Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. METHODS: Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant-related DIHS (n = 6). RESULTS: Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV-6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. CONCLUSIONS: TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.

Sweet's syndrome associated with Mycobacterium avium infection.

A 68-year-old woman presented with a 3-month history of nontender, erythematous nodules on the right side of the neck. Subsequently, tender, circinate erythematous plaques appeared on the limbs, accompanied by peripheral leucocytosis. A biopsy specimen obtained from an erythematous plaque revealed diffuse infiltration of neutrophils in the dermis. Treatment with prednisolone improved the erythematous lesions, but upon tapering of prednisolone, numerous areas of indurated erythema with pustules recurred on the face and back accompanied by high fever. Computed tomography of the lung revealed multiple lesions. A smear of gastric juice contained acid-fast bacilli that were identified as Mycobacterium avium by DNA-DNA hybridization. Treatment with multiple antibiotics did not result in a favourable response of the M. avium infection, and dome-shaped, subcutaneous abscesses developed on the limbs and trunk. Sweet's syndrome may thus occur in association with nontuberculous mycobacterial infection.

Dramatic improvement of psoriatic erythroderma after acute hepatitis: analysis of cytokine synthesis capability in peripheral blood T cells.

We report a patient with psoriasis and hepatitis C virus infection who initially presented with psoriatic erythroderma and eventually showed complete clearance of psoriatic lesions following acute hepatitis induced by etretinate treatment. Cytokine synthesis capabilities in peripheral blood T cells obtained at different stages were evaluated in this patient. A dramatic increase in the frequency of interferon-gamma-producing CD8+ T cells in peripheral blood was observed during the erythrodermic stage. In contrast, the frequencies of interleukin (IL)-4- and IL-13-producing CD4+ T and CD8+ T cells were remarkably high at the resolution stage. These results clearly indicate that a shift towards type 2 cytokine predominance contributes to the resolution of severe psoriasis.

Homing receptor and chemokine receptor on intraepidermal T cells in psoriasis vulgaris.

Intraepidermal T lymphocytes found in psoriatic skin lesions are involved in the development and maintenance of lesional pathology. It has become clear that differential expression of homing and chemokine receptors determines the specific migration of T cells to distinct tissues and microenvironments, including psoriasis lesions. The aim of the present study was to clarify expression of homing (CLA, VLA-4, and LFA-1) and chemokine (CCR4, CCR6, CCR7, and CXCR3) receptors on intraepidermal T cells in psoriatic lesions using flow cytometry. The vast majority of intraepidermal T cells in psoriatic lesions expressed CLA and LFA-1, whereas 58% of CD4+ and 85% of CD8+ T cells expressed VLA-4. The majority of CD4+ T cells and about half of the CD8+ T cells expressed CCR4 and CCR6, whereas less than one-third of CD4+ and CD8+ T cells expressed CXCR3 or CCR7. In patients with psoriasis the percentages of T cells expressing CLA, CCR4, and CCR6 were much higher in the epidermis of psoriatic plaques than in the peripheral blood. Thus, CLA, CCR4, and CCR6 may play a more important role in the migration of T cells to psoriatic epidermis.

Preferential expression of alphaEbeta7 integrin (CD103) on CD8+ T cells in the psoriatic epidermis: regulation by interleukins 4 and 12 and transforming growth factor-beta.

BACKGROUND: Intraepidermal T lymphocytes are a critical element for sustaining the lesional pathology of psoriasis. Integrin alphaEbeta7 (CD103), a ligand for E-cadherin, may play a role in the localization of pathogenic T cells within the epidermis of psoriatic lesions. However, little information is available regarding alphaEbeta7 expression on intraepidermal T cells in psoriasis. OBJECTIVES: To examine alphaEbeta7 expression on intraepidermal T cells in psoriatic lesions and the regulation of alphaEbeta7 expression on T cells in response to cytokines. METHODS: T-cell expression of alphaEbeta7 was examined by immunohistochemistry and flow cytometry. In vitro regulation of alphaEbeta7 expression on CD4+ or CD8+ T cells purified from peripheral blood of healthy donors was also examined. RESULTS: Immunohistochemical staining revealed expression of alphaEbeta7 on a greater proportion of epidermal T cells than dermal T cells. Nearly 30% of intraepidermal CD4+ T cells were found to express alphaEbeta7 on flow cytometry, whereas more than 80% of intraepidermal CD8+ T cells expressed this integrin. In contrast, few T cells expressed alphaEbeta7 in the peripheral blood of psoriatic patients. The in vitro culture experiment confirmed that alphaEbeta7 was preferentially expressed on CD8+ T cells after stimulation with anti-CD3 monoclonal antibodies. Addition of transforming growth factor-beta and interleukin-4 upregulated alphaEbeta7 expression on T cells, whereas interleukin 12 downregulated this. Furthermore, alphaEbeta7 expression on established memory CD8+ T cells was not so reversible as that on CD4+ T cells. CONCLUSIONS: Preferential and stable expression of alphaEbeta7 on CD8+ T cells may be involved in the lesional pathology of psoriasis.

