Varicella zoster virus as a possible trigger for the development of pityriasis lichenoides et varioliformis acuta: retrospective analysis of our institutional cases.

Although numerous infective agents, including varicella zoster virus (VZV), have been described in association with pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC), none has been identified consistently in these lesions. We sought to immunohistochemically identify VZV glycoprotein (g)E antigens in the vascular endothelium in PLEVA and PLC lesions, based on our previous observation that gE was detected in the vascular endothelium and eccrine unit up until 2 months and 2.5, respectively, years after herpes zoster (HZ) infection. In five of the six cases of PLEVA, VZV gE was identified in the endothelial cells and eccrine epithelium, as observed in HZ lesions, whereas VZV gE was detected in only one of seven patients with PLC. None of the patients with PLEVA who had VZV gE-positive vascular endothelial cells had experienced previous episodes of HZ. VZV may be one of the aetiological agents for PLEVA while other aetiological factors could exist in PLC.

Lichen amyloidosus as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

BACKGROUND: Although a number of pathological processes resulting in amyloid deposition have been described in lichen amyloidosus (LA), no attention has been paid to the involvement of sweat glands/ducts in the pathogenesis of LA. According to recent studies, follicular structures are usually spared in serial histological sections of LA, and deposits of amyloid are likely to be confined to areas that display xerosis, suggesting that decreases in skin wetness by sweating disturbance seem to initiate LA. OBJECTIVES: To investigate whether sweating disturbance could represent an early event that triggers LA, and whether resolution of LA could be induced by restoring the sweating disturbance. METHODS: By using the impression mould technique, which allows an accurate quantification of individual sweat glands/ducts actively delivering sweat, we examined sweat responses to thermal stimulus in LA lesions before and after treatment with a moisturizer. RESULTS: Sweating disturbance was most profoundly detected in the 'hub' structure of the LA papule, and this disturbance due to leakage of sweat could be restored by short-term treatment with a moisturizer, particularly when used under occlusion. CONCLUSIONS: This study was limited by the relatively small sample size. Treatment of LA should be primarily directed at preventing leakage of sweat into the dermis or epidermis and therefore sweat delivery to the skin surface could be made easier.

The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represent contrasting poles of severe drug eruptions, and sequential reactivations of several herpesviruses have exclusively been demonstrated in the former. No previous studies, however, were extended beyond the acute stage. We sought to investigate whether herpesvirus reactivations could also be observed in SJS/TEN and beyond the acute stage of both diseases. METHODS: Patients with SJS (n = 16), SJS/TEN overlap (n = 2), TEN (n = 10), and DIHS/DRESS (n = 34) were enrolled. We performed a retrospective analysis of Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and cytomegalovirus (CMV) DNA loads sequentially determined by real-time polymerase chain reaction during a 2-year period after onset. RESULTS: Persistently increased EBV loads were detected in SJS during the acute stage and long after resolution, but not in others. In contrast, high HHV-6 loads were exclusively detected in DIHS/DRESS during the acute stage. The dynamics of herpesvirus reactivation varied in DIHS/DRESS according to the use of systemic corticosteroids: While EBV loads were higher in patients not receiving systemic corticosteroids, CMV and HHV-6 loads were higher in those receiving them. CONCLUSIONS: Distinct patterns of herpesvirus reactivation according to the pathological phenotype and to the use of systemic corticosteroids were observed during the acute stage and follow-up period, which may contribute, at least in part, to the difference in the clinical manifestations and long-term outcomes. Systemic corticosteroids during the acute stage may improve the outcomes in DIHS/DRESS.

Herpes simplex virus reactivation as a trigger of mucous lesions in pemphigus vulgaris.

