Search

Human monocyte-derived dendritic cells (MoDC) have both histamine H1 and H2 receptors and can induce CD86 expression by histamine. Nevertheless, it has not been reported whether human epidermal Langerhans cells (LC) have histamine receptors or not. In this study, using RT-PCR, we investigated the expression of H1 and H2 receptor mRNA on DC with the features of LC (LC-like DC) that were generated in vitro from peripheral blood monocytes, LC derived from CD34+ hematopoietic progenitor cells, and LC obtained from human epidermis. We compared the histamine-induced CD86 expression among these cells. In contrast to MoDC, LC and LC-like DC did not express H1 or H2 receptors. In addition, they could not augment the CD86 expression by histamine. Interestingly, when transforming growth factor-beta1 (TGF-beta1) was added to the culture of MoDC, the expression of H1 and H2 receptors and the histamine-induced CD86 expression were abrogated in a concentration-dependent fashion. Finally, in the assessment of the cell surface expression of histamine receptors using fluorescence-labeled histamine, histamine could bind to MoDC and dermal dendritic cells obtained from the skin, whereas there was no specific binding of histamine to LC-like DC or LC obtained from the skin. These data suggest that LC do not express either H1 or H2 receptors, mainly because of the effect of TGF-beta1. This made a striking contrast with the expression of the functional H1 and H2 receptors on MoDC and dermal dendritic cells.

We have previously established a non-invasive method to evaluate the maturity of cornified envelopes (CEs), and have reported the appearance of immature CEs in the stratum corneum (SC) with poor barrier function, such as the SC of the face. The purpose of the present study was to evaluate CEs in inflammatory skin disorders, and to clarify the relationship between the appearance of the immature CEs and parakeratosis, which is often used as a marker for defective keratinization in inflammatory skin disorders. Cornified envelopes in the outermost SC of involved areas of psoriasis vulgaris (PV) and atopic dermatitis (AD) were strikingly heterogeneous, and consisted of immature CEs stained with anti-involucrin and mature CEs stained with Nile red, whereas CEs of the uninvolved areas were relatively homogeneous, exhibiting mature phenotype. The ratio of immature CEs was significantly higher in the involved areas of PV and AD than that in the corresponding uninvolved areas, suggesting that defective CE maturation may, at least in part, account for the inflammatory disorders. Simultaneous evaluation of CE maturity and parakeratosis was carried out by a combination of involucrin immunostaining and nuclear staining of detergent-dissociated corneocytes. In the involved area of PV, four types of corneocytes in regard to the combination of involucrin staining and nuclear remnant were observed, while both immature CEs and parakeratosis were more often detected in the involved areas of PV than in the uninvolved areas or the upper arm of healthy subjects as a normal control. Thus, corneocytes with involucrin-positive immature CEs were not always associated with parakeratosis at the cellular level. In the involved areas of PV, the ratio of immature CEs and that of parakeratosis were heterogeneous, depending on the cases, and no correlation between the ratios was observed. Inter-individual and intraindividual variations in CE maturity were also suggested by the heterogeneous localization of involucrin in the psoriatic epidermis as examined by immunohistochemistry. In addition, in the face of healthy subjects, four types of corneocytes were similarly detected, and the ratio of immature CEs was significantly higher than that of parakeratosis. These results obviously suggest that the maturation of CEs and disappearance of nuclei are differentially regulated in the epidermis.

Epithelial-mesenchymal interactions play a crucial role in the induction of life-long cyclic transformations of hair follicles. Many studies have already demonstrated several candidates for the soluble factors secreted from the mesenchymal components of the hair follicle, i.e. the follicular papilla (FP) and connective tissue sheath (CTS), which may be responsible for hair cycling. In this paper, we focused on cell-cell contact between FP cells (FPCs), between CTS cells (CTSCs), and between FPCs and CTSCs that may allow these mesenchymal components to function as a syncytium during hair cycling. Electron microscopic examination of the FP and the CTS obtained from human scalp revealed a tri-lamellar structure of the plasma membranes, which is a characteristic of gap junctions at the cell-cell contacting area. The immunohistochemical study with anticonnexin 43 Ab using a confocal laser scanning microscope demonstrated numerous spotted positive signals scattered throughout the FP. In the CTS, spotted positive signals were arranged linearly along the basement membrane of the hair follicle. In particular, these positive spots were aggregated in the transitional region between the FP and the CTS. By Western blot analysis of total protein extracts from the cultured FPCs and neonatal human dermal fibroblasts using anticonnexin 43 antibody, a positive band corresponding to connexin 43 was detected at 43 kDa on both the FPC lane and fibroblast lane. These findings suggest that the FP and the CTS form a communicating network through gap junctions, which may play a role in controlling the dynamic structural changes of hair follicles during hair cycling.

SummaryBackground Skin flaps have routinely been used as substitutes for oral mucosa after extensive resection of oral tissues. However, it remains unknown how the transplanted skin flaps perform as a host defence in the new environment of the oral cavity. Objectives To evaluate the expression of cornified cell envelope (CCE) precursors in pretransplanted (normal) skin, intraorally transplanted skin and normal oral mucosa, because CCEs are highly responsible for a protective barrier in each type of epithelium. Methods We used immunohistochemistry and immunoelectron microscopy to examine the expression of CCE precursors, small proline-rich protein (SPR) 2 and 3 and loricrin, in biopsy specimens of normal skin, transplanted skin and normal oral mucosa, including buccal and lingual (non-keratinized) mucosae, and palatal (keratinized) mucosa. Results Transplanted skin flaps were classified into two groups. About two-thirds of the transplanted skin flaps displayed a reddish appearance and were devoid of the stratum corneum (SC) together with a psoriasiform inflammatory tissue reaction. Others showed a native appearance, retaining the SC. While SPR2 expression was limited to the stratum granulosum (SG) in both normal and transplanted skin retaining the SC, it extended to the stratum spinosum (SS) of the transplanted skin lacking the SC and that of the normal oral mucosa. Although SPR3 expression was not found in normal skin or in the transplanted skin retaining the SC, it was strongly expressed in the SS of the transplanted skin lacking the SC and the non-keratinized oral mucosa, and in the SS and SG of the keratinized oral mucosa. Loricrin, which was expressed in the SG of normal skin, the transplanted skin retaining the SC and the keratinized oral mucosa, was not detected in the transplanted skin lacking the SC or in the non-keratinized oral mucosa. Immunoelectron microscopy confirmed the ultrastructural localization of SPR3 directly under the cytoplasmic membrane of keratinocytes of the transplanted skin lacking the SC and that of the oral mucosa. Conclusions The altered expression of SPR2, SPR3 and loricrin reflects the possible adaptation of epidermal keratinocytes in the new environment of the oral cavity.

