Case of atopic dermatitis concurrent with idiopathic thrombocytopenic purpura, whose serum thymus and activation-regulated chemokine level remained undetectable.

We report a 9-year-old Japanese female patient with atopic dermatitis associated with idiopathic thrombocytopenic purpura. She demonstrated high serum immunoglobulin (Ig)E and IgE specific to several environmental allergens, but extremely low serum thymus and activation-regulated chemokine (TARC) levels regardless of the disease progression. This case suggests platelets as the main source of serum TARC.

A novel splicing variant of CADM2 as a protective transcript of psoriasis.

CADM2, a candidate gene for psoriasis, was identified by a genome-wide association study using microsatellites in the Japanese population (561 cases and 561 controls). Moreover, haplotype analysis included an additional 68 SNPs and indicated that a 110-kb haplotype block was detected for the protective risk haplotype of psoriasis. We also identified an initial exon of novel splicing variants in this haplotype block. A functional analysis by qRT-PCR using RNAs from the blood of 56 cases and 64 controls significantly demonstrated an inverse correlation between expression frequencies in a novel splicing variant and the number of alleles associated with psoriasis. To confirm these results, we must perform replication studies using other ethnic groups and more functional analysis particularly for skin tissues.

Up-regulation of serpin SCCA1 is associated with epidermal barrier disruption.

BACKGROUND: Parakeratosis, the persistent presence of nuclei in the stratum corneum (SC) is associated with serious disruption of skin barrier function. Squamous cell carcinoma antigen 1 (SCCA1) is strongly up-regulated in inflamed and parakeratotic skin. OBJECTIVE: To find a biochemical marker for the SC barrier disruption, especially the disruption associated with parakeratosis. METHODS: An ELISA assay system was established to quantify SCCA1 in the extract of tape-stripped cornified cells. Transepidermal water loss (TEWL) and other skin parameters were measured and compared with the amount of SCCA1. Localization of SCCA1 was investigated immunohistochemically in various skin diseases with parakeratosis. Nuclei and SCCA1 on the skin surface were detected by staining of corniocytes collected on an adhesive-coated slide glass. RESULTS: SCCA1 showed strong up-regulation in lesional skin with psoriasis (466-fold), hayfever skin caused by Japanese ceder pollen (232-fold) and sun-exposed skin of healthy individuals (90-fold) compared to their normal sun-protected skin. The increased levels of SCCA1 were well correlated with increased values of TEWL and the number of parakeratotic cells in the SC. Furthermore, subjects with high levels of SCCA1 in the epidermis were more susceptible to barrier disruption by external stimuli, and this was accompanied with a further increase of SCCA1. We confirmed that localization of SCCA1 was limited to parakeratotic areas by using the skin surface staining technique. Immunohistochemical study also demonstrated that SCCA1 was always present at high levels in parakeratotic epidermis. CONCLUSION: All of our findings indicate that SCCA1 plays an important role in the induction of epidermal barrier disruption. SCCA1 may be a critical determinant of barrier function in the epidermis.

Neuroselective transcutaneous electrical stimulation reveals neuronal sensitization in atopic dermatitis.

BACKGROUND: The neuroselective transcutaneous electrical stimulator (NTES) can provoke itch and/or pain by the application of a 5-Hz alternating current. OBJECTIVE: We sought to examine whether there is any difference in the perception of the stimulus evoked by the NTES between patients with atopic dermatitis (AD) and healthy control subjects. METHODS: In all, 24 healthy control subjects and 24 patients with AD (nonlesional skin) were stimulated on 7 body sites using the NTES. Qualitative differences in the evoked perceptions and quantitative differences in the current intensity required to evoke perception were statistically analyzed. RESULTS: The NTES preferentially evoked itch in patients with AD. The current perception threshold was statistically lower in AD than in healthy control subjects on 3 body sites. LIMITATIONS: Tests were performed on limited body areas. CONCLUSION: We demonstrated that the NTES can reveal neuronal sensitization to itch in nonlesional atopic skin.

Fine mapping of a psoriasis-susceptibility locus within the HLA class II region by using microsatellite markers in an association study of Japanese cases and controls.

BACKGROUND: The association between psoriasis and the HLA antigens encoded by the Major Histocompatibility Complex (MHC) genomic region is well known, but the role of the HLA class II region in susceptibility to psoriasis is unclear. OBJECTIVE: The purpose of this study is to map the psoriasis-susceptibility locus within the HLA class II region. METHODS: Three hundred seventy five unrelated Japanese patients with psoriasis vulgaris and 375 unrelated Japanese healthy controls were studied by an association analysis using 15 polymorphic microsatellite markers. RESULTS: Statistically significant differences were found at three microsatellite loci. The most significant association of psoriasis vulgaris with the microsatellite markers was found with DRA_CA (pc=0.0000135), the second with DQCARII (pc=0.0000840) and the third with G5_11525 (pc=0.0240). These significant microsatellite markers are in close vicinity to the DQA2, DQB1, DRB1, DRA and BTNL2 genes. CONCLUSION: The results suggest that there are psoriasis susceptibility genes located within the HLA class II region and therefore strongly support previous findings of a positive association between psoriasis and certain alleles of the DQB1 and DRB1 genes.

