Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone

Has, Cristina; Nyström, Alexander; Saeidian, Amir Hossein; Bruckner‐Tuderman, Leena; Uitto, Jouni

doi:10.1016/j.matbio.2018.04.001

Cited by 100 publications

(107 citation statements)

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“…Identification of anchoring fibril deficiencies in dystrophic EB (DEB), the discovery of the anchoring fibril component type VII collagen (C7) (Burgeson et al, 1985;Keene et al, 1987), the discovery of C7's absence in recessive DEB (RDEB) skin (Bruckner-Tuderman et al, 1989), and the molecular cloning of the C7 COL7A1 gene (Parente et al, 1991) led to the discovery of DEB-associated COL7A1 mutations Hilal et al, 1993). Distinct molecular defects were later found in other rare EB simplex and JEB subtypes (Has et al, 2018;McGrath, 2015). Through all of these efforts, the molecular basis of the vast majority of EB subtypes was established.…”

Section: Introductionmentioning

confidence: 99%

Gene Therapy for Epidermolysis Bullosa

Marinkovich

Tang

2019

Journal of Investigative Dermatology

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Epidermolysis bullosa is a family of diseases characterized by blistering and fragility of the skin in response to mechanical trauma. Advances in our understanding of epidermolysis bullosa pathophysiology have provided the necessary foundation for the first clinical trials of gene therapy for junctional and dystrophic epidermolysis bullosa. These therapies show that gene therapy is both safe and effective, with the potential to correct the molecular and clinical phenotype of patients with epidermolysis bullosa. Improvements in gene delivery and in preventing immune reactions will be among the challenges that lie ahead during further therapeutic development.

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Section: Introductionmentioning

confidence: 99%

Gene Therapy for Epidermolysis Bullosa

Marinkovich

Tang

2019

Journal of Investigative Dermatology

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“…The evaluation of these structures by transmission electron microscopy is critical to the appraisal of therapies designed to ameliorate the severe blistering disease epidermolysis bullosa (EB). Dystrophic EB results from deficient anchoring fibrils (manifested by mutations in collagen VII) whereby junctional EB will most commonly occur if either integrin ɑ6β4 or laminin‐3‐3‐2 containing anchoring filaments are defective (Bruckner‐Tuderman and Has, ; Has et al, ). Given the significant differences in the appearance of the dermal–epidermal junction revealed by the two stabilization methods, we sought to demonstrate the localization patterns of integrin ɑ6β4, laminin‐3‐3‐2, and collagen VII in skin prepared by HPF/FS and compare it to skin immunolabeled with the same antibodies but processed by conventional aqueous methods.…”

Section: Resultsmentioning

confidence: 99%

“…Ultrastructural evaluation of the density and integrity of adherence molecules (collagen VII, laminin 3‐3‐2, and integrin ɑ6β4) at the dermal/epidermal junction is traditionally evaluated with reference to anchoring fibrils, anchoring filaments, and HD but also to the basal epithelial cell membrane, the LL, and the LD. Ultrastructural localization of these adherence molecules is an important element in assessing the effectiveness of therapies designed to ameliorate various forms of the severe blistering disease EB (Has et al, ). With the caveat that the ultrastructure of the subepithelial BM differs substantially by the two methods, we sought to determine if the localization of collagen VII, laminin 3‐3‐2, and integrin ɑ6β4 would also differ, given the likely interaction of these proteins with soluble components present in the matrix sol.…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Ultrastructure: A Direct Comparison between Conventional Specimen Preparation and High‐Pressure Freezing/Freeze‐Substitution