Background/aims: Touching the skin is of great importance for the Clinician for assessing roughness, softness, firmness, etc. This type of clinical assessment is very subjective and therefore non-reproducible from one Clinician to another one or even from time to time for the same Clinician. In order to objectively monitor skin texture, we developed a new sensor, placed directly on the Clinician's finger, which generate some electric signal when slid over the skin surface. Material and methods: The base of this Haptic Finger sensor is a thin stainless steel plate on which sponge rubber, PVDF foil, acetate film and gauze are layered. The signal generated by the sensor was filtered and digitally stored before processing. In a first in vitro experiment, the sensor was moved over different skin models (sponge rubber covered by silicon rubber) of varying hardness and roughness. These experiments allowed the definition of two parameters characterizing textures. The first parameter is variance of the signal processed using wavelet analysis, representing an index of roughness. The second parameter is dispersion of the power spectrum density in the frequency domain, corresponding to hardness. To validate these parameters, the Haptic Finger was used to scan skin surfaces of 30 people, 14 of whom displayed a skin disorder: xerosis (n = 5), atopic dermatitis (n = 7), and psoriasis (n = 2). Results and conclusion: The results obtained by means of the sensor were compared with subjective, clinical evaluations by a Clinician who scored both roughness and hardness of the skin. Good agreement was observed between clinical assessment of the skin and the two parameters generated using the Haptic Finger. Use of this sensor could prove extremely valuable in cosmetic research where skin surface texture (in terms of tactile properties) is difficult to measure.

Atopic dermatitis (AD) is characterized by the presence of Th2-type cells in the skin infiltration as well as in the peripheral blood, although a predominant infiltration of interferon-gamma (IFN-gamma)-producing cells is also reported in the chronic skin lesions of AD. Recently it has become clear that the development of Th1 or Th2 is strongly influenced by factors produced by the antigen presenting cells (APCs). To clarify whether APCs from AD patients play a favorable role in the differentiation of Th2 cells, we compared the production of cytokines and the expression of co-stimulatory molecules by monocytes (MOs) and monocyte-derived DCs (MoDCs) after stimulations with various reagents between 13 AD patients and 13 age-matched healthy controls. We examined their production of IL-1 beta, IL-10, IL-12p40, and IL-12p70, and their expression of CD23, CD40, CD54, CD80, CD83, CD86 and HLA-DR. We stimulated them with superantigens, lipopolysaccharide (LPS), agonistic anti-CD40 antibody, phytohemagglutinins (PHA), IL-1beta/TNF-alpha, IL-4, or IFN-gamma. The following results were obtained (1): IL-10 production was significantly enhanced in AD MOs after LPS stimulation. In contrast, IL-12p40 production was significantly lower in AD MOs than in HC MOs after a variety of stimulations (2). IL-12p40 was also significantly lower in AD MoDCs after LPS stimulation (3). The induction of CD23 with IL-4 was significantly higher in AD MOs. and finally (4), AD MoDCs augmented the expression of CD83, CD86, and HLA-DR less significantly than HC MoDCs after anti-CD40 Ab stimulation. These data indicate that AD APCs show some responses different from those observed in HC APCs after several stimulations, such as LPS, IL-1 beta/TNF-alpha, IL-4, or anti-CD40 Ab, and that these responses might play a role in the polarizing process of helper T cells into Th2 cells as recognized in AD patients.

This paper is a study on the development of a haptic sensor system for monitoring skin conditions. The sensor is an assembly of layered media. The base of the sensor is a stainless plate, on which a sponge rubber, a PVDF film with electrode patches, a protective surface layer of acetate film and a gauge are stacked in sequence. The sensor is attached to the forefinger and pressed against the surface of the skin. It is then slid over the skin to collect surface morphological features. Through the fundamental experiment using the artificial objects, two evaluation parameters characterizing skin conditions are determined. One is the variance of the signal processed with a wavelet analysis, which is the index of roughness. The other is a parameter showing the dispersion of power spectrum density in the frequency domain, which is the index of softness. The sensor system is then applied to the clinical test of skin with various conditions. Results show that the sensor output well describes the skin conditions and represents the subjective evaluations of dermatologist.

Objective: Based on our previous findings that, reflecting mild inflammation, the exposed facial skin shows much poorer functional properties of the stratum corneum (SC) in the dry and cold winter than those evaluated in the same individuals in the warm and humid summer time, we conducted a half-side test on the face to determine how the facial skin changes induced by a winter environment are improved by daily applications of a moisturizing cream as assessed by non-invasive biophysical and cytological methods. Methods: One side of the face of 16 young females was treated with a moisturizing cream twice daily for 6 weeks, with the other side serving as the non-treated control. Before treatment, 3 and 6 weeks after the start of the treatment, high-frequency conductance as a parameter of the skin surface hydration, transepidermal water loss (TEWL), a parameter of the water barrier function of the skin, and the skin surface lipid level were measured on the cheeks. Obtaining the SC from the skin surface by adhesive tape, interleukin (IL) 1α and IL-1 receptor antagonist (IL-1ra) in the SC and cornified envelope (CE) maturation were determined. Results: At first, baseline measurements conducted before treatment showed rather high TEWL values suggestive of an impaired skin barrier. During the treatment with the moisturizing cream, significantly higher conductance values and lower TEWL values were found on the moisturizer-treated side, accompanied by a decreasing IL-1ra/IL-1α ratio and immature CEs. Conclusion: These results suggested that the daily application of a moisturizing cream is effective in improving mild subclinical inflammation that is induced on the facial skin by the winter environment.

Diabetes mellitus induces many pathophysiologic changes in the skin. Even so, dermatologists still lack an animal model of diabetes that enables the direct evaluation of the various functional properties of the skin. Our group induced two types of an experimental type 1 diabetes model in hairless mice by administering either streptozotocin or alloxan, in order to examine the properties of the stratum corneum and epidermis of these animals. The plasma glucose concentrations of the mice at 3 wk after their i.v. injection were significantly higher than those of control mice (streptozotocin, 3.2-fold; alloxan, 3.7-fold). The stratum corneum water content was significantly reduced in both types of diabetic mice, whereas the transepidermal water loss remained unchanged. The amino acid content with normal epidermal profilaggrin processing was either normal or elevated in the stratum corneum of the streptozotocin-treated mice. In contrast, the stratum corneum triglyceride content in the streptozotocin-treated mice was significantly lower than the control level, even though the levels of ceramides, cholesterols, and fatty acids in the stratum corneum were all higher than the control levels. The streptozotocin-treated group also exhibited decreases in basal cell proliferation and epidermal DNA content linked with an increase in the number of corneocyte layers in the stratum corneum, suggesting that the rates of epidermal and stratum corneum turnover were slower in the streptozotocin-treated animals than in the normal controls. In contrast, there were no remarkable changes in any of the epidermal differentiation marker proteins examined. This finding in diabetic mice, namely, reduction in both the epidermal proliferation and stratum corneum water content without any accompanying impairment in the stratum corneum barrier function, is similar to that found in aged human skin. Our new animal model of diabetes will be useful for the study of diabetic dermopathy as well as the mechanisms of stratum corneum moisturization.

