Bifidobacteria are the most prevalent members of the intestinal microbiota in mammals and other animals, and they play a significant role in promoting gut health through their probiotic effects. Recently, the potential applications of Bifidobacteria have been extended to skin health. However, the beneficial mechanism of Bifidobacteria on the skin barrier remains unclear. In this study, keratinocyte HaCaT cells were used as models to evaluate the protective effects of the cell-free supernatant (CFS), heat-inactivated bacteria, and bacterial lysate of Bifidobacterium animalis CGMCC25262 on the skin barrier and inflammatory cytokines. The results showed that all the tested samples were able to upregulate the transcription levels of biomarker genes associated with the skin barrier, such as hyaluronic acid synthetase (HAS) and aquaporins (AQPs). Notably, the transcription of the hyaluronic acid synthetase gene-2 (HAS-2) is upregulated by 3~4 times, and AQP3 increased by 2.5 times when the keratinocyte HaCaT cells were co-incubated with 0.8 to 1% CFS. In particular, the expression level of Filaggrin (FLG) in HaCaT cells increased by 1.7 to 2.7 times when incubated with Bifidobacterial samples, reaching its peak at a concentration of 0.8% CFS. Moreover, B. animalis CGMCC25262 also decreased the expression of the proinflammatory cytokine RANTES to one-tenth compared to the levels observed in HaCaT cells induced with tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). These results demonstrate the potential of B. animalis CGMCC25262 in protecting the skin barrier and reducing inflammatory response.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase. The dysregulation of SYK is closely related to the occurrence and development of allergic diseases, autoimmune diseases and cancer. SYK has become an attractive target for drug discovery due to its important biological functions. This article reviews the biological function of SYK, the relationship between SYK and disease, and therapies targeting SYK. In addition, inspired by new technologies such as proteolysis targeting chimeras (PROTACs) and phosphatase recruiting chimeras (PHORCs), we propose the development of new therapeutic approaches for targeting SYK, such as SYK PROTACs and SYK PHORCs, which may overcome deficiencies of existing methods.

In this work, a lightweight compliant glove that detects scratching using data from microtubular stretchable sensors on each finger and an inertial measurement unit (IMU) on the palm through a machine learning model is presented: the SensorIsed Glove for Monitoring Atopic Dermatitis (SIGMA). SIGMA provides the user and clinicians with a quantifiable way of assaying scratch as a proxy to itch. With the quantitative information detailing scratching frequency and duration, the clinicians would be able to better classify the severity of itch and scratching caused by atopic dermatitis (AD) more objectively to optimise treatment for the patients, as opposed to the current subjective methods of assessments that are currently in use in hospitals and research settings. The validation data demonstrated an accuracy of 83% of the scratch prediction algorithm, while a separate 30 min validation trial had an accuracy of 99% in a controlled environment. In a pilot study with children (n = 6), SIGMA accurately detected 94.4% of scratching when the glove was donned. We believe that this simple device will empower dermatologists to more effectively measure and quantify itching and scratching in AD, and guide personalised treatment decisions.

Although the polyphenols have been studied to alleviate inflammation, there are still challenges to delivering the polyphenols with stabilized formulation due to their low water solubility and susceptibility to oxidation. Herein, the transdermal delivery system of polyphenol mixture (PM), including quercetin (Q), phloretin (P), and ellagic acid (E), is developed using double emulsion for applying to atopic dermatitis (AD). Through the in vitro anti-degranulation assay, the optimal molar ratio of each polyphenol (Q:P:E = 5:1:1) is obtained, and the PM shows at most a 43.6% reduction of degranulation of immune cells, which is the primary factor of AD. Moreover, the water-in-oil-in-water double emulsion (W/O/W) enhances the PM's stability and has a higher anti-degranulation effect than the oil-in-water emulsion (O/W). In the in vivo 1-chloro-2,4-dinitrobenzene (DNCB)-induced mice AD model, PM reduces more AD symptoms than every single polyphenol. The PM-encapsulated W/O/W (PM_W/O/W) shows the most effectiveness in AD by decreasing dermatitis score, i.e., skin/ear thickness, mast cells, and serum IgE level. Finally, this suggests that the findings on the optimal ratio of PM and double emulsion-based delivery would be beneficial in treating AD and can be applied to other allergic diseases.

The microbial environment is an important factor that contributes to the pathogenesis of atopic dermatitis (AD). Recently, it was revealed that not only bacteria itself but also extracellular vesicles (EVs) secreted from bacteria affect the allergic inflammation process. However, almost all research carried out so far was related to local microorganisms, not the systemic microbial distribution. We aimed to compare the bacterial EV composition between AD patients and healthy subjects and to experimentally find out the beneficial effect of some bacterial EV composition.

Twenty-seven AD patients and 6 healthy control subjects were enrolled. After urine and serum were obtained, EVs were prepared from samples. Metagenomic analysis of 16s ribosomal DNA extracted from the EVs was performed, and bacteria showing the greatest difference between controls and patients were identified. In vitro and in vivo therapeutic effects of significant bacterial EV were evaluated with keratinocytes and with Staphylococcus aureus-induced mouse AD models, respectively.