BACKGROUND: Although infectious agents have long been implicated in the induction or exacerbation of pemphigus vulgaris (PV), a convincing role for the agent in the aetiology of PV has not been established. OBJECTIVES: To establish the association with PV and herpes simplex virus (HSV). PATIENTS AND METHODS: We examined saliva for the presence of HSV DNA after the onset of PV initially localized to the oral lesions in addition to conventional serological tests and immunohistochemistry. RESULTS: We successfully detected high levels of HSV DNA in the saliva samples from six of 16 patients with PV at the earliest stage, who had no episodes of herpes simplex. The prevalence (37·5%) of detecting HSV DNA in the patients with PV was lower than that of eczema herpeticum (56·5%), but comparable to that in patients with herpes labialis (30·0%). Copy numbers of the HSV DNA were rather higher than those with herpes labialis and with eczema herpeticum. In general, detection of HSV DNA in saliva was transient and restricted to the earliest phase of the disease. In addition, anti-HSV immunoglobulin (Ig) G titres in patients with PV were significantly higher than those in patients with virologically confirmed HSV-induced disorders. All salivary HSV DNA-positive patients with PV had run a more complex, intractable course refractory to conventional therapy. CONCLUSIONS: Detection of HSV DNA in saliva is a useful and noninvasive, quantitative method for establishing the role of HSV in the pathogenesis of PV and for identifying individuals at greater risk for subsequently developing refractory PV.

Detection of varicella-zoster virus antigens in lesional skin of zosteriform lichen planus but not in that of linear lichen planus.

BACKGROUND: Distinctions between 'linear lichen planus' (LP) and 'zosteriform LP' are difficult to determine solely based on clinical findings. OBJECTIVE: The aim of this study is to determine whether the presence of the varicella-zoster virus (VZV) antigens could be used to differentiate the zosteriform LP from the linear LP. METHODS: We immunohistochemically investigated the presence of in vivo localization of VZV antigens in 8 LP lesions (zosteriform LP: n = 5, linear LP: n = 3). RESULTS: We describe 2 cases of zosteriform LP without apparent prior episodes of herpes zoster, in whom VZV antigens were detected in the eccrine epithelium. Further analysis showed that VZV antigens were exclusively detected in the eccrine epithelium in the zosteriform LP lesions, but not in the linear LP lesions. CONCLUSION: Etiological differences exist between zosteriform LP and linear LP. The presence of VZV antigens in lesional skin of the former indicates a possible triggering role of this virus in the pathogenesis of this variant.

Varicella-zoster virus antigen expression of eccrine gland and duct epithelium in herpes zoster lesions.

BACKGROUND: It is well known that varicella-zoster virus (VZV) exhibits tropism for the epidermis and follicular epithelium, while little attention has been paid to eccrine gland and duct involvement by VZV. The presence of herpetic syringitis in immunocompromised hosts suggested the possibility of eccrine gland and duct involvement by VZV. OBJECTIVES: To determine whether VZV antigens could be detected in eccrine gland or duct epithelium of herpes zoster (HZ) lesions obtained at various intervals after the onset of a rash, and whether this expression could also be detected in eccrine units from other inflammatory disease lesions suggestive of VZV infection. METHODS: We investigated immunohistochemically in vivo localization of VZV glycoprotein E (gE) antigen in HZ lesions and control inflammatory disease lesions, using the murine monoclonal antibody directed against the VZV gE. RESULTS: VZV gE was differentially detected in the epidermis, follicular and eccrine epithelium, and dermal infiltrating cells in HZ lesions obtained at various intervals after onset. The VZV gE was most persistently detected in eccrine units, regardless of the age of individual HZ lesions, compared with keratinocytes and follicular epithelium. the ge expression was also observed in other inflammatory disease lesions suggestive of vzv infection. CONCLUSIONS: Immunohistochemical detection of VZV gE in eccrine epithelium can be a subtle clue to the diagnosis of HZ which displays most unusual manifestations, and VZV-related disorders.

Nonpigmenting fixed drug eruption as a possible abortive variant of toxic epidermal necrolysis: immunohistochemical and serum cytokine analyses.

Nonpigmenting fixed drug eruption (NPFDE) is clinically indistinguishable from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in its initial presentation. The traditional paradigm that epidermal changes are absent in NPFDE cannot be easily reconciled with the clinical resemblance to SJS/TEN. We therefore investigated whether NPFDE is pathogenetically different from pigmented FDE (PFDE) or SJS/TEN and which factors are responsible for the lack of hyperpigmentation. NPFDE lesions before challenge were characterized by larger numbers of CD8+ intraepidermal T cells associated with a paucity of melanocytes, compared with those in PFDE. Very high levels of serum interleukin (IL)-10 were noted after clinical challenge. We conclude that NPFDE is a clinical syndrome with heterogeneous histological expression. NPFDE with epidermal involvement may be an abortive form of SJS/TEN, in which progression to TEN can be prevented by IL-10.