Objective: To evaluate, in the context of a randomized study, the ‘Sole Si Sole No GISED’ project, the effectiveness of an educational intervention to improve sun protection behaviour in schoolchildren. Methods: A large number of primary schools (classes II and III) in Italy were randomized to an educational intervention or control group: The intervention was conducted by trained teachers using ad hoc developed materials. Attitudes toward sun exposure and behaviour while in the sun were assessed at baseline and 1 year after concluding the educational intervention. In a subgroup of children, melanocytic naevi were counted on the upper limbs at the same intervals. The pilot phase of the study was started in 2001. Results: During the pilot phase, a total of 4,233 children was recruited. Of these, 2,116 were randomized to the active intervention and 2,117 to the control group. No difference for any of the study variables was documented between the 2 groups at baseline. About 20% of the children reported intense sun exposure during the year preceding the study. About 88% of the children reported adequate modalities of sun protection. Sunscreens were commonly used. A total of 508 children (12%) reported a history of sunburns in the year preceding the start of the study. Melanocytic naevi were counted in a total of 1,503 children (852 in the experimental and 651 in the control group). No differences in terms of skin, hair and eye colours were documented between the experimental and the control groups. The mean naevus count at baseline was 9.6 (median 7) in the experimental group and 10.1 (median 8) in the control group. Conclusion: About 50% of the total expected number of children was recruited during the pilot phase of the study. Randomization proved to be an excellent modality to select 2 samples similar for all the important study variables examined. A history of sunburns was reported less frequently than expected. The ‘Sole Si Sole No GISED programme’ is one of the few examples of a controlled evaluation of the effectiveness of an educational intervention in Italy.

Background/aims: The past morphological studies on individual corneocytes have so far mainly focused on their two-dimensional characteristics, particularly on their projected area, which have been widely employed for the estimation of the turnover rate of the stratum corneum because of the practical use. However, sometimes a poor correlation has been reported between the projected area of corneocytes and actually measured turnover time of the stratum corneum. The objective of the present study is to perform detailed three-dimensional measurements of individual corneocytes with atomic force microscope. Through analyses of the obtained data, we tried to find morphological parameters that reflect more closely the differentiation process of the corneocytes in the stratum corneum than the frequently used two-dimensional projected area. Methods: We measured such morphological parameters as the volume, average thickness and real surface area of individual corneocytes isolated from the covered skin (the flexor surface of the upper arm) and the exposed skin (the cheek) of 12 healthy individuals belonging to different age brackets, in addition to their projected area. We further introduced a new parameter, a flatness index calculated by dividing the projected area of corneocytes by their thickness. Similarly, we measured corneocytes obtained from eight patients with atopic dermatitis (AD) and psoriatic patients. Results: Obtained results showed that most of these morphological parameters varied greatly depending upon the anatomical location and age of the subjects. Needless to say great differences were found between healthy skin and lesional skin of atopic dermatitis or psoriasis. However, the volume and thickness of corneocytes collected from the same location of normal skin of the covered area (upper arm) with tape-strippings were noted to decrease as they differentiated in the stratum corneum, showing an increase in their surface area and projected area with a resultant increase in the flatness index. Moreover, the corneocyte collected from the lesional skin of AD or psoriasis showed a great decrease in flatness index, reflecting their poor differentiation in the stratum corneum due to its enhanced turnover rate. Most of all, we found a poor correlation between the projected area and the various three-dimensional morphologic parameters of the corneocytes, indicating that the projected area does not reflect the volume or thickness of corneocytes that are also greatly influenced by the differentiation process of corneocytes in the stratum corneum. Conclusions: To estimate the differentiation speed of the corneocytes, we suggest using their flatness index rather than the two-dimensional cell surface area, because the former is a concept that takes into account the three-dimensional characteristics of corneocytes.

The surface contours of lesional skin of certain skin diseases, such as parapsoriasis en plaque (PEP) and extramammary Paget's disease (EMPD), in which there is a massive infiltration by non-epidermal cells, looks somewhat different from that of the adjacent normal skin, needless to state that they are apparently different from that of ordinary chronic inflammatory dermatoses where we found acanthotic epidermis accompanied by hyperkeratosis. We attempted to objectively characterize these unique skin surface changes qualitatively and quantitatively using non-invasive methods. Negative impression replicas were taken from the lesional skin of patients with EMPD or PEP as well as from the adjacent uninvolved skin. The findings were confirmed histologically. The replicas were examined by using computerized image analysis. Several parameters were analyzed that correlate with the changes in the anisotropy of the skin furrows (VC1), average skin roughness (KSD), average length of skin furrows (LEN), and number of skin furrows (NUM). There were significant decreases in KSD and NUM in EMPD, indicating a smoother skin surface in the lesional skin than in the adjacent normal skin. In contrast, the PEP lesion had an increase in VC1 and LEN and a decrease in NUM, which suggests larger skin ridges in the lesional skin than in the uninvolved skin. Thus the unique skin surface of the cutaneous disorders accompanied by epidermal invasion by non-epidermal cells, such as EMPD and PEP, was characterized both qualitatively and quantitatively using computerized image analysis of negative impression replicas.