The proportions of Lactococcus, Leuconostoc and Lactobacillus EVs were significantly higher and those of Alicyclobacillus and Propionibacterium were lower in the control group than in the AD patient group. Therefore, lactic acid bacteria were considered to be important ones that contribute to the difference between the patient and control groups. In vitro, interleukin (IL)-6 from keratinocytes and macrophages decreased and cell viability was restored with Lactobacillus plantarum-derived EV treatment prior to S. aureus EV treatment. In S. aureus-induced mouse AD models, L. plantarum-derived EV administration reduced epidermal thickening and the IL-4 level.

We suggested the protective role of lactic acid bacteria in AD based on metagenomic analysis. Experimental findings further suggest that L. plantarum-derived EV could help prevent skin inflammation.

The skin is the site for the photosynthesis of vitamin D and is a target tissue for the active metabolite of vitamin D. An increasing body of evidence indicates that vitamin D produced during phototherapy may be responsible for the positive effects observed during treatment of some skin diseases. Topical or oral application of vitamin D derivatives are used alone or with phototherapy. This paper reviews what is known about the use of phototherapy to enhance vitamin D levels, the use of vitamin D analogues with phototherapy, the efficacy of combination therapies, and controversies regarding some of the outcomes. Vitamin D can play a beneficial role in treating psoriasis, even though the exact role of vitamin D in the pathogenesis and severity of psoriasis remains unclear. The role of vitamin D in vitiligo, atopic dermatitis, polymorphic light eruption, and mycosis fungoides must be further investigated.

Atopic dermatitis affects 15-30% of children worldwide. Onset of disease usually occurs within the first year of life, over half of which regress by 6 years of age. The aim of this study was to investigate the risk factors related to the persistence of infantile atopic dermatitis.

In this birth cohort study, patients were enrolled prenatally and followed until 6 years of age; 246 patients had infantile atopic dermatitis at 6 months of age. Family history, maternal and paternal total and specific Immunoglobulin E (IgE) levels, and cord blood IgE were recorded. Clinical examination, questionnaire survey, and blood samples for total and specific IgE of the children were collected at each follow-up visit.

Of the 246 patients with infantile atopic dermatitis at 6 months of age, 48 patients had persisted atopic dermatitis at 6 years of age (19.5%). Risk factors associated with persistent infantile atopic dermatitis included egg white sensitization (odds ratio: 3.801, P = 0.020), and atopic dermatitis involving two or more areas at 6 months old (odds ratio: 2.921, P = 0.018) after multivariate analysis with logistic regression. Patients with persistent infantile atopic dermatitis had a higher risk of asthma before 6 years old (39.6% vs 24.2%, P = 0.032).

Egg white sensitization and the initial involvement of two or more areas at 6 months of age were associated with the persistent infantile atopic dermatitis. Patients with persistent infantile atopic dermatitis are more likely to develop asthma by 6 years of age.

Atopic dermatitis (AD) (or atopic eczema) is a chronic inflammatory skin condition that affects children and adults and has an important impact on quality of life. Topical corticosteroids (TCS) are the first-line therapy for this condition; however, they can be associated with significant adverse effects when used chronically. Tacrolimus ointment (in its 2 manufactured strengths of 0.1% and 0.03%) might be an alternative treatment. Tacrolimus, together with pimecrolimus, are drugs called topical calcineurin inhibitors (TCIs).

To assess the efficacy and safety of topical tacrolimus for moderate and severe atopic dermatitis compared with other active treatments.

We searched the following databases up to 3 June 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 5, 2015), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), and the Global Resource of Eczema Trials (GREAT database). We searched six trials registers and checked the bibliographies of included studies for further references to relevant trials. We contacted specialists in the field for unpublished data.A separate search for adverse effects of topical tacrolimus was undertaken in MEDLINE and EMBASE on 30 July 2013. We also scrutinised the U.S. Food and Drug Administration (FDA) websites for adverse effects information.

All randomised controlled trials (RCTs) of participants with moderate to severe atopic dermatitis (both children and adults) using topical tacrolimus at any dose, course duration, and follow-up time compared with other active treatments.

Two authors independently screened and examined the full text of selected studies for compliance with eligibility criteria, risk of bias, and data extraction. Our three prespecified primary outcomes were physician's assessment, participant's self-assessment of improvement, and adverse effects. Our secondary outcomes included assessment of improvement of the disease by validated or objective measures, such as SCORAD (SCORing Atopic Dermatitis), the EASI (Eczema Area and Severity Index), and BSA (Body Surface Area) scores.

