at the level of right Th2. In spite of the prompt start of antiviral therapy, a secondary new vesiculous erythema developed on his trunk. Clinically, it was quite difficult to differentiate the lesion from the generalized HZ. Rapid PCR assay of effusion and crust for VZV was performed. A PCR assay of VZV was positive for the crust taken from the primary lesion, while it was negative for the effusion and crust of the secondary widespread lesion. We diagnosed the secondary widespread lesion as an EM‐type drug eruption induced by acyclovir, or an EM associated with herpes zoster. We then stopped the use of acyclovir and applied steroid ointment of a very strong class for the secondary lesions, which improved after a few days. A PCR assay for VZV was useful for ruling out the generalized HZ in our case with secondary developed vesiculous lesions.

Emergence of Photosensitivity with Decreased Treg Cells in a Patient with Mycosis Fungoides Treated with Anti-CC Chemokine Receptor 4 Antibody Mogamulizumab.

Mogamulizumab is a therapeutic monoclonal antibody that targets the CC chemokine receptor 4 (CCR4). The treatment exhibits strong cytotoxicity for adult T-cell leukaemia/lymphoma (ATLL) cells via antibody-dependent cellular cytotoxicity (ADCC), although it carries the risk of serious adverse reactions to the skin, such as StevensJohnson syndrome (1, 2). We report here a patient with mycosis fungoides (MF) at tumour stage treated with mogamulizumab, who developed a photosensitivity reaction during the course of treatment. At the onset of photosensitivity, a reduction in both circulating and skin infiltrating regulatory T cells (Tregs) was observed.

Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment

BACKGROUND Sensitive skin is a condition of cutaneous hypersensitivity to environmental factors. Lactic acid stinging test (LAST) is commonly used to assess sensitive skin and composed of four distinct sensations (pain, burning sensation, itch, and crawly feeling). A link between sensitive skin and barrier dysfunction has been proposed in atopic dermatitis (AD) patients. However, clinical and laboratory factors that are associated with sensitive skin remain unelucidated. OBJECTIVE To investigate relationship between sensitive skin and AD-associated markers. METHODS Forty-two Japanese AD patients and 10 healthy subjects (HS) were enrolled. AD patients were divided into extrinsic (EAD; high IgE levels) and intrinsic (IAD; normal IgE levels) types. We conducted 1% LAST by assessing the four distinct sensations and calculated the frequencies of sensitive skin in EAD, IAD, and HS. We also performed clinical AD-related tests, including transepidermal water loss (TEWL), visual analogue scale (VAS) of pruritus, and quality of life, and measured laboratory markers, including blood levels of IgE, CCL17/TARC, lactate dehydrogenase (LDH) and eosinophil counts, and concentration levels of serum Th1/Th2 cytokines. Filaggrin (FLG) mutations were examined in 21 patients. These values were subjected to correlation analyses with each of the four sensation elements. RESULTS According to the standard criteria for LAST positivity, the frequencies of LAST-positive subjects were 54.8% and 10.0% in AD and HS, respectively (P=0.014). EAD patients showed a significantly (P=0.026) higher frequency of positive LAST (65.6%) than did IAD patients (20.0%). Among the four LAST sensation elements, the crawly feeling and pain scores positively correlated with VAS of pruritus, total serum IgE, mite-specific IgE, CCL17/TARC, and/or LDH. There was no association of the LAST scores with serum Th1/Th2 cytokine levels. Notably, neither TEWL nor FLG mutations correlated with LAST positivity or any sensation scores. CONCLUSIONS The frequency of sensitive skin is higher in EAD than in IAD. Sensitive skin is associated with AD severity, but not necessarily with barrier condition.

Atopic dermatitis presenting as generalized poikiloderma with filaggrin gene mutation.