Antigen-presenting cells (APCs) participate in the initiation of the inflammatory process in various immune-mediated dermatoses through the activation of antigen-specific T lymphocytes. The skin contains several different subsets of APCs. To investigate the role of these APCs in T-cell immune-mediated inflammation, we examined the distribution and numbers of epidermal and dermal CD1a(+) dendritic cells (DCs), factor XIIIa(+) dermal DCs, and CD68(+) macrophages in five T-cell-mediated inflammatory skin diseases. Immunohistochemistry of CD1a, factor XIIIa, and CD68 was performed using paraffin-embedded tissue obtained from a total of 51 patients with eczematous dermatitis (histologically spongiotic dermatitis), psoriasis, lichen planus, acute graft-versus-host disease (GVHD), and chronic GVHD. The numbers of positive cells for each staining were compared with those in site-matched normal skin control specimens from aged-matched subjects. In spongiotic dermatitis and lichen planus, the numbers of epidermal and dermal CD1a(+) cells and factor XIIIa(+) cells were significantly greater than in normal control skin, while in psoriasis only factor XIIIa(+) cells were significantly increased in number. Acute and chronic GVHD showed a reduced number of dermal CD1a(+) cells. Interestingly, factor XIIIa(+) cells were decreased in acute GVHD while they were increased in chronic GVHD. There was a significant reduction in epidermal CD1a(+) cells in acute GVHD, but not in chronic GVHD. The differences in the numbers of APCs in lesional skin appeared to reflect differences in the pathophysiology of these inflammatory skin diseases.

It is known that, in patients of allergic asthma and rhinitis, the late-phase reaction (LPR) occurs 6–12 h after allergen challenge, but there are few reports concerning cytokine production in the cutaneous LPR in atopic dermatitis (AD). We report here the results of our study on the relationship between the cutaneous LPR and the production of cytokines such as IL-4, IL-5, IL-2 and IFN-γ by peripheral blood mononuclear cells (PBMC) of AD patients. We selected 29 pure AD patients with no history of atopic airway diseases who showed high serum IgE antibody against Dermatophagoides farinae and performed skin prick testing with three different antigens and observed the resultant cutaneous reactions in 23 of the AD patients. Furthermore, we measured the cytokine production by the cultured PBMC under the stimulation of the antigens and compared it with the results of the skin tests. 13 (57%) of these 23 AD patients demonstrated positive LPR in response to D. farinae, and the mean concentration of IL-5 produced by PBMC was higher in these LPR-positive AD patients compared to the LPR-negative ones. Additionally, we noticed that there was a positive correlation between the mean diameter of the erythema of LPR and the level of IL-5 production by PBMC in the LPR-positive patients. We suggest that there are at least two groups in AD patients, i.e. LPR-positive and LPR-negative ones. The observation of LPR can be an important and practical way to classify AD patients into subgroups, which may enable us to regard IL-5 or eosinophils as a target for treatment.

The strong association of acute guttate psoriasis and streptococcal throat infection has suggested a role for streptococcal antigens in the pathogenesis of psoriasis. We have reported that psoriatic peripheral blood mononuclear cells (PBMCs) showed significantly lower responses to cytoplasmic membrane-associated protein (CAP) isolated from group A beta-hemolytic streptococci, a kind of streptococcal superantigen. The objectives were to evaluate the abnormal cytokine production by psoriatic PBMCs to streptococcal superantigen, CAP. We compared the production of four different cytokines, i.e. IL-4, IL-5, IL-10, and IFN-gamma, by PBMCs between psoriatic patients and healthy controls after stimulation with CAP or two different staphylococcal superantigens, staphylococcal enterotoxin A (SEA) or E (SEE). When PBMCs were stimulated with CAP, the production of IL-10 was significantly lower by psoriatic PBMCs than by those from healthy controls, whereas those of IL-4, IL-5, or IFN-gamma were not different between the two groups. Such a significant decrease in IL-10 production by psoriatic PBMCs was not observed when they were stimulated with staphylococcal superantigens. Flow cytometric analysis of intracytoplasmic IL-10 demonstrated defective IL-10 production by psoriatic PBMCs in both CD3+ T cells and CD14+ monocytes. There was a significant positive correlation between IFN-gamma production by PBMCs and the proliferation of Vbeta8+ T cells preferentially stimulated by CAP. These data demonstrating the defective IL-10 production by psoriatic PBMCs stimulated with streptococcal superantigen seem to explain why only psoriatic patients evolve sustained and Th-1 deviated skin lesions after streptococcal upper respiratory infection.

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

We have generated mutant mice for epidermal-type fatty acid binding protein by the gene targeting technique and examined the phenotype in detail. Despite a lack in the expression of epidermal-type fatty acid binding protein mRNA and its protein in the skin and other tissues of the mutant mice, the animals appeared normal in gross and histologic examination. Northern blot analysis of other fatty acid binding proteins revealed a distinct elevated gene expression of heart-type fatty acid binding protein in the skin of the homozygous mice. In analyses of the skin, no differences were observed in contents of major fatty acids, electron microscopic appearance as well as inflammatory responses in ear skin between the mutant and wild-type mice. Basal transepidermal water loss of homozygous mice was lower than that of the wild mice. When acetone was applied to the skin for disruption of the water permeability barrier, recovery in transepidermal water loss was delayed, although maximum transepidermal water loss upon acetone treatment was similar between homozygous and wild-type mice in terms of size and time course. The molecular mechanism by which epidermal-type fatty acid binding protein contributes to the water barrier function of the skin remains to be elucidated.

Skin disorders such as atopic dermatitis, psoriasis and senile xerosis show a tendency to exacerbate in winter. We investigated the seasonal influence on the functional parameters of the skin in healthy female volunteers of different age groups. Biophysical noninvasive measurements, including transepidermal water loss (TEWL) as a parameter for the barrier function of the stratum corneum (SC), high-frequency conductance as a parameter for the hydration state of the SC, temperature, color and casual surface lipid levels, were conducted during the later summer and winter months in 39 healthy adult Japanese females ranging in age from 24 to 78 years. The measurements were made on the cheek, the exposed area, and flexor forearm, the semicovered area, in the same climate-controlled chamber. The barrier function of the SC was found to be significantly impaired in winter both on the cheek and flexor forearm. This difference between summer and winter was much larger on the cheek than on the forearm. The hydration state of the SC was significantly lower in winter on the flexor forearm, whereas no such seasonal change was apparent on the cheek where sebum levels did not show any seasonal change. We measured the corneocyte size in 24 out of the 39 subjects to estimate a seasonal change of the turnover rate of the SC. It tended to be smaller only on the exposed cheek skin, suggesting an enhanced turnover of the SC in winter, whereas it was somewhat larger on the semicovered flexor forearm. The skin surface temperature and redness were also significantly higher on the cheek in winter. We think that subclinical inflammation resulted in the enhanced turnover rate of the SC associated with elevated TEWL levels observed on the face in winter. In conclusion, the obtained data suggest that the exposed facial skin becomes more irritable under the influence of the dry and cold environment of winter even in healthy individuals where the barrier function of the SC is relatively poor as compared to the skin of other areas.