We included 20 studies, with 5885 participants. The variability of drug doses, outcomes, and follow-up periods made it difficult to carry out meta-analyses.A single trial showed that tacrolimus 0.1% was better than low-potency TCS by the physician's assessment (risk ratio (RR) 3.09, 95% confidence interval (CI) 2.14 to 4.45, 1 study, n = 371, moderate-quality evidence). It was also marginally better than low-potency TCS on face and neck areas and moderate-potency TCS on the trunk and extremities by the physician's assessment (RR 1.32, 95% CI 1.17 to 1.49, 1 study, n = 972, moderate level of evidence) and for some of the secondary outcomes. Compared with pimecrolimus 1%, people treated with tacrolimus were almost twice as likely to improve by the physician's assessment (RR 1.80, 95% CI 1.34 to 2.42, 2 studies, n = 506, moderate quality of evidence). Compared with the lower concentration of 0.03%, the tacrolimus 0.1% formulation reduced the risk of not having an improvement by 18% as evaluated by the physician's assessment (RR 0.82, 95% CI 0.72 to 0.92, 6 studies, n = 1640, high-quality evidence). Tacrolimus 0.1% compared with moderate-to-potent TCS showed no difference by the physician's assessment, and 2 secondary outcomes (1 study, 377 participants) and a marginal benefit favouring tacrolimus 0.1% was found by the participant's assessment (RR 1.21, 95% CI 1.13 to 1.29, 1 study, n = 974, low quality of evidence) and SCORAD.Based on data from 2 trials, tacrolimus 0.03% was superior to mild TCS for the physician's assessment (RR 2.58, 95% CI 1.96 to 3.38, 2 studies, n = 790, moderate-quality evidence) and the participant's self-assessment (RR 1.64, 95% CI 1.41 to 1.90, 1 study, n = 416, moderate quality of evidence). One trial showed moderate benefit of tacrolimus 0.03% compared with pimecrolimus 1% on the physician's assessment (RR 1.42, 95% CI 1.02 to 1.98, 1 study, n = 139, low-quality evidence), but the effects were equivocal when evaluating BSA. In the comparison of tacrolimus 0.03% with moderate-to-potent corticosteroids, no difference was found in most of the outcomes measured (including physician's and participant's assessment and also for the secondary outcomes), but in two studies, a marginal benefit favouring the corticosteroid group was found for the EASI and BSA scores.Burning was more frequent in those using calcineurin inhibitors than those using corticosteroid tacrolimus 0.03% (RR 2.48, 95% CI 1.96 to 3.14, 5 studies, 1883 participants, high-quality evidence), but no difference was found for skin infections. Symptoms observed were mild and transient. The comparison between the two calcineurin inhibitors (pimecrolimus and tacrolimus) showed the same overall incidence of adverse events, but with a small difference in the frequency of local effects.Serious adverse events were rare; occurred in both the tacrolimus and corticosteroid groups; and in most cases, were considered to be unrelated to the treatment. No cases of lymphoma were noted in the included studies nor in the non-comparative studies. Cases were only noted in spontaneous reports, cohorts, and case-control studies. Systemic absorption was rarely detectable, only in low levels, and this decreased with time. Exception is made for diseases with severe barrier defects, such as Netherton's syndrome, lamellar ichthyosis, and a few others, with case reports of a higher absorption. We evaluated clinical trials; case reports; and in vivo, in vitro, and animal studies; and didn't find any evidence that topical tacrolimus could cause skin atrophy.

Tacrolimus 0.1% was better than low-potency corticosteroids, pimecrolimus 1%, and tacrolimus 0.03%. Results were equivocal when comparing both dose formulations to moderate-to-potent corticosteroids. Tacrolimus 0.03% was superior to mild corticosteroids and pimecrolimus. Both tacrolimus formulations seemed to be safe, and no evidence was found to support the possible increased risk of malignancies or skin atrophy with their use. The reliability and strength of the evidence was limited by the lack of data; thus, findings of this review should be interpreted with caution. We did not evaluate costs.

Atopic dermatitis (AD) is a public health problem, with an increasing prevalence worldwide. AD is a chronic inflammatory disease characterised by skin lesions and severe itching. Immunologically, AD has two forms, IgE-mediated and cell-mediated, but it may also be idiopathic. In the pathogenesis of AD, the gene mutations for filaggrin, a filament-aggregating protein present in the epidermis, are of pivotal importance, but other genetic factors are also operating, including those linked to family atopy.

We evaluated the role of family atopy, and of the results of the atopy patch test (APT) in parents, in children with mite-induced AD. 64 children, 38 males and 26 females, mean age 4.97 years, were included for the diagnosis of AD and underwent APT and skin prick test (SPT) with dust mite extracts, with evaluation of atopy and result of APT also in parents.

A positive family history of atopy was shown for children with positivity to both APT and SPT compared to those with negative or only one positive result to APT or SPT (p=0.08). Significant associations were found concerning APT results in children and parents. In particular, children of a positive-APT parent had an 18-fold higher risk of APT-positivity in comparison with children of negative-APT parents, while the risk was 6.6-fold higher if APT was positive in father.

Family atopy and a positive APT in fathers are risk factors to develop cell-mediated AD, as assessed by the APT, in children.

Due to the steadily increasing incidence of atopic dermatitis, there is a great medical need for new therapies and improved animal models.

To provide more detailed analysis of a Sprague-Dawley rat dermatitis model.