Predictive biomarkers for cytomegalovirus reactivation before and after immunosuppressive therapy: A single-institution retrospective long-term analysis of patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic syndrome (DRESS).

OBJECTIVES: Cytomegalovirus (CMV) reactivation in patients with severe drug eruption on immunosuppressive therapy often leads to fulminant disease and even mortality, yet there are no biomarkers to accurately predict CMV reactivation either before or after immunosuppressive therapy. We aimed to assess whether patients who develop CMV reactivation (CMV-positive cases) have distinct immunological profiles from CMV-negative cases before and after immunosuppressive therapy. METHODS: We performed serial cytokine/chemokine and regulatory T cells (Tregs) assessments of 45 patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic syndrome (DRESS) during a follow-up period of nearly three years after onset. RESULTS: Elevated IL-8, IL-10, IL-12p40, IL-15, TNF-α, G-CSF, and MIP-1α levels at baseline were associated with later development of CMV reactivation, while after starting treatment, IL-10 and IL-15 levels were associated with the onset of CMV reactivation; the use of corticosteroids obscured the large differences in these cytokines at baseline. CMV-positive cases were found to have normal Tregs frequencies at baseline, while negative cases had elevated frequencies. Higher eotaxin, IL-10, and G-CSF levels and lower IL-12p40 levels at baseline might be used for predicting the development of lethal CMV disease. CONCLUSIONS: The algorithm based on these results showed an accurate association with CMV reactivation.

In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption.

BACKGROUND: Although a severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN), subsequent evolution of the two conditions is quite different. It remains unknown, however, which factors determine whether these lesions resolve spontaneously or subsequently progress to TEN. OBJECTIVES: Because epidermal injury in TEN can be locally reproduced in the evolving FDE lesions, we sought to investigate how epidermal damage can be induced in the evolving FDE lesions and how disease progression to TEN can be prevented, by analysing the FDE lesions induced by clinical challenge with the causative drug. METHODS: We immunohistochemically investigated in vivo dynamics of T-cell trafficking and activation that occur in the evolving FDE lesions using sequential biopsy specimens obtained at multiple time points from the FDE lesions. RESULTS: Intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable homogeneous population of memory T cells, transiently acquire a natural killer-like phenotype and express cytotoxic granules upon activation. The influx into the epidermis of CD4+ T cells including Foxp3+ regulatory T cells (Tregs) during the evolution serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells. Interleukin-15 derived from the lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells even in the absence of antigenic stimulus over a prolonged period of time (> 4 years). CONCLUSIONS: Whether Tregs could migrate to the lesions upon activation of intraepidermal CD8+ T cells would determine whether the inflammation becomes resolved spontaneously or progresses to TEN.

Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans.

One expected result from toxicogenomics technology is to overcome the barrier because of species-specific differences in prediction of clinical toxicity using animals. The present study serves as a model case to test if the well-known species-specific difference in the toxicity of coumarin could be elucidated using comprehensive gene expression data from rat in-vivo, rat in-vitro, and human in-vitro systems. Coumarin 150 mg/kg produced obvious pathological changes in the liver of rats after repeated administration for 7 days or more. Moreover, 24 h after a single dose, we observed minor and transient morphological changes, suggesting that some early events leading to hepatic injury occur soon after coumarin is administered to rats. Comprehensive gene expression changes were analyzed using an Affymetrix GeneChip approach, and differentially expressed probe sets were statistically extracted. The changes in expression of the selected probe sets were further examined in primary cultured rat hepatocytes exposed to coumarin, and differentially expressed probe sets common to the in-vivo and in-vitro datasets were selected for further study. These contained many genes related to glutathione metabolism and the oxidative stress response. To incorporate human data, human hepatocyte cultured cells were exposed to coumarin and changes in expression of the bridging gene set were examined. In total, we identified 14 up-regulated and 11 down-regulated probe sets representing rat-human bridging genes. The overall responsiveness of these genes to coumarin was much higher in rats than humans, consistent with the reported species difference in coumarin toxicity. Next, we examined changes in expression of the rat-human bridging genes in cultured rat and human hepatocytes treated with another hepatotoxicant, diclofenac sodium, for which hepatotoxicity does not differ between the species. Both rat and human hepatocytes responded to the marker genes to the same extent when the same concentrations of diclofenac sodium were exposed. We conclude that toxicogenomics-based approaches show promise for overcoming species-specific differences that create a bottleneck in analysis of the toxicity of potential therapeutic treatments.