Background: Acetylcholine has been suspected to be a pathogenetic factor for cholinergic urticaria (CU), without definite evidence. In contrast, there are scattered reports of CU associated with acquired generalized hypohidrosis. We have recently examined 2 patients with CU in both of whom we noticed the presence of extensive hypohidrosis that occurred only in winter. Objective: In these 2 patients, acquired hypohidrosis due to superficial obstruction of the acrosyringium was suspected as the cause. Both case 1, a 22-year-old Japanese man, and case 2, a 21-year-old Japanese man, began to have anhidrosis and numerous red macules on their body whenever they felt hot in winter. These symptoms ceased to appear in summer. Methods: We studied histologically their lesional skin in addition to provocation tests for CU. Results: The diagnosis of CU was confirmed by the provocation of typical wheals after physical exercise in both cases. Histological study revealed findings suggestive of the presence of occlusion of the superficial acrosyringium. Conclusion: We think that such a hypohidrosis due to occlusion of superficial sweat ducts may also play a role in many other patients with CU of unknown etiology that becomes exacerbated in winter when sweating is not a frequent event.

Self renewing epidermis are characterized by a fine balance between growth and differentiation of immature keratinocytes including stem cells. Recent progress showed various molecules that played important roles for this control. Here we focus on two molecules, cyclin-dependent kinase inhibitor p 21 and Notch receptor. First, p21 has been shown to the contribution to proliferation and differentiation of keratinocytes. Recently we know that loss of p21 function increases the pluripotent keratinocyte population with multi-potential (stem cells) . Second, Notch was identified as one of key molecules for cell fate decision in Drosophila. Even in mammalian Notch homologues have important functions for the control of cell fate decision and growth/differentiation due to cell-cell communication. In keratinocytes Notch 1 signaling leads to growth arrest via p21 activation and differentiation. These works will advance our knowledge on controlling mechanism for homeostasis and tumor formation in not only epidermis but also other epithelia tissue.

We report a case of an extraordinarily large tumorous form of ALHE developing on the occiput of a 57-year-old Japanese male. Histologically, it was characterized by increased numbers of small blood vessels, fibrosis, and lymph follicle formations with massive eosinopilia in the dermis in addition to an occluded artery in the deep dermis.

The functional deficiencies of the stratum corneum (SC) have been well documented in the skin of atopic dermatitis (AD) patients. AD tends to affect certain predilection areas chronically such as the face, neck and the flexural folds of the extremities. From the paucity of the information about the functional characteristics of the SC in such skin areas, we conducted biophysical measurements at the predilection sites of AD, i.e. the cheek, anterior surface of the neck, nape, antecubital fossa and popliteal fossa and relatively uninvolved sites such as the elbow, mid volar forearm, knee and mid calf in 34 AD patients and in 40 normal individuals. Reflecting the great interlocation variations in the SC noted even in the normal individuals, we found location-dependent as well as severity-dependent changes of SC function in the AD patients. Thus, the values of transepidermal water loss (TEWL) obtained on the cheek and, unexpectedly, the elbow were quite high, whereas those on the poplieal fossa were very low; even those values recorded on the lesional skin of the latter of the AD patients were significantly lower than those of the cheek of normal healthy individuals (p < 0.05). Moreover, the TEWL values measured at the nonlesional skin of AD patients were much closer to those of the normal healthy skin than to those of the lesional skin in most areas. Similarly, the SC hydration state that is influenced by the amount of skin surface lipids showed prominent location-dependent changes in addition to a severity-dependent change. It was much higher even in the lesional skin of the face and neck than in the normal skin of the extensor surface of the limbs. The corneocyte size, which inversely correlates with the turnover rate of the SC, was larger even on the lesional skin of the extremities than that of the normal cheek. It is only in skin surface pH that such location dependency was not demonstrable; it uniformly revealed higher values in the lesional and nonlesional skin of AD patients regardless of the sites. From these comparative data obtained at the predilection sites and relatively unaffected sites of AD, we think that those functional abnormalities of the SC reported in AD patients simply reflect the severity of underlying inflammatory changes rather than inherently defective SC functions.

The stratum corneum (SC) is such an efficient barrier that only 2-5 g per h per cm2 of transepidermal water loss (TEWL) occurs in normal skin. The SC also plays another important role at the skin surface in keeping our skin smooth and flexible by binding water. We exposed a simulation model of in vivo SC to various, excessive physical insults in vitro, such as irradiation with 1 J per cm2 of UVB, 50 J per cm2 of UVA, or 3000 rad of X-ray, heating at 90 degrees C for 3 min, freezing at -196 degrees C for 60 s or repeated placement in an extremely dry or humid condition. None of them could cause any permanent change in the SC functions. Only the application of chemical agents such as lipid solvents or a detergent or the affliction of trauma resulted in a functional derangement of the SC. Because the viable skin tissues are more vulnerable to the effects of the environment than the SC, most of the abnormalities of the SC functions developing after environmental insults are secondarily caused by enhanced epidermal proliferation induced under the influence of underlying inflammation. These functional abnormalities were found to be demonstrable with biophysical measurements long after the disappearance of skin redness, the clinically observable sign of inflammation. The SC abnormalities in inflamed skin are also detectable as a change in the content of chemical mediators. For example, the ratio between proinflammatory IL-1 and its receptor antagonist (IL-1ra) whose production by epidermal keratinocytes is markedly enhanced by various proinflammatory stimuli, showed a deviation towards an excess of the latter in inflammatory skin. Facial skin that is always exposed to the environment is unique in that its SC shows such a deviation in the IL-1/IL-1ra ratio suggestive for the presence of mild inflammation even in normal individuals.

To elucidate the pathogenesis of T cell-mediated inflammatory skin diseases, we examined the exact sites where CD8(+) T cells proliferate, correlating them with the localization of antigen-presenting dendritic cells. We performed CD8/Ki-67 double immunohistochemical staining and single staining for CD1a, CD68, and factor XIIIa on sections of paraffin-embedded tissue samples of inflammatory dermatoses in which T lymphocytes are thought to play a crucial role. The dermatoses were lichen planus (12 samples), acute graft-versus host disease (GVHD) (12 samples), chronic GVHD (10 samples), spongiotic dermatitis (8 samples) and psoriasis (7 samples). Labelling for Ki-67 among CD8(+) T cells was predominantly observed in the subepidermal lymphoid infiltrate, and was scanty in the epidermis. This suggested that proliferation of CD8(+) T cells occurred preferentially in the dermis. The labelling index for Ki-67 among dermal and epidermal CD8(+) cells was quite different among the different diseases studied (P < 0.05). They were rich in the subepidermal portion of the dermis of spongiotic dermatitis, acute GVHD and chronic GVHD, but rare in the dermis of psoriasis and lichen planus. A moderate infiltrate was also observed in lesional epidermis of spongiotic dermatitis, acute GVHD and chronic GVHD, whereas they was almost none in the epidermis of psoriasis and lichen planus. CD1a(+) dermal dendritic cells were densely distributed within the lymphoid infiltrate in the affected dermis of spongiotic dermatitis, psoriasis and lichen planus, whereas they were minimal in GVHD. These dermal dendritic cells are candidates as stimulators on T cells in the dermis. In conclusion, the proliferative status of T cells could be an important clue in the elucidation of the pathophysiology of T cell-mediated inflammatory dermatoses.

