Alterations in the microenvironment of junctional epidermolysis bullosa keratinocytes: a gene expression study.

Integrin α6β4 subunits and type XVII collagen are critical transmembrane proteins involved in cell-matrix adhesion in skin, while laminin 332 serves as their ligand in the basement membrane zone (BMZ). Those proteins contribute to the composition of hemidesmosomes (HDs) and pathogenic variants in their corresponding genes cause junctional epidermolysis bullosa (JEB). Although the genotype-phenotype relationships in JEB have been extensively studied, the pathogenetic changes of extracellular matrix (ECM) and cell-matrix adhesion resulting from gene mutations remain unclear.

A new silicon phthalocyanine dye induces pyroptosis in prostate cancer cells during photoimmunotherapy.

Photoimmunotherapy (PIT) combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers (PS) and is a promising new cancer therapy. We designed and synthesized, in a highly convergent manner, the silicon phthalocyanine dye WB692-CB2, which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines. In the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen (PSMA).

Divergent and Compensatory Effects of BMP2 and BMP4 on the VSMC Phenotype and BMP4's Role in Thoracic Aortic Aneurysm Development.

Vascular smooth muscle cells (VSMCs) play a key role in aortic aneurysm formation. Bone morphogenetic proteins (BMPs) have been implicated as important regulators of VSMC phenotype, and dysregulation of the BMP pathway has been shown to be associated with vascular diseases. The aim of this study was to investigate for the first time the effects of BMP-4 on the VSMC phenotype and to understand its role in the development of thoracic aortic aneurysms (TAAs).

Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion.

Plectin, a highly versatile and multifunctional cytolinker, has been implicated in several multisystemic disorders. Most sequence variations in the human plectin gene (PLEC) cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin-blistering disorder associated with progressive muscle weakness. In this study, we performed a comprehensive cell biological analysis of dermal fibroblasts from three different patients with EBS-MD, where PLEC expression analyses revealed preserved mRNA levels in all cases, whereas full-length plectin protein content was significantly reduced or completely absent.

Amino Acid Substitution in the Cysteine-Rich Region of the Integrin β4 Subunit Causes Late-Onset Mild Junctional Epidermolysis Bullosa without Extracutaneous Involvement.

Integrin α6β4, encoded by ITGA6 and ITGB4, is a transmembrane component of hemidesmosomes and plays an important role in connecting keratinocytes with extracellular matrix proteins. ITGB4 or ITGA6 biallelic pathogenic variants cause junctional epidermolysis bullosa (JEB) with pyloric atresia, which is associated with high lethality. Patients who survive usually develop JEB of intermediate severity and urorenal manifestations.

Endoplasmic reticulum stress and the inflammatory response in allergic contact dermatitis.

Maintaining homeostasis is central to organismal health. Deviation is detected by a variety of sensors that react to alarm signals arising from injury, infection, and other inflammatory triggers. One important element of this alarm system is the innate immune system, which recognizes pathogen-/microbe- or damage-associated molecular patterns via pattern recognition receptors localized in the cytosol or in membranes of innate immune cells such as macrophages, dendritic cells, and mast cells but also of T cells, B cells, and epithelial cells.

IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity.

Background: Contact sensitizers may interfere with correct protein folding. Generation of un-/misfolded proteins can activate the IRE-1 or PERK signaling pathways initiating the unfolded protein response (UPR) and thereby determine inflammatory immune responses. We have analyzed the effect of sensitizers with different potencies on the induction of UPR activation/inhibition and the subsequent generation of a pro-inflammatory micromilieu in vitro as well as the effect of UPR modulation on the inflammatory response in the murine contact hypersensitivity (CHS) in vivo.

Feeding of a fat-enriched diet causes the loss of resistance to contact hypersensitivity.

Background: Low-molecular weight chemicals or metal ions can cause allergic contact dermatitis, an inflammatory skin disease. Mice lacking Toll-like receptors 2 and 4 (TLR2/4 mice) are resistant to contact hypersensitivity (CHS). In the Western population obesity is increasing, which is known to have a proinflammatory impact.

Innate Immune Mechanisms in Contact Dermatitis.