Development and characterization of a monoclonal antibody specific for fucosyltransferase VII (Fuc-TVII): discordant expression of CLA and Fuc-TVII in peripheral CD4+ and CD8+ T cells.

Although cutaneous lymphocyte-associated antigen (CLA) is thought to be specifically expressed on skin "homing" T cells, it has become clear that CLA is not directly involved in binding to E-selectin but represents an excellent marker for high levels of fucosyltransferase VII (Fuc-TVII): Fuc-TVII can regulate the ability of T cells to migrate into the skin by generating a binding site for E-selectin. In this study, by using a novel monoclonal antibody for Fuc-TVII, we investigated whether expression of Fuc-TVII could be selectively detected in various CLA+ cell lines and peripheral blood T cells. Fuc-TVII was readily detected in the cytoplasm, but not in the membrane, of CLA+ cell lines. Cytoplasmic Fuc-TVII expression was also detectable in both CD4+ and CD8+ T cells purified from peripheral blood mononuclear cells. Nevertheless, there were significant numbers of CLA-expressing CD4+ or CD8+ T cells that did not coexpress Fuc-TVII, and vice versa: either the CD4+ or the CD8+ T cell population consisted of a variable ratio of CLA+ Fuc-TVII+, CLA+ Fuc-TVII-, and CLA- Fuc-TVII+ cells; and CLA+ Fuc-TVII- cells were the most abundantly identifiable phenotype in peripheral blood CD4+ and CD8+ T cells. Thus, according to their expression pattern, skin "homing" T cells can be subdivided into at least three populations, CLA+ Fuc-TVII+, CLA+ Fuc-TVII-, and CLA- Fuc-TVII+ cells. Our study provides convincing evidence that skin "homing" T cells are phenotypically heterogenous and that Fuc-TVII expression, in combination with CLA expression, is a useful phenotypic marker for identifying skin "homing" T cells in mixed cell populations.

Expression of cutaneous lymphocyte-associated antigen regulated by a set of glycosyltransferases in human T cells: involvement of alpha1, 3-fucosyltransferase VII and beta1,4-galactosyltransferase I.

Cutaneous lymphocyte-associated antigen (CLA), which plays a key part in skin homing of human CD4+ memory T cells via CLA/E-selectin binding, is upregulated by IL-12 and downregulated by IL-4. Although alpha1,3-fucosyltransferase VII is essential for synthesis of the CLA carbohydrate epitope, little is known about how the CLA expression is regulated by a number of glycosyltransferases. A 6 wk long-term culture for the in vitro differentiation of naïve Th cells to memory Th1 cells was employed. By repeated activation in the presence of IL-12, naïve T cells differentiated into memory Th1 cells, resulting in the upregulation of CLA expression. The switching of cytokine from IL-12 to IL-4 at three cycles resulted in a marked downregulation of CLA. The transcript levels of 16 glycosyltransferases and P-selectin glycoprotein ligand-1, all considered to be potentially involved in CLA synthesis, were determined after each cycle. The level of CLA expression was well correlated with the amounts of alpha1,3-fucosyltransferase VII and beta1,4-galactosyltransferase I. Both were upregulated by IL-12 and downregulated by IL-4. In particular, alpha1,3-fucosyltransferase VII levels decreased markedly in the presence of IL-4. P-selectin glycoprotein ligand-1 and Core 2 beta1, 6-N-acetylglucosaminyltransferase were progressively up-regulated by repeated IL-12 stimulation, but they were not downregulated by IL-4. The transcript levels of some genes examined were constitutive without any correlation to CLA expression. These results suggest that the level of CLA expression is determined by alpha1, 3-fucosyltransferase VII and beta1,4-galactosyltransferase I, the other enzymes merely participating in the synthesis of CLA. In peripheral blood mononuclear cells, IL-12 and IL-4 profoundly upregulated and downregulated the alpha1,3-fucosyltransferase VII transcripts, respectively, but not the beta1,4-galactosyltransferase I ones, within only 2 h of in vitro culture. This suggested that alpha1,3-fucosyltransferase VII is transcriptionally regulated directly by IL-12 and IL-4.