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

It was previously reported that peripheral blood mononuclear cells (PBMC) from the patients with psoriasis vulgaris (PV) showed a reduced proliferative response in vitro to the stimulation of a lyophilized preparation of penicillin-treated low virulence Su-strain of Streptococcus pyogenes group 3, OK-432. In this study, at first it was examined whether OK-432 acts as a superantigen. By analyzing the usage of Vbeta T-cell receptor (TCR) of proliferating T cells stimulated with OK-432, it was found that OK-432 stimulated preferentially Vbeta2 TCR-bearing T cells. Next, to find differences in in vitro responses of PBMC among various types of sterile pustular dermatoses such as pustulosis palmaris et plantaris (PPP), acrodermatitis continua of Hallopeau (AC), and generalized pustular psoriasis (GPP), the proliferative responses of PBMC obtained from these patients under the stimulation of OK-432 were compared. When the PBMC was stimulated with interleukin (IL)-2, no significant difference was found in their proliferative responses among those obtained from the patients with these sterile pustular dermatoses, PV or healthy controls. However, like those from PV patients, PBMC from AC and GPP patients showed significantly smaller responses to OK-432 than those from the healthy controls. In contrast, the proliferative responses of PBMC from the patients with PPP to OK-432 was comparable to those from healthy controls. These results, in addition to its unique clinical and histopathological characteristics, suggest that PPP has a different pathogenetic background from that underlying PV, AC, or GPP.

Background Synthesis of cysteinyl leukotrienes (LTs) is known to play a part in the pathogenesis of inflammatory diseases. Objectives To define the involvement of cysteinyl LTs in atopic dermatitis (AD). Methods Synthesis of cysteinyl LTs was assessed in patients with AD and healthy volunteers by measuring urinary LTE4, a useful index of systemic cysteinyl LT synthesis, using liquid chromatography/tandem mass spectrometry. Results Mean ± SD urinary LTE4 levels in patients with AD (125 ± 69 pg mg−1 creatinine, n = 20) were significantly higher (P

With the increasing elderly population in Japan, skin problems have become a greater concern. A heparinoid-containing moisturiser is frequently used in Japan, but there is a lack of evidence for its efficacy in treating senile xerosis. To determine whether there is a correlation between age and the hydration state of the stratum corneum (SC) assessed by skin capacitance, and to evaluate the efficiency of a heparinoid-containing moisturiser and a bed bath to treat senile xerosis.We recruited 73 individuals to assess the hydration state of the SC on their flexor forearm by measuring their skin capacitance. To evaluate the efficacy of a heparinoid-containing moisturiser on senile xerosis, we recruited seven inpatients with an inactive daily life (IDL) who had senile xerosis. They were treated with the moisturiser in addition to a bed bath in two different protocols, and we measured the skin capacitance on their flexor forearms on days 0, 7 and 14.There was a weak negative correlation (-0.3854, P 0.01) between skin capacitance and age. Following the moisturiser treatments, the seven inpatients had increased hydration of both arms on days 7 and 14. The skin capacitance of the right forearm slightly decreased on day 14, even though it was significantly different from day 0 (P 0.05).These findings indicate that treatment with a heparinoid-containing moisturiser together with a bed bath is an effective method for treating patients who have senile xerosis and IDL.

Summary Various groups have reported the efficacy of treatment with topical silicone gel sheet (SGS) for keloids and hypertrophic scars. Because its hydrating effect on the stratum corneum (SC) has been suggested as a mechanism underlying its therapeutic effectiveness, we evaluated it by comparing it with simple plastic film occlusion. With biophysical instruments we assessed the water content of the skin surface as well as its water evaporation on the flexor aspects of bilateral forearms of 10 healthy volunteers for 30 min after removal of dressing of SGS or a plastic film that were applied either for 1 day or for 7 days. Occlusion with SGS or plastic film induced hydration of the skin surface, which was followed by an initial quick and later slow process of dehydration when the skin was exposed to the ambient atmosphere. The magnitude of the increase in hydration induced by SGS was always smaller than that of the plastic film occlusion and, unlike the latter treatment, hydration became less with repetition of SGS treatment. On day 7, the SC hydration quickly reduced to the level of non-treated control skin after removal of the dressings. An in vivo test demonstrated that the water-holding capacity of the SC normalised after 7 days of SGS treatment. SGS probably produces a favourable condition for the skin by protecting it from various environmental stimuli, while keeping the SC in an adequately but not over-hydrated condition.

BACKGROUND/AIMS: The physical properties of the stratum corneum (SC) change with its water content, which is regulated by the presence of water solutes (natural moisturizing factors) and lipids in the SC, and are considered to be responsible for the induction of desquamation, skin surface roughness, and fine wrinkles. Recently a new type of tactile sensor developed for evaluating the physical properties of objects has been introduced as a simple, non-invasive method to evaluate them; because the data obtained with this sensor have not yet been characterized in detail, we compared them with other physical parameters of the skin. METHODS: A change in resonant frequency (Deltaf ) was measured under various levels of pressure applied by a tactile sensor placed on the cheeks of 29 women. We also measured high-frequency conductance that reflects the hydration state of the skin surface, water holding capacity of the SC, transepidermal water loss (TEWL), skin flexibility, skin elasticity, amino acid composition of the SC, and desquamation index of the SC at the same time, and evaluated the correlation between Deltaf and other physical parameters. RESULTS: The correlation between Deltaf and high-frequency conductance of the SC, and that between Deltaf and the water holding capacity of the SC were substantially high. Deltaf under high pressure was more closely correlated with the acidic amino acid ratio of the SC. Deltaf also showed a correlation with desquamation index for thickness of the SC as well as with skin elasticity, independent of the applied pressure. CONCLUSIONS: Because Deltaf determined with the tactile sensor correlated with other physical parameters specific to the properties of the SC, such as high frequency conductance of the SC, its water holding capacity, ratio of acidic amino acids, and the desquamation index for thickness, the physical properties of the SC may be adequately evaluated with the measurements of Deltaf.