Sprague-Dawley rats were actively sensitized by intraperitoneal injections of dinitrophenylated ovalbumin (DNP-OVA) plus alum. Skin reactions were elicited by repeated epicutaneous challenge with 2,4-dinitrofluorobenzene (DNFB).

The ear thickness exhibited a significant increase from the first challenge. A relatively steep increase in ear thickness was observed at the fifth DNFB application. After the fifth DNFB application, total serum immunoglobulin (Ig) E and IgG1 levels reached a plateau at 1 h compared with the normal group. The peak production of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 was found at 1 h, while that of intercellular adhesion molecule (ICAM)-1 was found at 24 h. Infiltration of CD4+ T cells, CD8+ T cells, eosinophils and mast cells increased in the skin lesion.

The indices such as thickness and inflammatory cell infiltration in the lesional skin were increased by repeated hapten application; TNF-α, MCP-1 and ICAM-1 increased with the development of the dermatitis.

Drynaria fortunei (Kunze) J. Sm has been widely used in traditional medicine for the treatment of inflammation, hyperlipidemia, arteriosclerosis, rheumatism, and bone healing. We investigated the anti-inflammatory effects of a 70% ethanol extract of Drynaria fortunei (DFE).

We evaluated the anti-inflammatory effects of topically applied DFE on house dust mite Dermatophargoides farinae-induced atopic dermatitis-like skin lesions in NC/Nga mice.

Treatment of NC/Nga mice with DFE reduced the dermatitis score, ear thickness, and serum levels of IgE, IgG1, and IL-6. Histopathological analyses of ear and skin lesions showed inhibition of the thickening of the epidermis and reduced epidermal/dermal infiltration of inflammatory cells. In ear lesions, mRNA expression levels of IL-4, IL-6, and tumor necrosis factor-α were reduced by DFE treatment.

DFE inhibited the development of dermatitis-like skin lesions in NC/Nga mice. These results suggest that DFE may be a therapeutic candidate for the treatment of AD.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease affecting > 10% of children and 1-3% of adults, and can cause significant morbidity. The incidence of AD seems to be increasing. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for patients with recalcitrant AD with elevated IgE levels, based on its efficacy in treating asthma and allergic rhinitis. We report a study of 10 patients with AD (aged 19-35 years) who received anti-IgE treatment for persistent asthma. All patients, regardless of IgE value, were treated with a fixed schedule of eight cycles of omalizumab 300 mg administered subcutaneously at intervals of 2 weeks. Eczema symptoms were scored at baseline and after 2, 4 and 6 months of treatment. There was a steady improvement in the objective SCORAD (SCORing Atopic Dermatitis), with significantly lower scores observed at the 6-month evaluation. At 2 months after the end of treatment, two patients had a very good result (SCORAD reduction of > 50%), five patients had a satisfactory result (reduction of 25-50%), and three patients had no clinically relevant result (reduction of 25-50%). No patient had worsening of the AD (increase of > 25% in SCORAD), and once a clinical improvement occurred, none of the patients experienced worsening of their eczema symptoms while on omalizumab. With the caveats of the financial expense and unknown long-term risks of malignancy associated with omalizumab, this drug should be considered for treatment-resistant patients with AD, particularly patients with high IgE level whose symptoms are not controlled by routine therapies. Omalizumab has proven useful in treating asthma, but it may also prove valuable for other conditions, such as allergic rhinitis, food allergies, chronic urticaria, and AD, as shown by the present study.

Astragalus membranaceus (AM) is one of the most popular health-promoting herbs in East Asia, and has been used in traditional medicine for more than 2000 years. This study was performed to examine whether AM suppresses atopic dermatitis (AD)-like skin lesions in BALB/c mice. Seven-week-old female BALB/c mice were sensitized with 1-chloro-2,4-dinitrobenzene (DNCB) to induce allergic dermatitis. Skin sections were stained with hematoxylin and eosin (H&E) to assess epidermal and dermal hyperplasia, which were determined by measuring the thicknesses of the epidermis and dermis, respectively. The serum immunoglobulin G (IgE) concentration was quantified by enzyme-linked immunosorbent assay (ELISA). In addition, the levels of interleukins (IL)-4, -5, -6, and -13 and tissue necrosis factor (TNF)-α were measured in mouse serum. Significance was determined by one-way analysis of variance (ANOVA). Topical AM markedly improved the AD skin lesions in DNCB-induced mice. The AD skin lesions were significantly thinner in the AM treatment group compared with untreated controls, and the hyperkeratosis disappeared. Topical treatment of AM also restored nuclear factor-κB (NF-κB) expression. In addition, the serum IgE level was reduced. AM suppressed the expression of Th2 cytokines (IL-4, -5, -6, and -13) and significantly decreased the TNF-α level. AM is effective for treating AD by regulating cytokines. AM may be an alternative or complementary therapeutic option for treating patients with AD. More in-depth studies are necessary to clarify the mechanisms of AM.

