Shinji Shimada

Mast Cells Play a Key Role in Host Defense against Herpes Simplex Virus Infection through TNF-α and IL-6 Production

The essential contribution of mast cells (MCs) to bacterial host defense has been well established; however, little is known about their role in viral infections in vivo. Here, we found that intradermal injection with herpes simplex virus 2 (HSV-2) into MC-deficient Kit(W/Wv) mice led to increased clinical severity and mortality with elevated virus titers in HSV-infected skins. Ex vivo HSV-specific tetramer staining assay demonstrated that MC deficiency did not affect the frequency of HSV-specific cytotoxic T lymphocytes (CTLs) in draining lymph nodes. Moreover, the high mortality in Kit(W/W-v) mice was completely reversed by intradermal reconstitution with bone marrow-derived MCs (BMMCs) from wild-type, but not TNF(-/-) or IL-6(-/-) mice, indicating that MCs or, more specifically, MC-derived tumor necrosis factor (TNF) and IL-6 can protect mice from HSV-induced mortality. However, HSV did not directly induce TNF-α or IL-6 production by BMMCs; supernatants from HSV-infected keratinocytes induced the production of these cytokines by BMMCs without degranulation. Furthermore, IL-33 expression was induced in HSV-infected keratinocytes, and blocking the IL-33 receptor T1/ST2 on BMMCs significantly reduced TNF-α and IL-6 production by BMMCs. These results indicate the involvement of MCs in host defense at HSV-infected sites through TNF-α and IL-6 production, which is induced by keratinocyte-derived IL-33.

Severe dermatitis with loss of epidermal Langerhans cells in human and mouse zinc deficiency

Zinc deficiency can be an inherited disorder, in which case it is known as acrodermatitis enteropathica (AE), or an acquired disorder caused by low dietary intake of zinc. Even though zinc deficiency diminishes cellular and humoral immunity, patients develop immunostimulating skin inflammation. Here, we have demonstrated that despite diminished allergic contact dermatitis in mice fed a zinc-deficient (ZD) diet, irritant contact dermatitis (ICD) in these mice was more severe and prolonged than that in controls. Further, histological examination of ICD lesions in ZD mice revealed subcorneal vacuolization and epidermal pallor, histological features of AE. Consistent with the fact that ATP release from chemically injured keratinocytes serves as a causative mediator of ICD, we found that the severe ICD response in ZD mice was attenuated by local injection of soluble nucleoside triphosphate diphosphohydrolase. In addition, skin tissue from ZD mice with ICD showed increased levels of ATP, as did cultured wild-type keratinocytes treated with chemical irritants and the zinc-chelating reagent TPEN. Interestingly, numbers of epidermal Langerhans cells (LCs), which play a protective role against ATP-mediated inflammatory signals, were decreased in ZD mice as well as samples from ZD patients. These findings suggest that upon exposure to irritants, aberrant ATP release from keratinocytes and impaired LC-dependent hydrolysis of nucleotides may be important in the pathogenesis of AE.

Antimicrobial Peptide LL-37 Produced by HSV-2-Infected Keratinocytes Enhances HIV Infection of Langerhans Cells

Herpes simplex virus (HSV)-2 shedding is associated with increased risk for sexually acquiring HIV. Because Langerhans cells (LCs), the mucosal epithelium resident dendritic cells, are suspected to be one of the initial target cell types infected by HIV following sexual exposure, we examined whether and how HSV-2 affects HIV infection of LCs. Although relatively few HSV-2/HIV-coinfected LCs were detected, HSV-2 dramatically enhanced the HIV susceptibility of LCs within skin explants. HSV-2 stimulated epithelial cell production of antimicrobial peptides (AMPs), including human β defensins and LL-37. LL-37 strongly upregulated the expression of HIV receptors in monocyte-derived LCs (mLCs), thereby enhancing their HIV susceptibility. Culture supernatants of epithelial cells infected with HSV-2 enhanced HIV susceptibility in mLCs, and this effect was abrogated by blocking LL-37 production. These data suggest that HSV-2 enhances sexual transmission of HIV by increasing HIV susceptibility of LCs via epithelial cell production of LL-37.