Keene

Tufa

2019

The Anatomical Record

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It is generally agreed within the microscopy community that the quality of ultrastructure within the connective tissue matrix resulting from high-pressure freezing followed by freeze-substitution (HPF/FS) far exceeds that gained following the "conventional" preparation method, which includes aqueous fixation, dehydration, and embedding. Exposure to cryogen at high pressure is the only cryopreservation method capable of vitrifying tissue structure to a depth exceeding 200 μm. Cells within connective tissues prepared by HPF/FS are universally larger, filling the commonly seen void at the juncture between cell and matrix. Without significant shrinkage of cells and the coincident extraction of the cytosolic components, well-resolved organelles are less clustered within an expanded cytosol. Much of the artifact from "conventional" methods occurs as large space filling and also smaller fibrilassociated proteoglycans are extracted during fixation. However, the visualization of some matrix features by electron microscopy is actually dependent on the collapse or extraction of these "masking" components. Herein, we argue that an impression of ultrastructure within commonly studied matrices, in particular skin, is best gained following the evaluation of both conventional preparations and tissue prepared by HPF/FS. Anat Rec, 303:1514Rec, 303: -1526Rec, 303: , 2020 Microscopists have traditionally relied on aqueous fixation, dehydration, and embedding in resin (herein referred to as the "conventional" preparation) for the evaluation of extracellular matrix (ECM) ultrastructure. It was in the mid-1960s when Farquhar and Palade (1965) combined the use of glutaraldehyde followed by osmium tetroxide

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“…EB has been studied intensively, and the genetic causes and disease mechanisms of the different EB types are rather well understood (1)(2)(3). The initial simple assumption that a single pathogenic gene variant/mutation explains all symptoms still holds true in principle.…”

Section: Epidermolysis Bullosa As a Paradigma Tic Skin Fragility Disomentioning

confidence: 99%

Skin Fragility: Perspectives on Evidence-based Therapies

Bruckner‐Tuderman¹

2020

Acta Derm Venerol

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The term skin fragility describes skin that blisters and breaks easily upon mild friction or trauma. Skin fragility can have many causes, ranging from genetic variants to a compromised immune system, infections or adverse drug reactions. Studies of genetic skin fragility disorders, such as epidermolysis bullosa, have provided better understanding of their causes and mechanisms. At least 20 genes may be involved in epidermolysis bullosa, and secondary phenomena, such as inflammation or fibrosis, can worsen the disease. No cure is yet available, but international research is developing novel approaches to cure the disease and alleviate its symptoms. This article reviews these new developments and appraises their clinical implementation.The term skin fragility disorders describes a group of conditions in which the structural integrity of the skin is compromised and its resistance to external shear forces diminished. Skin fragility can have different causes, ranging from genetic variations to inflammatory or physical phenomena. The genetic skin fragility disorders, collectively called epidermolysis bullosa, serve as a paradigm for the study of causes and mechanisms of skin fragility. Recent biomedical research has revealed substantial genetic heterogeneity of the epidermolysis bullosa group, delivered ample new knowledge on its pathophysiology, and facilitated the design of evidence-based therapeutic strategies. The therapy development process extends from in vitro testing to preclinical validation in animal models, and clinical trials. This article reviews different approaches to curative and symptom-relief therapies, and appraises their status and perspectives for clinical implementation. ActaDV ActaDV Advances in dermatology and venereologyActa Dermato-Venereologica 95 Evidence-based therapies for skin fragility Theme issue: Blistering skin disorders ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica L. Bruckner-Tuderman 96 Theme issue: Blistering skin disorders ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica L. Bruckner-Tuderman 98 Theme issue: Blistering skin disorders Advances in dermatology and venereology Acta Dermato-Venereologica 99 Evidence-based therapies for skin fragility Theme issue: Blistering skin disorders ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica L. Bruckner-Tuderman 100

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Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone

Cited by 100 publications

References 140 publications

Gene Therapy for Epidermolysis Bullosa

Gene Therapy for Epidermolysis Bullosa

Connective Tissue Ultrastructure: A Direct Comparison between Conventional Specimen Preparation and High‐Pressure Freezing/Freeze‐Substitution

Skin Fragility: Perspectives on Evidence-based Therapies

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