Interferon (IFN)-γ, a potent T helper 1 (Th1) cell cytokine, is suggested to suppress Th2 cell responses. Here, we aimed to investigate whether pCpG-Muγ, a plasmid continuously expressing murine IFN-γ, is an effective treatment of atopic dermatitis, a Th2-dominant skin disease. Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) atopic mice with early dermatitis were transfected with pCpG-Muγ by a hydrodynamic tail vein injection at a dose of 0.05 or 0.2 pmol per mouse. The skin lesions improved only in mice receiving the high dose of pCpG-Muγ. IFN-γ gene transfer resulted in a high mRNA expression of IFN-γ and interleukin (IL)-12 and regulatory T cell (Treg) related cytokines, such as IL-10 and transforming growth factor-β, in the spleen, whereas it reduced the IL-4 mRNA expression, and serum levels of immunoglobulin (Ig) G1 and IgE. In addition, the gene transfer markedly inhibited the epidermal thickening, infiltration of inflammatory cells into the skin, the occurrence of dry skin and pruritus. No exacerbating effect on the Th1-mediated contact dermatitis was observed after IFN-γ gene transfer. Taken together, these results indicate that sustained IFN-γ gene transfer induced polarized Th1 immunity under Th2-dominant conditions in NC/Nga mice, leading to an improvement in the symptoms of acute atopic dermatitis without adverse side effects.

Atopic dermatitis (AD) is a common, chronic or chronically relapsing, multifactorial skin disease that mainly occurs in children but affects also adults. AD usually begins early in life and often concerns people with a personal or family history of asthma and allergic rhinitis. AD is characterized by eczematous changes in the epidermis and originates from a late, T-cell mediated reaction associated to the formation and production of memory T-cell of TH2 type, occurrence of homing receptor at skin level and cutaneous lymphocyte-associated (CLA) antigens. Extrinsic or allergic AD, but not intrinsic AD, shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens. A pivotal role in the pathogenesis of AD is played by filaggrin, a protein contained in the granular layer of the epidermis regulating the aggregation of keratin filaments. Mutation in the filaggrin gene causes decreased barrier function of the corny layers of the epidermis. This favours the enter through the skin of environmental allergens, especially the house dust mite, that further facilitates such entering by the proteolytic activity of its major allergen Der p 1. In fact, recent advances suggest that the dust mite, more than foods, is the major cause of allergic AD. As far as the causal diagnosis of AD is concerned, there is notable evidence supporting the capacity of the atopy patch test (APT) to reproduce the pathophysiologic events of AD. This makes APT a valuable diagnostic tool for AD.

Topical corticosteroids and calcineurin inhibitors are well-known treatments of atopic dermatitis (AD) but differ in their efficacy and side effects. We recently showed that betamethasone valerate (BM) although clinically more efficient impaired skin barrier repair in contrast to pimecrolimus in AD.

This study elucidates the mode of action of topical BM and pimecrolimus cream in AD.

Lesional AD skin samples after topical treatment with either BM or pimecrolimus were subjected to gene expression profile analysis.

Betamethasone valerate resulted in a significant reduction in mRNA levels of genes encoding markers of immune cells and inflammation, dendritic cells, T cells, cytokines, chemokines, and serine proteases, whereas pimecrolimus exerted minor effects only. This corroborates the clinical finding that BM reduces inflammation more effectively than pimecrolimus. Genes encoding molecules important for skin barrier function were differently affected. Both BM and pimecrolimus normalized the expression of filaggrin and loricrin. BM, but not pimecrolimus, significantly reduced the expression of rate-limiting enzymes for lipid synthesis and the expression of involucrin and small proline-rich proteins, which covalently bind ceramides. This may explain the lack of restoration of functional stratum corneum layers observed after BM treatment.

The gene expression profiles are consistent with our previous findings that corticosteroids may exert a more potent anti-inflammatory effect but may impair the restoration of the skin barrier. Corticosteroids are still the main treatment for severe and acutely exacerbated AD; pimecrolimus may be preferable for long-term treatment and stabilization.

Conflicting data exist on the number of invariant NKT (iNKT) cells in atopic dermatitis (AD); furthermore, no data have been published on their functional capacity.

The frequency and number of circulating CD3+6B11+ iNKT cells and their CD4+ and CD4- subpopulations were evaluated in peripheral blood obtained from 41 patients with AD by four-color flow cytometry. Likewise, functional properties of iNKT cells were measured by five-color intracellular cytokine staining.

The number and percentage of total iNKT cells and their CD4/CD8 subpopulations were significantly lower than the controls. Of further importance, the CD4-CD8- (double negative, DN) iNKT subgroup showed the strongest positive correlation with total iNKT cells. In addition, the DN subgroup exhibited the most pronounced functional alteration with significantly decreased levels of intracellular IFNγ and significantly increased levels of intracellular IL-4 in AD patients compared with the controls.

The significantly altered number and cytokine production of iNKT cells from AD patients suggests that these cells may play an important role in the pathogenesis of AD.