Oral Administration of the CCR5 Inhibitor, Maraviroc, Blocks HIV Ex Vivo Infection of Langerhans Cells within the Epithelium

TO THE EDITOR Preexposure prophylaxis (PrEP) with oral administration of an antiretroviral is a potential method for preventing acquisition of HIV. A controlled trial in men who have sex with men (the iPrEx trial) showed that daily oral use of tenofovir disoproxil fumarateemtricitabine (TDF-FTC; Truvada) reduced transmission rates by 44% (Grant et al., 2010). In addition, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission among HIV-negative heterosexual partners of HIV-positive individuals (Cohen et al., 2011). Similar trials, however, with TDF-FTC (the FEM-PrEP trial) or TDF alone (the VOICE trial) were stopped because of poor outcomes (van der Straten et al., 2012). Different results among various trials, which used identical antiretroviral regimens, could be explained by varying compliance with drug use and/or varying drug concentration and activity within the exposed tissue (Patterson et al., 2011). Langerhans cells (LCs) are CCR5þ dendritic cells located within genital skin and mucosal epithelium (Lederman et al., 2006). In female rhesus macaques exposed intravaginally to simian immunodeficiency virus, up to 90% of initially infected target cells were LCs (Hu et al., 2000). Ex vivo experiments with human foreskin explants show that epidermal LCs are target cells for HIV, providing a likely explanation for why circumcision greatly reduces the probability of acquiring HIV (Ganor et al., 2010). LCs also express CD4 and CCR5, but not CXCR4, within the tissue and demonstrate the distinctive characteristics of emigrating from tissue to draining lymph nodes in order to interact with T cells after contact with pathogens (Kawamura et al., 2000). Indeed, epidermal LCs are readily infected ex vivo with R5 HIV, but not with X4 HIV, and promote high levels of infection upon interaction with cocultured CD4þ T cells (Kawamura et al., 2000; Ogawa et al., 2013). Thus, LCs probably have an important role in disseminating HIV soon after exposure to virus. Epidemiologic observations have found that the majority of HIV strains isolated from patients soon after initial infection are R5 HIV strains (i.e., they utilize CCR5; Lederman et al., 2006). Not surprisingly, individuals with homozygous defects in CCR5 are largely protected from sexually acquiring HIV (Lederman et al., 2006). In addition, three different CCR5-binding topically applied compounds protected female macaques from sexually acquiring simian/human immunodeficiency virus: the N-terminally modified chemokine analog PSC-RANTES, the small-molecule inhibitor CMPD167, and maraviroc (MVC) (Lederman et al., 2006; Veazey et al., 2010). In addition to topical application to vaginal mucosa, oral delivery of CMPD167 protected macaques from vaginal simian/human immunodeficiency virus challenge (Veazey et al., 2005). Given these data, orally administered MVC may prove to be particularly important in PrEP regimens, although its ability to prevent HIV acquisition is unknown. In the current study, 20 healthy volunteers were randomly divided into four equal groups; they received 300 mg of MVC orally twice daily for 1, 2, 3, or 14 days. To obtain epidermal tissues, all subjects underwent suction blistering of the skin before and 2 hours after the last MVC dose. All subjects had plasma and semen collected 2 hours after their last dose. MVC concentrations in serum, semen, and epidermal tissues were determined by using the liquid chromatography– mass spectometry method, as described previously (Takahashi et al., 2010). Mean concentration±SD in the epidermis was 21.91±13.80, 23.36± 13.28, and 31.54±20.61 nM for individuals taking drug for 1, 2, or 3 days (n1⁄45 for each), respectively. MVC concentrations tended to be higher with a longer dosing period. Consistent with recent data showing high levels of MVC in genital tissue (Dumond et al., 2009), these results indicate that MVC rapidly distributes into the skin at high concentrations. In addition, MVC was detected in semen of all subjects (Supplementary Figure S1 online). To understand how HIV traverses skin and genital mucosa, an ex vivo model was developed whereby resident LCs within epithelial tissue explants are exposed to HIV and then allowed to emigrate from tissue, thus mimicking conditions that occur after mucosal exposure to HIV (Kawamura et al., 2000; Ogawa et al., 2013). In this model, although relatively few productively infected LCs are identified, these cells induce high levels of HIV infection when cocultured with resting autologous CD4þ T cells (Kawamura et al., 2000). In preliminary experiments, HIV infection of LCs, as well as subsequent virus transmission from emigrated LCs to cocultured CD4þ T cells, was decreased in a dose-dependent manner when skin explants were pretreated with various concentrations of MVC before See related commentary on pg 2662

Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells

We report a case of an 88‐year‐old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium‐to‐large‐sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death‐1 (PD‐1), Bcl‐6 and CXCL13. Flow cytometry analysis showed that CD4+ PD‐1hi T cells also expressed CD10, inducible T‐cell co‐stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T‐cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)‐cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH‐cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.