Dear Editor, Poikiloderma is a characteristic skin condition consisting of pigmentation, depigmentation, telangiectasia and atrophy, and is seen in a number of diseases. Here, we report a patient with atopic dermatitis (AD) with filaggrin (FLG) gene mutation, presenting as marked generalized poikiloderma. A 26-year-old man was referred to us for evaluation of his recalcitrant itchy eruption. In his childhood, the patient had asthma and eczematous lesions, diagnosed as AD, which gradually turned to poikiloderma in his late teens. His AD had been treated with topical corticosteroids, but he denied their extensive usage. On examination, the patient had a poikilodermatous eruption on the chest (Fig. 1a) and back (Fig. 1b), extending to the neck and proximal parts of the limbs. The eruption was a mixture of small pigmentary and depigmentary elements with fine telangiectasia (Fig. 1c). Concomitantly, there were eczematous lesions on the antecubital fossae and dorsal aspects of the hands. He had palmar hyperlinearity (Fig. 1d) and scaly dry skin on the extremities, especially on the shins. No photosensitivity, nail abnormality or cataracta was found. His SCORAD level was 50.5, and visual analog scale of pruritus was 41. Laboratory examination revealed high levels of total serum immunoglobulin (Ig)E (13 207 kU/L; normal, <160) and serum CCL17/TARC (1124 pg/mL; normal, <450). The following values were normal or negative: complete blood counts, leukocyte differentiation, antinuclear and anti-DNA antibodies, complements and soluble interleukin-2 receptor. Histopathologically, a biopsy from poikiloderma showed moderate elongation of rete ridges with melanosis on their tips (Fig. 1e). There was a perivascular infiltrate of lymphocytes intermingled with melanophages in the upper dermis. Cellular atypia of lymphocytes was not observed. The patient’s blood was subjected to FLG mutation analysis to detect the eight reported mutations specific to Japanese (R501X, 3321delA, S1695X, Q1701X, S2554X, S2889X, S3296X and K4022X). Genotyping was performed using polymerase chain reaction and restriction enzyme digest analysis,

Erythrokeratodermia variabilis: first Japanese case documenting GJB3 mutation.

Dear Editor, Cell–cell communication mediated by gap junctions, consisting of connexins, is a crucial function of all cells in multicellular organisms to maintain tissue homeostasis, synchronize their response, and control growth and development. Erythrokeratodermia variabilis (EKV; Online Mendelian Inheritance in Man no. 133200) is an autosomal dominant or recessive genodermatosis characterized by the coexistence of transient erythematous patches and fixed hyperkeratotic plaques. EKV is caused by pathogenic mutations in connexin genes, GJB3 and GJB4 coding for the connexin proteins Cx31 and Cx30.3, respectively. Here, we describe a Japanese case of EKV documented for the first time to have a missense mutation in GJB3 and confirmed the low expression of Cx31 in the patient’s epidermal keratinocytes. A 2-year-old Japanese girl presented with a generalized erythematous eruption. The patient developed erythematous lesions on her cheeks at birth, which extended to other body sites at the age of 3 months. She was born to non-consanguineous, unaffected parents. On examination, she had asymptomatic, irregularly shaped, sharply demarcated, erythematous patches on her cheeks, trunk (Fig. 1a) and four extremities (Fig. 1b). These lesions were transient, but reappeared repeatedly. Persistent indurated erythematous plaques were also found on the lower limbs (Fig. 1b). Her palms and soles were remarkably hyperkeratotic (Fig. 1c). Her whole body was covered with fine scales. Histopathological examination obtained from a calf plaque showed hyperkeratosis and papillomatosis, representing the “church spire” configuration (Fig. 2a). A mild dermal lymphocytic infiltrate was observed. Gene analysis of her blood cells disclosed a heterozygous G?C transition at nucleotide 125 (c.125G>C) of GJB3, leading to the substitution of arginine 42 by proline (R42P). No mutation was found in GJB4. Deparaffinized sections of the biopsy specimen were immunohistochemically stained for Cx31. A specimen from the same site of a normal individual of the same age was used as control. Positive intercellular staining was found in the upper half of the epidermis of the normal skin (Fig. 2b). However, the patient’s skin showed no intercellular staining for Cx31, although it exhibited a cytoplasmic expression pattern of Cx31 (Fig. 2c). The patient was treated with topical emollients, keratolytics and corticosteroids with limited improvement. Her parents did not consent to gene analysis. Several mutations in GJB3 and GJB4 have been found mainly in the European patients with EKV. Nakamura et al.

Langerhans cell histiocytosis presenting as a nodule beneath the clitoral hood

ease. However, our case had been administrated none of those therapies and did not have any serious complication other than hypertension and diabetes. Furthermore, there has been no other report with multiple apocrine poroma or only two lesions like our case, or poromatosis including apocrine poroma. From those facts, our case might have occurred accidentally, however, experiences of more cases will be required to speculate whether the case with multiple apocrine poroma was accidental or not.