Immunophilin, FK506-binding protein 12 (FK506BP), is a receptor protein for the immunosuppressive drug FK506 by the FK506BP/FK506 complex. However, the precise function of FK506BP in inflammatory diseases remains unclear. Therefore, we examined the protective effects of FK506BP on atopic dermatitis (AD) in tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-induced HaCaT cells and 2,4-dinitrofluorobenzene-induced AD-like dermatitis in Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice using a cell-permeable PEP-1-FK506BP. Transduced PEP-1-FK506BP significantly inhibited the expression of cytokines, as well as the activation of NF-κB and mitogen-activated protein kinase (MAPK) in TNF-α/IFN-γ-induced HaCaT cells. Furthermore, topical application of PEP-1-FK506BP to NC/Nga mice markedly inhibited AD-like dermatitis as determined by a histological examination and assessment of serum IgE levels, as well as cytokines and chemokines. These results indicate that PEP-1-FK506BP inhibits NF-κB and MAPK activation in cells and AD-like skin lesions by reducing the expression levels of cytokines and chemokines, thus suggesting that PEP-1-FK506BP may be a potential therapeutic agent for AD.

Korean red ginseng (KRG, Panax ginseng C.A. Meyer) has traditionally been considered to harbor anti-allergic effects, however its action on atopic dermatitis (AD) is unclear. Therefore, we investigated the effect of KRG on AD using NC/Nga mice as an AD model. In addition, we examined the effect of aprepitant (substance P specific neurokinin receptor antagonist) on AD.

The KRG extract and aprepitant were administered orally to NC/Nga mice. The efficacy of KRG and aprepitant was evaluated by assessing total clinical severity score, ear thickness, serum IgE level and histology. In addition, mRNA and protein expression were measured by real-time RT-PCR and immunohistochemistry, respectively.

The KRG extract significantly reduced the total clinical severity score, ear thickness and the level of serum IgE in AD mouse model, whereas aprepitant reduced only the serum IgE level. KRG not only decreased TNF-α, IFN-γ and substance P but also reduced the infiltration of FOXP3+ regulatory T (Treg) cells and CD1a+ Langerhans cells in the lesions, whereas aprepitant decreased only substance P and the infiltration of Treg cells.

These results suggest that KRG extract may be a potential therapeutic modality for AD and aprepitant could be used as adjunctive agent to control pruritus in AD.

Eczema is a chronic inflammatory disorder of the skin that affects up to 30% of children. It often afflicts infants in the first few months of life and can be the first indicator of the atopic march. Recent results from birth cohort studies have uncovered novel information regarding genetic and environmental factors that promote the development of eczema. Birth cohort studies provide an optimal study design to elucidate these associations and prospectively track longitudinal data including exposure assessment and health outcomes from birth into early life and childhood. This is especially relevant for eczema given the age specific emergence of this disease. In this review, we will provide a general overview of pediatric eczema and discuss the important findings in the literature with respect to genetics and environmental exposures, highlighting those derived from birth cohort studies. Additionally, we will review how these relate to the atopic march, the hygiene hypothesis and the integrity of the skin barrier.

The atopy patch test (APT) was recently defined as an important tool in diagnosis of atopic dermatitis (AD) and also of rhinitis and asthma caused by hypersensitivity to the house dust mites. We evaluated 465 children (279 males and 186 females) aged 0.4-17.6 years (mean 6.6 +/- 3.8 years), by dividing them into four groups: group A, current AD (40 patients); group B, current AD with respiratory symptoms (156 patients); group C, past AD with respiratory symptoms (203 patients); and the control group, respiratory symptoms with no history of AD (66 patients). The APT was significantly more frequently positive in groups with current AD (groups A and B) or past AD (group C) than in the control group, while skin prick test (SPT) and radioallergosorbent test (RAST) were significantly more frequently positive in the control group. With multivariate analysis, for APT, significant differences were found in the comparison between group A vs group B (odds ratio (OR) 1.55) and between group A vs group C (OR 1.81). The mean age was significantly lower in group A than in groups B, C, and the control group and with less significance in groups C vs D. Children sensitized to mites with current or past AD, with or without respiratory symptoms, have a different response to diagnostic tests, which is characterized by a highly significantly more frequent positive APT in comparison with subjects who have respiratory symptoms but a negative history for AD, who show the common response to SPT and RAST.

Probiotics have been suggested to be useful in children with atopic eczema-dermatitis syndrome (AEDS).

To assess the clinical effect of Lactobacillus sakei supplementation in children with AEDS.

In a double-blind, placebo-controlled trial, children aged 2 to 10 years with AEDS with a minimum SCORing of Atopic Dermatitis (SCORAD) score of 25 were randomized to receive either daily L sakei KCTC 10755BP or daily placebo supplementation for 12 weeks. Changes in SCORAD scores and serum chemokine levels from baseline were evaluated.

Eighty-eight children were enrolled, and 45 were allocated to probiotic treatment. Seventy-five children completed the study, with 4 dropouts in the probiotic group and 9 in the placebo group. At week 12, SCORAD total scores adjusted by pretreatment values were lower after probiotic treatment than after placebo treatment (P = .01). There was a 31% (13.1-point) improvement in mean disease activity with probiotic use compared with a 13% (5.2-point) improvement with placebo use (P = .008). Significant differences in favor of probiotic treatment were also observed in proportions of patients achieving improvement of at least 30% and 50%. Compared with placebo, probiotic administration was associated with lower pretreatment-adjusted serum levels of CCL17 and CCL27 (P =.03 for both), which were significantly correlated with SCORAD total score (r = 0.59 and 0.63, respectively; P < .001).