Allergies are highly prevalent hypersensitivity responses to usually harmless substances. They are mediated by the immune system which causes pathologic responses such as type I (rhinoconjunctivitis, allergic asthma, atopy) or type IV hypersensitivity (allergic contact dermatitis). The different types of allergy are mediated by effector and memory T cells and, in the case of type I hypersensitivity, B cells.

Luteolin as a modulator of skin aging and inflammation.

Luteolin belongs to the group of flavonoids and can be found in flowers, herbs, vegetables and spices. It plays an important role in defending plants, for example against UV radiation by partially absorbing UVA and UVB radiation. Thus, luteolin can also decrease adverse photobiological effects in the skin by acting as a first line of defense.

Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect.

Acute graft-versus-host disease causes significant mortality in patients undergoing allogeneic hematopoietic cell transplantation. Immunosuppressive treatment for graft-versus-host disease can impair the beneficial graft-versus-leukemia effect and facilitate malignancy relapse. Therefore, novel approaches that protect and regenerate injured tissues without impeding the donor immune system are needed.

[Extended understanding of pathogenesis and treatment of contact allergy].

Background: While the pathogenesis of contact allergy in recent years has increasingly focused on the mechanisms of the innate immune response, valid therapeutic options are still lacking.

Aims: This article intends to shed light on the background of contact allergy development as well as possible risk factors and to highlight potential new therapeutic options.

Materials And Methods: Allergic contact dermatitis (ACD) as well as the sensitization and trigger phase, potential risk factors as well as the therapy options including (current) PubMed-listed literature are described.

Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders.

Background: Missense mutations in keratin 5 and 14 genes cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS) by collapsing of the keratin cytoskeleton into cytoplasmic protein aggregates. Despite intense efforts, no molecular therapies are available, mostly due to the complex phenotype of EBS, comprising cell fragility, diminished adhesion, skin inflammation and itch.

Methods: We extensively characterized KRT5 and KRT14 mutant keratinocytes from patients with severe generalized EBS following exposure to the chemical chaperone 4-phenylbutyrate (4-PBA).

Plant Allergen-Induced Contact Dermatitis.

Although manifold beneficial effects of plant compounds for the treatment of skin disorders are known, cutaneous exposure to plants can also result in various types of incompatibility reactions such as contact dermatitis. In this mini-review, we briefly describe the different clinical forms of contact dermatitis (photoinduced, irritative, and allergic form) and highlight recent publications in the field of contact dermatitis. Major topics are recent recommendations regarding testing for plant contact dermatitis, advances in understanding the immunological mechanisms of plant contact dermatitis, and case reports for plant contact dermatitis.

Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome.

Retarded growth and neurodegeneration are hallmarks of the premature aging disease Cockayne syndrome (CS). Cockayne syndrome proteins take part in the key step of ribosomal biogenesis, transcription of RNA polymerase I. Here, we identify a mechanism originating from a disturbed RNA polymerase I transcription that impacts translational fidelity of the ribosomes and consequently produces misfolded proteins.

Pathomechanisms of Contact Sensitization.

Contact sensitization is the initial process involved in the development of an allergic reaction to xenobiotic environmental substances. Here, we briefly describe the differences between irritant and allergic contact dermatitis. Then, we highlight the essential steps involved in the development of an ACD reaction, i.

Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma Progression.

Squamous cell carcinoma (SCC) is one of the most common skin cancers and causes significant morbidity. Although the expression of the epithelial adhesion molecule collagen XVII (ColXVII) has been linked to SCC invasion, only little is known about its mechanistic contribution. Here, we demonstrate that ColXVII expression is essential for SCC cell proliferation and motility.

The Effect of Inhibitory Signals on the Priming of Drug Hapten-Specific T Cells That Express Distinct Vβ Receptors.

Drug hypersensitivity involves the activation of T cells in an HLA allele-restricted manner. Because the majority of individuals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T cell response. Thus, we have used a T cell-priming assay and nitroso sulfamethoxazole (SMX-NO) as a model Ag to investigate the activation of specific TCR Vβ subtypes, the impact of programmed death -1 (PD-1), CTL-associated protein 4 (CTLA4), and T cell Ig and mucin domain protein-3 (TIM-3) coinhibitory signaling on activation of naive and memory T cells, and the ability of regulatory T cells (Tregs) to prevent responses.

UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome.

Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients.

Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment.

Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.