Neuroselective transcutaneous electric stimulation reveals body area-specific differences in itch perception.

BACKGROUND: Electrically evoked itch has been reported, although the electrodes, the frequency, and the pulse duration used were not standardized. OBJECTIVE: To examine whether a neuroselective transcutaneous electrical stimulator (NTES; Neurometer; Neurotron, Inc, Baltimore, Md) can evoke itch and whether it can provoke itch on any body area. METHODS: Twelve healthy subjects were stimulated on 30 body sites by 5 Hz alternating current produced by the NTES. We classified the evoked perceptions into two sensations (with and without itch) and divided the examined sites into 7 groups: G1, head and neck; G2, arm; G3, palm; G4, the dorsal surface of the hand; G5, knee and leg; G6, dorsal foot; and G7, ankle. The data were then statistically analyzed. RESULTS: The NTES preferentially evoked itch at the G4 and G7 sites, and a sensation without itch at the G1 site. LIMITATION: Tests were performed on limited body areas. CONCLUSION: The NTES can provoke itch, it was discovered that there are body area-specific differences in itch sensation.

Localization of IL-8 and complement components in lesional skin of psoriasis vulgaris and pustulosis palmaris et plantaris.

BACKGROUND: Munro's microabscesses are a characteristic histopathologic feature of psoriasis vulgaris; however, the pathomechanisms underlying the migration of transepidermal leukocytes (PMNs) have not been fully elucidated yet. OBJECTIVE AND METHODS: Since the lesional scale extracts contain potent chemoattractants, such as IL-8 and C5a fragments, we studied their location in the lesions of psoriasis vulgaris and PPP with immunohistochemical techniques. RESULTS: Localization of IL-8 was not detected in the subcorneal keratinocytes but was demonstrated only in the basal keratinocytes together with migrating PMNs. In contrast, the presence of a complement fragment, C3b, was observed on the cell membranes of subcorneal keratinocytes, suggesting that these were the sites of complement activation. CONCLUSION: Such distinct localization of IL-8 and complement components suggests that the intraepidermal migration of PMNs takes place first according to the concentration gradient of IL-8, and thereafter they are guided by complement components to the final destination, the subcorneal portion of the lesional skin.

Cellular basis of the role of diesel exhaust particles in inducing Th2-dominant response.

There is growing evidence that diesel exhaust particles (DEP) can induce allergic diseases with increased IgE production and preferential activation of Th2 cells. To clarify the cellular basis of the role of DEP in the induction of Th2-dominant responses, we examined the effects of DEP on the cytokine production by T cells stimulated with anti-CD3/CD28 Ab and on that by monocyte-derived dendritic cells (MoDCs) stimulated with CD40L and/or IFN-gamma. We examined IFN-gamma, IL-4, IL-5, IL-8, and IL-10 produced by T cells and TNF-alpha, IL-1beta, IL-10, and IL-12 produced by MoDCs using real-time PCR analysis or by ELISA. To highlight the effects of DEP, we compared the effects of DEP with those of dexamethasone (DEX) and cyclosporin A (CyA). DEP significantly suppressed IFN-gamma mRNA expression and protein production, while it did not affect IL-4 or IL-5 mRNA expression or protein production. The suppressive effect on IFN-gamma mRNA expression was more potent than that of DEX and comparable at 30 mug/ml with 10(-7) M CyA. The suppressive effect on IFN-gamma production was also more potent than that of either DEX or CyA. DEP suppressed IL-12p40 and IL-12p35 mRNA expression and IL-12p40 and IL-12p70 production by MoDCs, while it augmented IL-1beta mRNA expression. Finally, by using a thiol antioxidant, N-acetyl cysteine, we found that the suppression of IFN-gamma production by DEP-treated T cells was mediated by oxidative stress. These data revealed a unique characteristic of DEP, namely that they induce a Th2 cytokine milieu in both T cells and dendritic cells.

Indolent herpetic whitlow of the toe in an elderly patient with diabetic neuropathy.

We report a case of indolent herpetic whitlow of the toe occurring in an elderly male patient with poorly controlled diabetes mellitus. In this case, the mechanism of transmission was not clear, although he was in a habit of taking a hot spring bath. This patient's symptoms were unusual for herpes simplex; he had no pain in the presence of diabetic neuropathy. The standard therapeutic dose of acyclovir was not effective in suppressing the lesions, and a higher dose was required to induce complete healing.

Immunopathogenesis of psoriasis.