Supplementation of L sakei in children with AEDS was associated with a substantial clinical improvement and a significant decrease in chemokine levels, reflecting the severity of AEDS.

Human skin can defend itself against potentially invading microorganisms by production of antimicrobial peptides (AMPs). The expression of AMPs in atopic dermatitis (AD) is still emerging. To gain more insight into the role of AMPs in AD, we systematically analyzed the expression of ribonuclease 7 (RNase 7), psoriasin, and human beta-defensins (hBD)-2 and -3 in AD compared with psoriatic and healthy control skin as well as after experimental barrier disruption. Immunostaining revealed enhanced expression of all AMPs in the lesional skin of untreated AD and psoriasis when compared with non-lesional skin and controls. Accordingly, induced in vivo secretion of RNase 7, psoriasin, and hBD-2 was detected using ELISA on lesional skin in AD and in even higher concentrations in psoriasis. The secretion of AMPs did not correlate with severity of AD and Staphylococcus aureus colonization. Skin barrier disruption caused enhanced immunoreactivity of hBD-2 and hBD-3 after 24 hours. Strong secretion of RNase 7 was already detected after 1 hour, whereas hBD-2 secretion was significantly enhanced after 24 hours only under occlusion. Thus, a disturbed skin barrier may trigger AMP induction in AD and psoriasis. The functional role of AMP in AD, especially with regard to the control of S. aureus colonization, needs further analysis.

Atopic dermatitis (AD) is a common complex disease that frequently follows a chronic relapsing course and affects the quality of life of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Patients with AD have a unique predisposition to colonization or infection by a number of microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. A multipronged approach directed at healing or protecting the skin barrier and addressing the immune dysregulation is necessary to improve the likelihood of successful outcomes.

B cell-activating factor (BAFF) is a tumour necrosis factor superfamily member best known for its role in the survival and maturation of B cells. BAFF activity is seen in naïve and effector/memory T cells.

To investigate the level and role of BAFF in serum of patients with atopic dermatitis (AD).

Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.

Patients were characterized as having atopic eczema (AE) (n = 90) or non-AE (n = 77); the remainder were healthy control subjects (n = 78). Serum BAFF level in children with AE (1625.04 +/- 708.32 pg/mL) was significantly higher than in non-AE children (1194.69 +/- 448.44 pg/mL, P < 0.0001) or healthy controls (1062.89 +/- 444.74 pg/mL, P < 0.0001). Serum APRIL level was not different between the three groups. Serum BAFF level significantly correlated with total serum IgE level (gamma = 0.42, P < 0.0001) and total eosinophil count. It was also positively correlated with serum BAFF and egg-specific IgE level (gamma = 0.252, P = 0.045) in AE.

Serum BAFF level is high in AE and might be a useful marker for AE.

Mutations in the human filaggrin gene (FLG) are associated with atopic dermatitis (AD) and are presumed to provoke a barrier abnormality. Yet additional acquired stressors might be necessary because the same mutations can result in a noninflammatory disorder, ichthyosis vulgaris.

We examined here whether FLG deficiency alone suffices to produce a barrier abnormality, the basis for the putative abnormality, and its proinflammatory consequences.

By using the flaky-tail mouse, which lacks processed murine filaggrin because of a frameshift mutation in the gene encoding profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality, further localized the defect, identified its subcellular basis, and assessed thresholds to irritant- and hapten-induced dermatitis.

Flaky-tail mice exhibit low-grade inflammation with increased bidirectional, paracellular permeability of water-soluble xenobiotes caused by impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens at doses that produce no inflammation in wild-type mice, flaky-tail mice experience a severe AD-like dermatosis with a further deterioration in barrier function and features of a T(H)2 immunophenotype (increased CRTH levels plus inflammation, increased serum IgE levels, and reduced antimicrobial peptide [mBD3] expression).

FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD.

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Diarylheptanoids such as oregonin and hirstanonol are demonstrated to have anti-inflammatory and anti-oxidant effects. The present study was to investigate the effect of hirsutenone, one of the diarylheptanoids, against tumor necrosis factor (TNF)-alpha-stimulated responses in human keratinocytes. Hirsutenone attenuated the TNF-alpha-induced production of cytokine IL-8, prostaglandin E(2) and chemokine CCL27, and the formation of reactive oxygen/nitrogen species in keratinocytes. Immunosuppressants (dexamethasone and cyclosporin A) inhibited the TNF-alpha-elicited formation of IL-8, prostaglandin E(2) and CCL27, but did not affect formation of reactive species. Bay 11-7085 (an inhibitor of NF-kappaB activation) and anti-oxidant N-acetylcysteine attenuated the TNF-alpha-induced formation of inflammatory mediators and reactive species. Hirsutenone, dexamethasone, cyclosporin A and Bay 11-7085 inhibited the TNF-alpha-induced phosphorylation of inhibitory kappaB and the activation of nuclear factor (NF)-kappaB. The results show that hirsutenone seems to reduce the TNF-alpha-stimulated production of inflammatory mediators in keratinocytes by suppressing the activation of NF-kappaB that may be mediated by reactive oxygen species. The findings suggest that hirsutenone may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease.