A case of oral mucosal fixed eruption caused by methacrylate

A 45-year-old otherwise healthy Japanese woman had suffered from multiple ulcers on her oral mucosa and blistering erythema on her hands for 2 years. She denied taking any medicines or dietary supplements. Oral mucosal and cutaneous examination showed sharply defined ulcers and erosions of her oral mucosa, and multiple sharply defined round bullous erythemas on her hands (Fig. 1a,b). The results of laboratory examinations were normal. In the serological tests, antibody titres for herpes simplex virus (HSV)-1 and HSV-2 were not elevated in her clinical course. Also, anti-desmoglein 1 and anti-desmoglein 3 antibodies were not detected. Biopsies were obtained from the buccal mucosal lesion (Fig. 2a) and the erythema on the back of her finger (Fig. 2b). Histological examination showed apoptotic keratinocytes in the epidermis, and infiltrating lymphocytes in the epidermis and dermis. Immunofluorescence analysis showed no deposition of IgM, IgG, IgA, or serum complement (C3). During follow-up, the patient’s symptoms were exacerbated after treatment of cavities. Two days after treatment, a blister appeared on her right lower buccal

Neutrophilic panniculitis with non-caseating granulomas in a Crohn's disease patient

ejd.2012.1737 Auteur(s) : Youichi Ogawa youichi73027@hotmail.com, Rui Aoki, Kazutoshi. Harada, Takamitsu Matsuzawa, Takashi Inozume, Naotaka Shibagaki, Tatsuyoshi Kawamura, Shinji Shimada Department of Dermatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato Chuo, Yamanashi 409-3898, Japan Crohns disease (CD) is an ulcerative granulomatous inflammatory disorder and accompanies numerous dermatologic complications, such as disease-associated skin findings (metastatic CD, contiguous perianal [...]

Gutter method: noninvasive management of ingrown nails caused by epidermal growth factor inhibitor treatment.

An ingrown nail with pyogenic granuloma (PG) is a stressful side-effect in patients treated with epidermal growth factor receptor (EGFR) inhibitors, because it is an intractable condition associated with pain and recurrence. We present a case of an ingrown nail caused by EGFR inhibitor treatment, which was treated using the gutter method. A 46-year-old woman presented with painful PG on the lateral nail fold of the right great toe (Fig. 1a). The lesion was noticed a few days before presentation, and the pain in the toe had gradually increased since then. The patient’s medical history included lung cancer with multiple brain metastases, for which she had been receiving treatment with gefitinib, an EGFR inhibitor, prescribed at a dose of 250 mg per day. The patient had developed a pruritic, maculopapular, erythematous, acneiform rash on her face after starting this drug, which had been treated with topical steroids. On physical examination, a painful granuloma-like nodule with crusting was seen in the lateral nail fold of the right toe, accompanied by paronychial inflammation. Based on these findings, a clinical diagnosis of ingrown nail caused by EGFR inhibitor treatment was made. We performed gutter-splint treatment using a plastic tube (Fig. 2). The size of the granulomatous lesion reduced almost immediately (Fig. 1b), and inflammation subsided within about 3 weeks after the treatment (Fig. 1c). Overexpression of EGFR has been associated with chemoresistance and poor prognosis in various tumours, including colorectal, ovarian, head and neck, breast, bladder and lung cancers. Treatment with EGFR tyrosine kinase inhibitors and EGFR-blocking antibodies can improve the prognosis for these patients. Because EGFR is expressed in keratinocytes of the interfollicular epidermis, outer root sheath, sebocytes, and some endothelial cells in the dermis, agents that inhibit EGFR are associated with dermatological sideeffects. The commonest cutaneous side-effects are acneiform rash, xerosis and hair abnormalities, with most patients experiencing a mild to moderate eruption that does not necessitate discontinuation of treatment. An ingrown nail or paronychia is one of the most stressful side-effects in patients receiving EGFR inhibitor treatment because it is associated with great pain in the affected toe. The incidence of paronychia was 17.7% in patients treated with cetuximab, another EGFR inhibitor. The pathogenesis of ingrown nails induced by EGFR inhibitor treatment remains unknown. It may be caused by skin fragility as a result of thinning of the stratum corneum, and reduced keratinocyte proliferation induced by the EGFR inhibitor. The nail penetrates the fragile skin of the nail fold, thereby leading to paronychia and PG formation. There are several treatments available to control the symptoms of ingrown nails, including nail-wedge resection, partial matrix phenolization, insertion of cotton wisps, topical antibiotic treatment and the gutter method. Nail-wedge resection can temporarily relieve paronychial inflammation, but the symptoms will recur as the nail grows. Partial matrix phenolization is an effective method for ingrown nails, but may result in severe damage to the nail fold and induction of onychogryphosis, and requires the use of phenol, which is a toxic agent. The cotton-insertion method is very easy to perform, but can be used only to treat slightly ingrown nails. In some cases, treatment with topical antibiotics suppresses an infection of the toe; however, paronychia due to EGFR inhibitor treatment is caused by invagination of the nail, and bacterial infection may PD

A case of dermatomyositis accompanied by spontaneous intramuscular hemorrhage despite normal coagulability

