Dry skin and blistering in childhood.
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ABSTRACT:
SUBMITTER: Dubois A
PROVIDER: S-EPMC5082558 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
Publications
Dry skin and blistering in childhood.
Dubois A A Arefi M M Splitt M P MP Leech S S Natarajan S S Rajan N N
Clinical and experimental dermatology 20161001 7
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Project description:Autoimmune blistering diseases (AIBDs) of the skin are characterized by autoantibodies against different intra-/extracellular structures within the epidermis and at the basement membrane zone (BMZ). Binding of the antibodies to their target antigen leads to inflammation at the respective binding site and degradation of these structures, resulting in the separation of the affected skin layers. Clinically, blistering, erythema and lesions of the skin and/or mucous membranes can be observed. Based on the localization of the autoantigen, AIBDs can be divided into pemphigus (intra-epidermal blistering diseases) and pemphigoid diseases (sub-epidermal blistering diseases), respectively. Although autoantigens have been extensively characterized, the underlying causes that trigger the diseases are still poorly understood. Besides the environment, genetic factors seem to play an important role in a predisposition to AIBDs. Here, we review currently known genetic and immunological mechanisms that contribute to the pathogenesis of AIBDs. Among the most commonly encountered genetic predispositions for AIBDs are the HLA gene region, and deleterious mutations of key genes for the immune system. Particularly, HLA class II genes such as the HLA-DR and HLA-DQ alleles have been shown to be prevalent in patients. This has prompted further epidemiological studies as well as unbiased Omics approaches on the transcriptome, microbiome, and proteome level to elucidate common and individual genetic risk factors as well as the molecular pathways that lead to the pathogenesis of AIBDs.
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Project description:Autoantibodies against desmoglein (Dsg) 1 and Dsg3 primarily cause blister formation in the autoimmune disease pemphigus vulgaris (PV). Src was proposed to contribute to loss of keratinocyte cohesion. However, the role and underlying mechanisms are unclear and were studied here. In keratinocytes, cell cohesion in response to autoantibodies was reduced in Src-dependent manner by two patient-derived PV-IgG fractions as well as by AK23 but not by a third PV-IgG fraction, although Src was activated by all autoantibodies. Loss of cell cohesion was progredient in a timeframe of 24 h and AK23, similar to PV-IgG, interfered with reconstitution of cell cohesion after Ca2+-switch, indicating that the autoantibodies also interfered with desmosome assembly. Dsg3 co-localized along cell contacts and interacted with the Src substrate cortactin. In keratinocytes isolated from cortactin-deficient mice, cell adhesion was impaired and Src-mediated inhibition of AK23-induced loss of cell cohesion for 24 h was significantly reduced compared to wild-type (wt) cells. Similarly, AK23 impaired reconstitution of cell adhesion was Src-dependent only in the presence of cortactin. Likewise, Src inhibition significantly reduced AK23-induced skin blistering in wt but not cortactin-deficient mice. These data suggest that the Src-mediated long-term effects of AK23 on loss of cell cohesion and skin blistering are dependent on cortactin-mediated desmosome assembly. However, in human epidermis PV-IgG-induced skin blistering and ultrastructural alterations of desmosomes were not affected by Src inhibition, indicating that Src may not be critical for skin blistering in intact human skin, at least when high levels of autoantibodies targeting Dsg1 are present.
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Project description:Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti-type VII collagen antibodies. Different reports have indicated an increased concentration of tumor necrosis factor alpha (TNF) in the serum and blister fluid of patients with subepidermal AIBDs. Furthermore, successful anti-TNF treatment has been reported for individual patients with AIBDs. Here, we show that in mice, induction of experimental EBA by repeated injections of rabbit-anti mouse type VII collagen antibodies led to increased expression of TNF in skin, as determined by real-time PCR and immunohistochemistry. To investigate if the increased TNF expression is of functional relevance in experimental EBA, we inhibited TNF function using the soluble TNF receptor fusion protein etanercept (Enbrel®) or a monoclonal antibody to murine TNF. Interestingly, mice receiving either of these two treatments showed significantly milder disease progression than controls. In addition, immunohistochemical staining demonstrated reduced numbers of macrophages in lesional skin in mice treated with TNF inhibitors compared to controls. Furthermore, etanercept treatment significantly reduced the disease progression in immunization-induced EBA. In conclusion, the increased expression of TNF in experimental EBA is of functional relevance, as both the prophylactic blockade of TNF and the therapeutic use of etanercept impaired the induction and progression of experimental EBA. Thus, TNF is likely to serve as a new therapeutic target for EBA and AIBDs with a similar pathogenesis.
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Project description:In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.
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Project description:Susceptibility to chronic inflammatory diseases is determined by immunogenetic and environmental risk factors. Resident microbial communities often differ between healthy and diseased states, but whether these differences are of primary aetiological importance or secondary to the altered inflammatory environment remains largely unknown. Here we provide evidence for host gene-microbiota interactions contributing to disease risk in a mouse model of epidermolysis bullosa acquisita, an autoantibody-induced inflammatory skin disease. Using an advanced intercross, we identify genetic loci contributing to skin microbiota variability, susceptibility to skin blistering and their overlap. Furthermore, by treating bacterial species abundances as covariates with disease we reveal a novel disease locus. The majority of the identified covariate taxa are characterized by reduced abundance being associated with increased disease risk, providing evidence of a primary role in protection from disease. Further characterization of these putative probiotic species or species assemblages offers promising potential for preventative and therapeutic treatment development.
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Project description:Separation of skin epidermis from the dermis by suction blistering has been used with high success rate for autologous skin epidermal grafting in burns, chronic wounds and vitiligo transplantation treatment. Although commercial products that achieve epidermal grafting by suction blistering are presently available, there is still limited knowledge and understanding on the dynamic process of epidermal-dermal separation during suction blistering. In this report we integrated a suction system to an Optical Coherence Tomography (OCT) which allowed for the first time, real-time imaging of the suction blistering process in human skin. We describe in this report the evolution of a suction blister where the growth is modeled with a Boltzmann sigmoid function. We further investigated the relationship between onset and steady-state blister times, blister growth rate, applied suction pressure and applied local skin temperature. Our results show that while the blister time is inversely proportional to the applied suction pressure, the relationship between the blister time and the applied temperature is described by an exponential decay.
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Project description:BackgroundVitiligo is an autoimmune disease of the skin with limited treatment options; there is an urgent need to identify and validate biomarkers of disease activity to support vitiligo clinical studies.ObjectiveTo investigate potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects.MethodsPatient skin was sampled via a modified suction-blister technique, allowing for minimally invasive, objective assessment of cytokines and T-cell infiltrates in the interstitial skin fluid. Potential biomarkers were first defined and later validated in separate study groups.ResultsIn screening and validation, CD8+ T-cell number and C-X-C motif chemokine ligand (CXCL) 9 protein concentration were significantly elevated in active lesional compared to nonlesional skin. CXCL9 protein concentration achieved greater sensitivity and specificity by receiver operating characteristic analysis. Suction blistering also allowed for phenotyping of the T-cell infiltrate, which overwhelmingly expresses C-X-C motif chemokine receptor 3.LimitationsA small number of patients were enrolled for the study, and only a single patient was used to define the treatment response.ConclusionMeasuring CXCL9 directly in the skin might be effective in clinical trials as an early marker of treatment response. Additionally, use of the modified suction-blister technique supports investigation of inflammatory skin diseases using powerful tools like flow cytometry and protein quantification.
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2016-03-26 | GSE79596 | GEO