Rigorous research in the field of probiotics is a fairly new phenomenon although first reports about beneficial effects of specific gut bacteria on human health originated already a century ago. A prerequisite for such a scrutiny has been a definition of criteria for probiotics. Recently, novel molecular technologies have characterized both potential targets of probiotic action, like gut microbiota and established and candidate probiotic strains in more detail. We thus propose here revised criteria for selection ofprobiotics. In addition to several promising clinical studies e.g., in the prevention and treatment of atopic eczema, certain probiotics have been found to maintain intestinal equilibrium by enhancing the gut mucosal barrier via manipulation of expression of several their own and the host's genes. Introduction of genetic engineering has provided advanced tools to amend probiotics' properties in the fight against different inflammatory conditions.

Basophils express not only high-affinity IgE receptors, but also low-affinity IgG receptors. Which, among these receptors, are expressed by human basophils is poorly known. Low-affinity IgG receptors comprise CD32 (FcgammaRIIA, FcgammaRIIB, and FcgammaRIIC) and CD16 (FcgammaRIIIA and FcgammaRIIIB). FcgammaRIIA, FcgammaRIIC, and FcgammaRIIIA are activating receptors, FcgammaRIIB are inhibitory receptors, FcgammaRIIIB are GPI-anchored receptors whose function is poorly understood. Basophils were reported to express FcgammaRII, but not FcgammaRIII. We aimed at further identifying basophil IgG receptors. Basophils from normal donors and from patients suffering from an allergic skin disease (atopic dermatitis), allergic respiratory diseases (allergic rhinitis and asthma), or a nonallergic skin disease (chronic urticaria) were examined. We found that normal basophils contain FcgammaRIII transcripts and express FcgammaRIIIB, but not FcgammaRIIIA, which were detected on 24-81% basophils from normal donors and on 12-100% basophils from patients. Noticeably, the proportion of FcgammaRIIIB(+) basophils was significantly lower in atopic dermatitis patients than in other subjects. This decreased FcgammaRIII expression was not correlated with an activated phenotype of basophils in atopic dermatitis patients, although FcgammaRIIIB expression was down-regulated upon basophil activation by anti-IgE. Our results challenge the two dogmas 1) that basophils do not express FcgammaRIII and 2) that FcgammaRIIIB is exclusively expressed by neutrophils. They suggest that a proportion of basophils may be lost during enrichment procedures in which FcgammaRIII(+) cells are discarded by negative sorting using anti-CD16 Abs. They unravel an unexpected complexity of IgG receptors susceptible to modulate basophil activation. They identify a novel systemic alteration in atopic dermatitis.

IL-13 has been implicated in the pathogenesis of allergic diseases, including atopic dermatitis (AD). However, a direct role of IL-13 in AD has not been established. We aimed to develop an inducible transgenic model in which IL-13 can be expressed in the skin and to define the resulting dermal phenotype and mechanisms involved. The keratin 5 promoter was used with a tetracycline-inducible system to target IL-13 to the skin. The clinical manifestations, dermal histology, cytokine gene regulation, and systemic immune responses in the transgenic mice were assessed. IL-13 was produced exclusively in the skin and caused a chronic inflammatory phenotype characterized by xerosis and pruritic eczematous lesions; dermal infiltration of CD4+ T cells, mast cells, eosinophils, macrophages, and Langerhans cells; upregulation of chemokine and cytokine genes, including thymic stromal lymphopoietin; and skin remodeling with fibrosis and increased vasculature. The dermal phenotype was accompanied by elevated serum total IgE and IgG1 and increased production of IL-4 and IL-13 by CD4+ cells from lymphoid tissues and peripheral blood mononuclear cells. IL-13 is a potent stimulator of dermal inflammation and remodeling and this transgenic model of AD is a good tool for investigating the underlying mechanisms in the pathogenesis of AD.

Atopic dermatitis (AD) is one of the most frequent chronic inflammatory skin diseases with an increasing prevalence. About 80% of adult AD patients are sensitized against seasonal or perennial aeroallergens and/or food allergens which may play a pivotal role in triggering or maintaining eczema. In addition to local and systemic therapy adjusted to the stage of the disease, the search for relevant trigger factors and then their avoidance plays a crucial role in managing AD. While the effectiveness of SIT is best established in allergic rhinitis, bronchial asthma and insect venom allergy, its use in AD is still controversial. Double-blind, placebo-controlled clinical studies are now available showing good efficacy of SIT in patients with AD. For food allergies there are clues from case reports and small clinical studies suggesting effectiveness of SIT both for food allergies and associated aeroallergens. Double-blind, placebo-controlled studies involving larger numbers of patients are needed to establish the clinical effectiveness and immunologic mechanisms of SIT in food allergies.