A 60-year-old man presented with a 1-month history of high fever and an erythematous rash on the back and trunk. Gottron’s papules and mechanic’s hand lesions were also observed. Muscle weakness was not detected by manual muscle testing. Laboratory examination showed elevations of creatine kinase (807 IU/l; 64–279) and aldolase (10.9 U/l; 2.1–6.1). Coagulation test was normal. Antinuclear antibody test result was positive, with a speckled pattern, and titer 1:80. Anti-DNA, anti-Jo-1, and anti-U1-RNP antibodies were negative. High-resolution computed tomography (HRCT) did not detect any internal organ abnormalities. An electromyogram of the muscles was normal. A muscle biopsy showed sparse infiltration of lymphocytes between the muscle fibers. On the basis of these findings, dermatomyositis was diagnosed. Administration of oral prednisolone (60 mg/day) was started. On day 25, patient was in respiratory failure. HRCT detected consolidation and ground glass opacities. Therefore, an i.v. pulse of methylprednisolone (1,000 mg/ day for 3 days) was initiated. Unfractionated heparin (UFH) (10,000 IU) was also started to prevent venous thrombosis. After this treatment, the patient had 2 episodes of spontaneous intramuscular hemorrhage. The first episode occurred after 6 days of pulse methylprednisolone treatment. The patient complained of rapid-onset back pain. A CT revealed intramuscular hemorrhage in the left deltoid with hematoma spread into the intra fascia (Fig. 1a). Activated partial thromboplastin time [APTT (89.2 s; normal range, 24.8–35.0)] was prolonged, and UFH administration was stopped. However, 3 days after the first hemorrhage, a second episode occurred despite normal coagulability. The patient complained of sudden cervical pain and a 12-cm subcutaneous hematoma was revealed with no injury detected. A CT demonstrated another intramuscular hematoma in the trapezius muscle (Fig. 1b). The patient’s hemoglobin had fallen from 97 to 67 g/l; coagulation parameters were all within normal ranges. The autoantibodies related to coagulation disorder were not detected. The patient needed a transfusion (2 units of packed red blood cells). The patient subsequently experienced an exacerbated IP and died. Dermatomyositis accompanied by spontaneous intramuscular hemorrhage is neither a recognized complication of dermatomyositis nor a side effect of its treatment. There have been 6 other reported cases of dermatomyositis accompanied by spontaneous intramuscular hemorrhages [1–5] (Table 1). In case 5, the patient had also received i.v. UFH, but APTT was normal [5]. The patients in cases 2 and 3 had not received any anticoagulant therapy [2]. In our case (no. 7, Table 1), the patient was treated with i.v. UFH and methylprednisolone. Therefore, there is a possibility that the first intramuscular hemorrhage was caused by abnormal coagulability. However, the coagulability at the time of the second hemorrhage was completely normal. We believe that the cause of the intramuscular hemorrhages observed in dermatomyositis patients with normal coagulability may imply the presence of intrinsic risk factors for spontaneous intramuscular hemorrhage in patients with dermatomyositis. Kissel et al. [6] found immune complex in the wall of intramuscular venules and arterioles, indicating that complement is deposited, bound, and activated within the intramuscular microvasculature in patients with dermatomyositis. In dermatomyositis, there is focal capillary depletion and the capillary density is significantly reduced [7]. These capillary changes were not revealed in F. Hanawa (&) T. Inozume K. Harada N. Andou T. Kawamura N. Shibagaki S. Shimada Department of Dermatology, University of Yamanashi, Faculty of Medicine, 110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan e-mail: fumieh@yamanashi.ac.jp

Case of rheumatoid papules: Is this a link between vasculitis and rheumatoid nodules?

necessity of oral steroid in addition to topical steroid, which is often enough to control typical EPDS. We speculate that systemic release of eosinophil chemotactic factors, possibly interleukin-5, may have occurred in our patient. However, further studies are required to elucidate the mechanism. Although skin biopsy of the erythroderma was unavailable, we suspect that this erythroderma was papuloerythroderma of Ofuji (PEO) because of the widespread erythematous papules with deck-chair sign. We speculate that the PEO-like erythroderma may have been caused by EPDS or the eosinophilia because the other diseases that can cause PEO were excluded. However, some unknown mechanisms might exist. As atypical lymphocytes have never been identified, we excluded cutaneous T-cell lymphomas from the differential diagnosis, but we are planning a careful follow up just in case. Sho HIROYASU, Daisuke TSURUTA, Takahisa YAMANE, Atsushi SHIOI, Hiromitsu TOYODA, Masamitsu ISHII, Hiromi KOBAYASHI Departments of Dermatology, 2 Cardiovascular Medicine and, Orthopedic Surgery, Osaka City University Graduate School of Medicine, and 4 Department of Hematology, Osaka City General Hospital, Osaka, Japan