Skin-homing interleukin-4 and -13-producing cells contribute to bullous pemphigoid: remission of disease is associated with increased frequency of interleukin-10-producing cells.

Although evidence is accumulating that type 2 cytokines play a part in the pathogenesis of bullous pemphigoid, little information is available concerning characterization of the cellular source of these cytokines involved in the pathogenesis of bullous pemphigoid. By using multiparameter flow cytometry, we investigated T cells capable of producing interleukin-2, -4, -10, and -13, interferon-gamma, and tumor necrosis factor-alpha and their correlated expression of skin-homing receptor (cutaneous lymphocyte-associated antigen) in peripheral blood and skin blister of patients with bullous pemphigoid. In peripheral blood of bullous pemphigoid patients, significantly increased frequencies of interleukin-4- and interleukin-13-producing cells were found as compared with those of healthy controls, and the majority of these type 2 cells was found in the cutaneous lymphocyte-associated antigen-positive population. The frequency of interferon-gamma-producing cells was also increased as compared with healthy subjects; however, the majority of this subset was found in the cutaneous lymphocyte-associated antigen-negative population. In the skin blister, the frequencies of interleukin-13- and interleukin-4-producing cells were much higher than those in the peripheral blood of bullous pemphigoid, whereas that of interferon-gamma producing cells was significantly lower. Furthermore, in bullous pemphigoid patients after therapy with systemic corticosteroids, the frequency of cutaneous lymphocyte-associated antigen-positive, but not cutaneous lymphocyte-associated antigen-negative, interleukin-13-producing cells was significantly decreased accompanied by an increased frequency of interleukin-10-producing cells, which was associated with clinical improvement. Thus, our results suggest that bullous pemphigoid is a unique organ-specific autoimmune disease characterized by an expansion of skin-homing interleukin-13-producing cells. In addition, corticosteroids may control such type 2 biased inflammatory responses in bullous pemphigoid by promoting the expansion of interleukin-10-producing cells.

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.

Increased circulating skin-homing cutaneous lymphocyte-associated antigen (CLA)+ type 2 cytokine-producing cells, and decreased CLA+ type 1 cytokine-producing cells in atopic dermatitis.

BACKGROUND: Skin-homing T cells are characterized by expression of cutaneous lymphocyte-associated antigen (CLA). Few data are available on the frequency of circulating CLA+ cytokine-producing T cells in atopic dermatitis (AD) patients. OBJECTIVES: We aimed to investigate cytokine synthesis capability vs. CLA expression in phorbol myristate acetate and ionomycin-stimulated, secretion-inhibited peripheral blood T cells of AD patients compared with healthy subjects and psoriatic patients. METHODS: Multiparameter flow cytometry was used. RESULTS: The expression of CLA among CD4+ T cells was significantly elevated in AD patients compared with healthy subjects and psoriatic patients, whereas there was no significant difference between each group in CLA expression among CD8+ T cells. The frequency of interleukin (IL)-4- and IL-13-producing cells in AD patients was significantly higher than in healthy subjects (in both CD4+ and CD8+ T-cell subsets) and psoriatic patients (in CD4+ T cells). In contrast, the frequency of interferon (IFN)-gamma-producing cells was significantly reduced in AD patients, among both CD4+ and CD8+ T cells, compared with healthy subjects and psoriatic patients. Moreover, in AD patients, the frequency of IL-4- and IL-13-producing cells was remarkably increased among the CLA+ subset (in both CD4+ and CD8+ T cells), whereas the frequency of IFN-gamma-producing cells was decreased in the CLA+ subset (in CD4+, but not in CD8+ T cells). CONCLUSIONS: These results provide evidence for the expansion of skin-homing type 2 cytokine-secreting T cells, associated with a reduction in skin-homing type 1 cytokine-producing T cells, in peripheral blood of AD patients.

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.