Virus-induced immune dysregulation as a triggering factor for the development of drug rashes and autoimmune diseases: with emphasis on EB virus, human herpesvirus 6 and hepatitis C virus.

There are a considerable amount of empirical and theoretic medical literature regarding the possible role of viruses in the development of drug rashes and autoimmune diseases: under these conditions, interactions of viruses with the immune system would serve as an accelerating factor of disease pathogenesis. Recent reports have provided evidence to indicate that immune responses against infections with Epstein Barr (EB) virus and human herpesvirus 6 (HHV-6), which are lymphotropic members of the herpes virus group, not only aid the direct elimination of the virus but also contribute to a favorable milieu for the initiation or acceleration of drug rashes. Viruses that can persist for the lifetime of the host despite strong immune responses against them, such as EB virus and hepatitis C virus (HCV), would be also relevant to the pathogenesis of autoimmune diseases. HCV has been reportedly associated with a wide variety of dermatoses that, in common, show histologically the lichenoid tissue reaction. Although porokeratosis that manifests lichenoid histopathological features had long been regarded as being associated with immunosuppression, we found that HCV could act as trigger for the development of porokeratosis during states of immunosuppression. Thus, the main purpose of this review is to describe recent work on the etiology of drug rashes and autoimmune disease with special reference to viral infections.

An immunohistochemical study of beta1,4-galactosyltransferase in human skin tissue.

An immunohistochemical investigation of beta1,4-galactosyltransferase (beta1,4-GalT) on human skin tissue was performed on formalin-fixed paraffin-embedded sections using a monoclonal antibody, MAb8628, which specifically recognizes a protein moiety of human beta1,4-GalT. Distribution of the galactose beta1,4-N-acetylglucosamine (Gal beta1,4GlcNAc)-R epitope was also detected by staining with Ricinus communis agglutinin (RCA) 120. The beta1,4-GalT was observed to be localized at the perinuclear region of epidermal keratinocytes. The fine localization was also observed at the supranuclear region in the cells of apocrine glands, eccrine ducts and glands. The positive staining with RCA 120 was well colocalized with the cells expressing the beta1,4-GalT. An electron microscopic study revealed that positive signals of beta1,4-GalT definitely reside in the Golgi apparatus. No immunoreactivity was observed in any other intracellular structure or on the cell surface. These findings strongly indicated that the beta1,4-GalT is the major enzyme responsible for the Gal beta1,4GlcNAc-R epitope synthesis in human skin tissue.

Microbial phosphorylation of compactin (ML-236B) and related compounds.

Several fungal strains were found to convert compactin (ML-236B) to 5'-phosphocompactic acid. The product was isolated by solvent extraction and column chromatography, and identified by IR, UV, 1H NMR, 13C NMR and 31P NMR spectroscopy. Related structures (monacolin K, L and X) were also transformed to their corresponding phosphorylated analogues. The products were re-converted back to respective parental compounds by treatment with alkaline phosphatase of calf intestine.

The cytokine profile in a transient variant of angioedema with eosinophilia.

Episodic angioedema with eosinophilia is characterized by recurrent angioedema, fever and weight gain with a remarkable eosinophilia. A transient type, predominantly reported in Japan, in which the disease is limited to a single attack, is usually less severe than the episodic type described in the U.S.A. and Europe, and provides an ideal disease model in which to study the mechanisms for resolution of eosinophilic inflammation. The aim of this study was to evaluate the relationship between cytokine responses and clinical course in three patients with the transient type. Serum levels of interleukin (IL) -5 were only marginally elevated even during an attack, unlike those in reported cases of the episodic type. Significant elevations in granulocyte-macrophage colony-stimulating factor levels were also noted during an attack in two cases in which it was measured. A dramatic increase in tumor necrosis factor (TNF) -alpha levels was subsequently observed in relation to resolution of clinical symptoms. No major changes in the serum levels of soluble Fas and soluble Fas ligand were found throughout the course. These results suggest that relatively lower levels of IL-5 and a subsequent increase in TNF-alpha levels are characteristic features of the transient type. The differences in clinical symptoms and course observed between the two types may be partly explained by the differences in the cytokine profiles.