The presence of skin microbiome on the surface of the skin and their involvement in the host immunological homeostasis and in the pathogenesis of inflammatory skin diseases is becoming elucidated. ...Staphylococcus aureus (S. aureus) has long been known to colonize the skin of patients with atopic dermatitis (AD), but its involvement in the pathogenesis of the disease was unknown. Recent studies have shown that AD patients experience a disruption of the bacterial balance (dysbiosis), in which the diversity of the microbiome decreases and the number of S. aureus increases during flare, and that this may contribute to the worsening of the dermatitis. Several S. aureus-targeted therapies have been developed and have shown some efficacy on AD.
TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require ...heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined.
Background Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which ...skin barrier function is disrupted in patients with AD remains unclear. Objectives Taking into account the fact that the TH 2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. Methods We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. Results IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. Conclusion STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
Background Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although ...many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. Objective We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin. Methods Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg -mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23–injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays. Results IL-23–injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysis–derived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust TH 1, TH 2, and also TH 17 activation are seen in IL-23–injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a TH 1-centered reaction, and flaky tail mice demonstrate a strong TH 17 polarization. Flg -mutated mice display filaggrin downregulation without significant inflammation. Conclusion No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23–injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.
Atopic dermatitis (AD) is generally regarded as a type 2 helper T (Th2)-mediated inflammatory skin disease. Although the number of IL-17A-producing cells is increased in the peripheral blood and in ...acute skin lesion of AD patients, the role of IL-17A in the pathogenesis of AD remains unclear. To clarify this issue, we used murine AD models in an IL-17A-deficient condition. In a repeated hapten application–induced AD model, skin inflammation, IL-4 production in the draining lymph nodes (LNs), and hapten-specific IgG1 and IgE induction were suppressed in IL-17A-deficient mice. Vγ4+ γδ T cells in the skin-draining LNs and Vγ5- dermal γδ T cells in the skin were the major sources of IL-17A. Consistently, in flaky-tail (Flgft/ftma/ma) mice, spontaneous development of AD-like dermatitis and IgE induction were attenuated by IL-17A deficiency. Moreover, Th2 differentiation from naive T cells was promoted in vitro by the addition of IL-17A. Taken together, our results suggest that IL-17A mediates Th2-type immune responses and that IL-17A signal may be a therapeutic target of AD.
•Estimated Yearly prevalence per million was 2.5 for SJS and 1 for TEN.•Mean age was 53.9 years for SJS, and 61.8 years for TEN.•Mortality rate was 4.1 % for SJS, and 29.9 % for TEN.•In TEN, mean age ...and mortality rates had increased from the previous survey.•High-dose steroid therapy showed the greatest reduction in mortality.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey.
The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey).
A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information.
Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52).
The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.
Abstract
Background
Human polyomaviruses (HPyVs) have been associated with several cutaneous inflammatory conditions. More investigation is needed to identify further presentations of cutaneous ...pathology associated with HPyVs. Our aim was to investigate the possible association of skin-tropic HPyVs with folliculitis, particularly eosinophilic pustular folliculitis (EPF).
Methods
This study included 55 Japanese patients, comprising 13 patients with EPF and 42 patients with suppurative folliculitis. HPyV DNAs were detected by quantitative polymerase chain reaction. Expression of viral antigen and geographically related viral genotypes were also assessed.
Results
Human polyomavirus 6 (HPyV6) DNA was found in 9 of 13 (69%) patients with EPF, a rate significantly higher than that found in suppurative folliculitis (1/42; 2%). Of the 7 HPyV6 DNA–positive EPF specimens analyzed, 4 were positive for HPyV6 small tumor antigen. All the HPyV6 strains detected in this study were of the Asian/Japanese genotype.
Conclusions
The predominant detection of HPyV6 DNA and the expression of viral antigen suggest a possible association between HPyV6 infection and EPF in a subset of patients. Worldwide studies are warranted to determine whether Asian/Japanese genotype HPyV6 is associated preferentially with the incidence and pathogenesis of this eosinophil-related skin disease that has an ethnic predilection for the East Asian population.
Eosinophilic pustular folliculitis (EPF) is an aseptic inflammatory disease of unknown etiology. Human polyomavirus 6 (HPyV6) was predominantly detected in specimens from Japanese patients with EPF. Findings suggest a possible association between HPyV6 and EPF in a subset of patients.
Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to ...induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified.
We sought to elucidate the functions of prostanoids in the development of AD.
The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line.
Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor–deficient mice but not in IL-33–deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor–deficient mice. Indomethacin increased protease-activated receptor 2–mediated TSLP production in keratinocytes in vitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin.
Prostaglandin E2–EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
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Background Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of ...skin inflammation have yet to be examined. Objective Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD and the underlying mechanism of eosinophil infiltration of the skin. Methods We induced croton oil–induced ICD in eosinophil-deficient ΔdblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow–derived basophils and evaluated eosinophil migration using a chemotaxis assay. Results ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts in vitro. Conclusion Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novel concept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the development of skin inflammation.
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