Psoriasis is characterized by sustained T cell activation by antigen-presenting cells (APCs) in the lesions, and by a deviation of T cell differentiation to type 1 helper T and type 1 cytotoxic T cells, although no specific antigens have yet been determined. These characteristics are at least promoted by decreased IL-10 expression and the increased IL-12 expression observed in both the skin and stimulated peripheral blood mononuclear cells of psoriatic patients. Some of the cytokines produced by activated T cells are suspected to stimulate the proliferation of psoriatic keratinocytes. Among them, interferon-gamma is the most likely candidate, although interferon-gamma does not promote the growth of normal keratinocytes. In addition to the abnormal proliferation, psoriatic keratinocytes show abnormal differentiation and resistance to apoptosis. So far, however, it is still unknown whether these phenotypic and functional characteristics of psoriatic keratinocytes are only the consequences of the stimulation by activated T cells or are at least based on an inherent susceptibility. Recently, it has become clear that chemokines derived from activated keratinocytes or endothelial cells play a crucial role in recruiting T cells in the skin and inducing the neutrophilic infiltration that leads to the formation of subcorneal pustules (Munro's microabscess). Finally, recent developments in the detection and analysis of gene expression have revealed the molecules responsible for these steps. Some of them have become target molecules for the treatment of psoriasis. And indeed, it has become possible now to treat patients with new, innovative drugs.

Ber-EP4 antigen is a marker for a cell population related to the secondary hair germ.

Ber-EP4 is an antibody to a cell membrane glycoprotein of unknown function. In the skin, Ber-EP4 immunoreactivity has been reported to be localized in structures composed of basaloid epithelial cells, i.e. fetal epithelial germ cells, basal cell carcinoma, and trichoepithelioma as well as eccrine or apocrine ducts. In this study, we further characterized the follicular expression of Ber-EP4 immunoreactivity at different stages of the hair cycle of human terminal hair follicles. In addition, to clarify the location of Ber-EP4(+) cells, we compared the Ber-EP4 immunoreactivity with the expression of keratin 15 and keratin 19. Positive staining by Ber-EP4 was found in the lower part of the epithelial strand of late catagen hair follicles, in the secondary hair germ of telogen hair follicles, and in the matrix of early anagen hair follicles but not in any parts of mature anagen hair follicles. In contrast, the follicular expression of keratin 15 detected by using LHK15 antibody was restricted to two distinct parts of anagen hair follicles, i.e. the outer root sheath above the hair bulb and that of the isthmus including the bulge area, and to the outer root sheath of late catagen and telogen hair follicles. The follicular expressions of keratin 19 and that of keratin 15 were apparently superimposed, whereas keratin 15 expression was more extended. The immunoreactivity of LHK15 antibody and antikeratin 19 antibody against the secondary hair germ of telogen follicles was negative or dim. Our results suggest that Ber-EP4 reacts with the secondary hair germ and possibly a cell population related to the secondary hair germ but not with the presumptive stem cell population as revealed immunohistochemically either by the keratin 15 or keratin 19 expression.

Narrowband (312-nm) UV-B suppresses interferon gamma and interleukin (IL) 12 and increases IL-4 transcripts: differential regulation of cytokines at the single-cell level.

OBJECTIVE: To determine whether 312-nm UV-B alters production of effector and regulatory cytokines by viable T cells that remain in psoriatic lesions during UV-B phototherapy. DESIGN: Prospective study. SETTING: General clinical research center of The Rockefeller University Hospital. PATIENTS: Ten adult patients with moderate to severe psoriasis vulgaris that was difficult to manage were sequentially enrolled in our protocols, and biopsies were taken at various time points from resolving lesions. INTERVENTION: Narrowband (312-nm) UV-B was given starting at 50% of a minimum erythema dose, then increased daily 10% to 15% if no apparent erythema was induced. Patients continued with treatment until maximal benefit was noted. In some experiments, T cells were irradiated ex vivo with standard TL-01 fluorescent bulbs (Philips Lighting Co, Somerset, NJ). MAIN OUTCOME MEASURES: Intracellular cytokine staining was done using flow cytometry to quantify numbers of cytokine-producing cells from epidermal and peripheral T cells. The production of messenger RNA for interleukin (IL) 12, interferon (IFN) gamma, tumor necrosis factor alpha, IL-4, and IL-10 was measured by quantitative reverse transcription-polymerase chain reaction. RESULTS: Ultraviolet-B treatment eliminated production of IL-12 messenger RNA and decreased production of IFN-gamma messenger RNA by more than 60% in irradiated psoriasis lesions (P<.03 for both). Within 1 to 2 weeks of starting UV-B treatment, the frequency of viable T cells producing IFN-gamma decreased 40% to 65%. In contrast, mRNA for IL-4 increased by 82% (P =.05) during UV-B treatment, and the number of IL-4-producing cells increased by 228% after 1 week of treatment. In vitro experiments established that, on the single-cell level, survival and cytokine production by type 1 T cells were differentially regulated by UV-B. CONCLUSIONS: Therapeutic UV-B suppresses the type 1 (proinflammatory) axis as defined by IL-12, IFN-gamma, and IL-8, and can selectively reduce proinflammatory cytokine production by individual T cells. Knowledge of the immunomodulatory effects of UV-B will help to integrate this modality in future therapeutics for psoriasis based on deliberate blockade of inflammatory molecular pathways in the type 1 T-cell pathway.