Apoptosis and the skin.

In multicellular organisms, homeostasis is maintained by a balance between cell proliferation and cell death. Two common forms of cell death, called apoptosis and necrosis, have been described. Apoptosis, which is often equated with programmed cell death, is a physiological form of cell death that is responsible for the deletion of cells. Apoptosis is morphologically and biochemically characterized by cell shrinkage, dense chromatin condensation, cellular budding, fragmentation, rapid phagocytosis by nearby cells, and DNA fragmentation into units of approximately 200 base pairs. Apoptosis can be triggered by a wide variety of stimuli such as cytokines, hormones, drugs, and viruses, and their signal transduction tightly regulated by genes such as Bcl-2. Effector caspases are finally activated, resulting in apoptotic cell death. In the skin, there is considerable evidence that apoptosis plays an important role in the pathogenesis of a wide variety of skin diseases. In lichenoid tissue reactions, the Civatte body or colloid body is a form of apoptotic keratinocytes which is mediated by T lymphocytes via Fas-FasL interaction or through the perforin-granzyme B pathway. In several skin tumors, Bcl-2 or FasL expression is involved in the proliferation or regression of the tumors, or in the escape from immune attack by T cells. Moreover, apoptosis is also responsible for the homeostasis of skin, such as the keratinocyte differentiation and hair cycle. In this review, we describe the basic concept of apoptosis and its relevance to skin diseases.

Distinct in vivo and in vitro cytokine profiles of draining lymph node cells in acute and chronic phases of contact hypersensitivity: importance of a type 2 cytokine-rich cutaneous milieu for the development of an early-type response in the chronic phase.

Although regional lymph nodes (LN) have been extensively studied as rich sources of effector T cells in contact hypersensitivity (CH), it remains unknown whether T cell responses in the LN reflect those in effector skin sites. We previously showed that repeated elicitation of CH results in a shift in the time course of Ag-specific CH from a delayed-type hypersensitivity response to an early-type response, a reflection of a shift in cutaneous cytokine expression from a type 1 to a type 2 profile. To investigate whether repeated elicitation of CH could also drive T cell development to the type 2 phenotype in the regional draining LN, sequential cytokine gene expression after hapten application was assessed during both the acute and the chronic phase of CH. In the draining LN the shift to type 2 cytokine production was also observed, but more mixed patterns of responses were induced than in the corresponding skin sites. The chronic LN cells (LNC), when stimulated in vitro, produced markedly lower levels of type 1 cytokines and higher levels of type 2 cytokines than the acute LNC. A successful passive transfer of an early-type response by the LNC was only induced in the recipient mice when the skin sites chronically treated with hapten were elicited. These results indicate that an early-type response by regional LNC would take place only in a milieu with sufficient levels of type 2 cytokines.

Staining for histologic diagnosis of aluminum osteopathy--application of confocal laser scanning microscopy to observation for offminum in bones from aluminum-treated, subtotally nephrectomized rats.

To histologically detect excess aluminum (Al) taken up by bones in a rat model of renal failure prepared by 5/6-nephrectomy, non-decalcified bone tissue sections from specimens of the tibia, femur, rib and ilium were stained with a newly developed lumogallion reagent and examined for aluminum by confocal laser scanning microscopy. The assay revealed that Al contents in the tibia and femur of Al-treated rats tended to be a few-fold higher, compared to controls. With the lumogallion stain technique, Al in bones could be detected and identified at Al concentrations of > or = 9.0 micrograms/g in bone tissues. The reaction of the metal with lumogallion is specific and proved to be positive even at concentrations of excess Al so low as to be undetectable by conventional methods. The present observation disclosed that, unlike the generally accepted view, the Al was accumulated not in the calcification front but was distributed diffusely or as aggregates at high concentration in osteoid tissues. Z mode scans of the slides permitted steric delineation of the state of Al accumulation in bone tissues. The method described herein is considered a useful means for clinical diagnosis of aluminum osteopathy.

Sensitive detection of trace aluminium in biological tissues by confocal laser scanning microscopy after staining with lumogallion.

This paper describes a method for the sensitive detection of aluminium in biological tissues by real time confocal laser scanning microscopy after staining with lumogallion. The method enabled detection of aluminium > or = 9 micrograms g-1 in bone and is more sensitive than the conventional histochemical methods with aluminium and solochrome azurine, etc. Lumogallion reacts specifically with aluminium to form a fluorescent complex so that the proposed method is useful for detection and identification of aluminium in tissues.