A growing body of evidence has indicated that T-cell-mediated immunity plays an important role in triggering and maintenance of psoriatic lesions. In this review we present our own experimental results as well as those from the literature related to the pathomechanism of the development of inflammatory changes in psoriatic lesions. First of all it is important to acknowledge the fact that psoriatic lesions are not uniform as assumed by many authors but that they are actually rather heterogeneous both clinically and histologically even within the same plaques. Lymphokines produced by activated T cells in psoriatic lesions have a strong influence on the proliferation of the epidermis, whose stimulated kertinocytes released several cytokines, which in turn enhance the activation state of T cells. Thus, they form a vicious cycle, a T-cell-mediated inflammation-sustaining loop. Although the interaction between T-cell-mediated immunity and epidermal keratinocytes may well explain the maintenance of background "chronic" inflammatory changes diffusely observed throughout psoriatic lesions, it is not enough to explain the island-like, "acute" inflammatory changes observed within and at the border of the plaque lesions. Characteristic neutrophil accumulation under the stratum corneum can be observed in the highly inflamed and therapeutically recalcitrant areas of psoriatic lesions. They are chemotactically attracted and activated there by synergistic action of chemokines, IL-8 and Gro-a released by the stimulated keratinocytes, and particularly C5a/C5a des arg produced via the alternative complement pathway activation possibly on the surface of corneocytes. In this review, we emphasize that the accumulation of neurophils is not simply a passive event. We think that those stimulated neutrophils are able to influence not only the growth and differentiation of epidermal keratinocytes but also the activation-state of T cells by aberrant expression of HLA-DR on their surfaces as well as by their effects. These T cells in turn influence the transepidermal neutrophil migration through the effect of their lymphokines on the keratinocyte production of pro-inflammatory mediators including C3. Therefore, we propose a neutrophil-associated inflammation-boosting loop that may well explain the localized "acute" inflammatory changes scattered over the "chronic" psoriatic plaques as well as in the acutely inflamed lesions of pustular psoriasis.

The skin of the back of the ASR hairless miniature swine shows a rough and scaly fissured appearance. Clinically it resembles that of ichthyosis vulgaris or senile xerosis in humans. By using the skin of this animal, we developed an assay system to evaluate the efficacy of different moisturizers. The study was carried out in winter months from January to March. To establish this system, we studied various topical agents including such ordinary emollients as petrolatum and 10% salicylic acid in petrolatum as well as those available as pseudodrugs from cosmetic companies or prescription drugs from pharmaceutical companies such as heparinoid- containing creams (w/o and o/w) and 10% urea creams. Applying 0.01 g of each agent to 7 randomly selected skin areas (2 × 2 cm2) on the back of a 6-month-old swine once daily for various periods of time, we measured high-frequency conductance, the parameter for the hydration state of the skin surface. As a result, we have established a simple assay system. It consists of applications of topical agents once daily for 5 days from Monday to Friday in the first week and of subsequent measurement of the skin surface hydration state once every week. Evaluation measurements were performed from day 14 to day 21 depending upon their moisturizing effects. We found that heparinoid-containing creams exerted highly effective moisturizing effects on the dry pig skin that lasted even over 3 weeks after discontinuation of the treatments that were carried out for the first 5 days.

Summary As is well known in the case of Langerhans cells, dendritic cells (DCs) play a crucial role in the initiation of immunity to simple chemicals such as noted in the contact hypersensitivity. Because DCs are scattered in non-lymphoid organs as immature cells, they must be activated to initiate primary antigen-specific immune reactions. Therefore, we hypothesized that some simple chemicals must affect the function of DCs. In this paper, we first demonstrated that human monocyte-derived DCs responded to such simple chemicals as 2,4-dinitrochlorobenzene (DNCB), 2,4,6-trinitrochlorobenzene (TNCB), 2,4-dinitrofluorobenzene (DNFB), NiCl2, MnCl2, CoCl2, SnCl2, and CdSO4 by augmenting their expression of CD86 or human leucocyte antigen-DR (HLA-DR), down-regulating c-Fms expression or increasing their production of tumour necrosis factor-α (TNF-α). In addition, the DCs stimulated with the chemicals demonstrated increased allogeneic T-cell stimulatory function. Next, we found that, among these chemicals, only NiCl2 and CoCl2 induced apoptosis in them. Finally, we examined the effects of these chemicals on CD86 expression by three different macrophage subsets and DCs induced from the cultures of human peripheral blood monocytes in the presence of macrophage colony-stimulating factor (M-CSF), M-CSF + interleukin-4 (IL-4), granulocyte–macrophage colony-stimulating factor (GM-CSF), and GM-CSF + IL-4, respectively. Among them, only DCs dramatically augmented their expression of CD86. These observations have revealed unique characteristics of DCs, which convert chemical stimuli to augmentation of their antigen presenting function, although their responses to different chemicals were not necessarily uniform in the phenotypic changes, cytokine production or in the induction of apoptosis.

Background/aims: Various attempts have been made to measure mechanical properties of the skin quantitatively and noninvasively. However, no attempt has been made to measure a tactile sense of our finger that palpates the skin; when we palpate the skin to search for any change, we at first rub the skin surface softly with a finger tip to detect a surface change and then press the finger against the skin to perceive any alteration in consistency. The problem here is how to record such tactile sense quantitatively, because the palpating examination for smoothness or softness of the skin totally depends on a subjective perception. A new tactile sensor from robot technology is equipped with a fingertip-like sensing probe oscillating at a resonant frequency of 60 kHz; it is capable of clearly sensing small differences in hardness of solid substances from a change in the oscillating frequency and from a displacement sensor that detects depressability of the skin. We have used this new measuring system to evaluate the hardness and elasticity of skin. Methods: We constructed a probe with two independent sensors, i.e., a newly developed tactile vibration sensor and a displacement sensor. To determine its usefulness we first used an in vitro skin model and subsequently used normal and lesional skin, such as neutrophilic erythema, keloid, hypertrophic scar, and scleroderma. Results: Two parameters were obtained with our probe: one that reflected superficial firmness of the skin, which mainly correlated with the hydration state of the stratum comeum, and the other that reflected the firmness of deeper tissue. Conclusion: Our results showed that this probe is useful for evaluating the physical properties of skin lesions that accompany changes in skin firmness.

Recently, it has been demonstrated that immunity to infectious agents is composed of innate immunity and acquired immunity, and that dendritic cells (DC) and macrophages, both of which are the participants in the innate immunity, play a crucial role in acquired immune responses, via their expression of several costimulatory molecules and production of cytokines. It is clear that the immune system responds not only to infectious organisms but also to simple chemicals. Allergic contact hypersensitivity reaction is a good example of the immune response to simple chemicals. In contrast to the immunity to microorganisms, however, the role of the innate immune system in responses to simple chemicals still remains unclear. This paper demonstrates that the activation and apoptosis of DC are directly induced by certain simple chemicals, and we suggest that DC, as cells involved in the innate immune system, play a crucial role in the immunity to simple chemicals.

Objective. The purpose of this study was to evaluate how well intraorally transferred skin flaps endure their new surroundings. Study Design. Biopsy specimens were taken from 20 patients who had undergone microsurgical reconstruction and as pretransferred skin from 5 of these patients at the time of surgery. The study used immunohistochemistry for immunocompetent cells, differentiation markers for the epidermis and desmosomal proteins, and immunoelectron microscopy for desmosomal protein, in addition to routine histologic examination, including Sudan IV, periodic acid–Schiff, and Grocott stains. We also measured the thickness of the epidermis and stratum corneum. Oral swabs from the skin flaps were examined for the presence of yeasts, particularly Candida albicans , by means of a culture method. Results. According to the results of periodic acid–Schiff and Grocott staining, 20 cases were divided into 2 groups: fungal element–positive cases (n = 15) and fungal element–negative cases (n = 5). All swabs from the former were positive for Candida albicans . In these fungus-positive cases, histopathologic evaluation revealed marked diminution of stratum corneum and pronounced epidermal hyperplasia. Immunohistochemistry demonstrated the dermal infiltration of numerous immunocompetent cells—CD4+, CD8+, CD20+, CD68+, neutrophil elastase+, and HLA-DR+ cells—and the scarce infiltration of IgA+ and IgG+ cells. There were scattered CD1a+, CD4+, CD8+, and HLA-DR+ cells and elastase+ neutrophils in the epidermis. Expression of cytokeratin subtypes (10, 14, 16, and 19), involucrin, and tenascin showed the characteristic features of epidermal proliferation. Enumeration of Ki-67+ keratinocytes showed an increase, indicating epidermal proliferation. Expression of desmoglein 1 and desmocollin 1 in the epidermal keratinocytes was decreased in comparison with that in the pretransferred skin. Immunoelectron microscopy for desmoglein 1 confirmed the reduced immunoreactive deposits along the desmosomal plaques. In the fungus-negative cases, all such changes were a great deal milder. Conclusions. Taken together, our results demonstrate that most intraorally transferred flaps are affected by an inflammatory process that is induced by the influence of the wet oral environment. They present psoriasiform tissue reactions characterized by epidermal hyperproliferation that are mostly due to Candida albicans infection. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:676-84)

Patients with hydroa vacciniforme (HV)-like eruptions and malignant potential have been reported from Asia and Mexico, and those patients frequently had an associated latent Epstein-Barr virus (EBV) infection. In order to elucidate the association of latent EBV infection with HV, we studied six children with typical manifestations of HV by detection of EBV genes and EBV-related RNAs in biopsy specimens from cutaneous lesions. Cutaneous lesions of all six children with typical HV contained EBV-encoded small nuclear RNA (EBER)+ cells in 3-10% of the dermal infiltrates, whereas no Bam HI-H, l-fragment (BHLF) mRNA, or transcripts encoding EA-D antigen, were detected. No EBER + cells were detected in other inflammatory or benign lymphoproliferative skin disorders tested. Polymerase chain reaction amplification confirmed the presence of EBV DNA sequences in five of six biopsy specimens from the patients. Latent EBV infection is associated with the development of cutaneous lesions of HV.

Initiation and aggravation of several inflammatory skin diseases are associated with Malassezia furfur. These are divided into at least two groups. In one group including tinea versicolor and Malassezia folliculitis, the growth of Malassezia furfur directly triggers the development of the cutaneous lesions. In another group including atopic dermatitis, seborrheic dermatitis, and psoriasis, cutaneous lesions already developed by other mechanisms are aggravated by the growth of Malassezia furfur. Recent progress of molecular biology techniques revealed that Malassezia furfur is divided into at least seven species. Since their clinical and histological findings are quite diverse, their differences cannot be explained solely by the difference in antigenicity of each Malassezia. Instead, the cutaneous defense mechanisms against Malassezia furfur must be considered. In this article, we reviewed the mechanisms at three levels: 1) barrier functions of the uppermost layer of the skin, the stratum corneum, 2) cytokine production by epidermal keratinocytes, and 3) immune and inflammatory responses by infiltrating neutrophils and T cells.

Background: The pathogenesis of nummular eczema (NE) is still unknown. It often develops on the lower legs of elderly individuals with xerotic changes during the winter months. Such winter exacerbation is also observed in atopic dermatitis, in which there is a high incidence of cutaneous immune reactivities against environmental aeroallergens. Objective: Because of the total lack of information about skin reactivities in NE patients, we performed immunological as well as functional studies in their uninvolved skin. Method: Prick tests and chamber scarification patch tests for representative aeroallergens were conducted on the flexor surface of the forearm in 26 NE patients, in 21 age-matched elderly persons without NE and in 43 healthy young controls. Results: We found that the elderly subjects, regardless of their background, showed a significantly higher immediate skin reactivity to Candida albicans than the young controls. In contrast, patch testing revealed that, unlike the age-matched elderly subjects who showed a decrease in incidence of positive patch test reations, the NE patients retained delayed contact sensitivity at a level comparable to that of the young healthy controls. They showed a significantly higher percentage of positive patch test reactions to Dermatophagoides farinae allergen (46%) and house dust allergen (35%) than the age-matched controls. Moreover, they also showed a significantly higher percentage of delayed hypersensitive reactions to C. albicans allergen (85%) than the age-matched controls (48%). Noninvasive functional assessment of the stratum corneum (SC) in unaffected skin areas of the lower legs in 8 NE patients demonstrated that, though the water barrier function of the SC was comparable to that of the age-matched controls, they showed a significantly lower hydration state of the SC than the age-matched controls. Conclusion: The xerotic skin of elderly individuals facilitates the development of cracking and fissuring of the skin surface in dry and cold winter. Such damage in the SC is sometimes aggravated by inadvertent scratching due to pruritus, allowing skin permeation of various environmental allergens. They may induce eczematous changes in those with preserved adequate delayed hypersensitivity despite their advanced age.