Epidermolysis Bullosa Acquisita: Ultrastructural and Immunological Studies

Yaoita, Hideo; Briggaman, Robert A.; Lawley, Thomas J.; Provost, Thomas T.; Katz, Stephen I.

doi:10.1111/1523-1747.ep12526124

Cited by 249 publications

(108 citation statements)

References 9 publications

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“…Anchoring fibrils are reduced in the skin of EBA patients, but the underlying mechanism leading to this reduction is unknown. 27,30 One possible mechanism is that binding of autoantibodies to type VII collagen may target functional epitopes on the NC1 domain and interfere with its adhesive function. This could perturb critical direct interactions between type VII collagen and other extracellular components within the DEJ or high papillary dermis such as type IV collagen, laminin-5, or fibronectin.…”

Section: Discussionmentioning

confidence: 99%

“…These EBA patients had 1) an active, chronic, mechanobullous disorder; 2) subepidermal blisters as assessed by routine light microscopy of lesional skin; 3) IgG deposits detected at the dermal-epidermal junction (DEJ) by routine direct immunofluorescence (DIF); 4) IgG deposits localized to the dermal floor of the patient's skin when the DEJ was fractured through the lamina lucida by treatment with 1 mol/L NaCl 24,25 ; 5) immunoreactivity to the NC1 domain of type VII collagen by ELISA and immunoblot analysis 26 ; and 6) IgG deposits detected within the sublamina densa region of the DEJ using direct immunoelectron microscopy. 27 Because sera from patients with BSLE have been shown to have autoantibodies to type VII collagen, 28 three sera from BSLE patients were also tested. Control serum samples were collected from 12 normal individuals (normal human sera, NHS) and 15 patients who had clinical, histological, and immunofluorescence findings consistent with the diagnosis of BP.…”

Section: Patients and Seramentioning

confidence: 99%

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The Cartilage Matrix Protein Subdomain of Type VII Collagen Is Pathogenic for Epidermolysis Bullosa Acquisita

Chen

Doostan

Bandyopadhyay

et al. 2007

The American Journal of Pathology

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Epidermolysis bullosa acquisita (EBA) is an acquired bullous disease of the skin characterized by IgG autoantibodies against type VII (anchoring fibril) collagen. We previously defined four immunodominant antigenic epitopes within the noncollagenous 1 (NC1) domain of type VII collagen. In this study, we produced an additional recombinant fusion protein from the NC1 domain corresponding to the N-terminal 227 amino acids (residues 1 to 227), which contains homology with cartilage matrix protein (CMP). Using enzyme-linked immunosorbent assay and immunoblot analysis, we tested sera from EBA patients (n ‫؍‬ 32), bullous systemic lupus erythematosus patients (n ‫؍‬ 3), bullous pemphigoid patients (n ‫؍‬ 15), and normal humans (n ‫؍‬ 12). Twenty-six of 32 EBA sera and two of three bullous systemic lupus erythematosus sera reacted with the CMP domain, whereas none of the control sera did. Affinity-purified anti-CMP EBA antibodies injected into hairless mice produced the clinical, histological, immunological, and ultrastructural features of EBA. F(ab) 2 fragments generated from anti-CMP EBA autoantibodies did not induce disease. Our studies provide the first evidence that EBA autoantibodies to the CMP subdomain of NC1 are pathogenic and induce blister formation. This is the first antigenic epitope on type VII collagen demonstrated to be a pathogenic target for EBA autoantibodies. Epidermolysis bullosa acquisita (EBA) is a severe, chronic, subepidermal bullous disease of the skin and mucosa characterized by skin fragility, blisters in traumaprone sites, scarring with milia formation, and nail dystrophy.1 It is a prototypic autoimmune disease in which EBA patients have in vivo tissue-bound and circulating IgG autoantibodies directed against type VII collagen, a major component of anchoring fibrils, structures that anchor the epidermis onto the dermis.2-8 EBA autoantibodies bind to type VII collagen within anchoring fibrils. EBA patients have a diminution of normal anchoring fibrils and subsequent epidermal-dermal disadherence. The clinical appearance of EBA patients and the histology of their cutaneous lesions are often very reminiscent of hereditary dystrophic epidermolysis bullosa. These two diseases are etiologically unrelated but share the common feature of decreased anchoring fibrils. In the case of inherited dystrophic epidermolysis bullosa, the cause of decreased or absent anchoring fibrils is a genetic defect in the gene that encodes for type VII collagen. 9,10Type VII collagen is composed of three identical ␣ chains, each consisting of a 145-kd central collagenous triple-helical segment characterized by repeating Gly-X-Y amino acid sequences, flanked by a large 145-kd amino-terminal noncollagenous domain (NC1), and a small 34-kd carboxyl-terminal noncollagenous domain (NC2). 6 -8,11,12 Within the extracellular space, type VII collagen molecules form anti-parallel, tail-to-tail dimers stabilized by disulfide bonding through a small carboxylterminal NC2 overlap between two type VII collagen molecules. The anti-para...

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Section: Discussionmentioning

confidence: 99%

Section: Patients and Seramentioning

confidence: 99%

The Cartilage Matrix Protein Subdomain of Type VII Collagen Is Pathogenic for Epidermolysis Bullosa Acquisita

Chen

Doostan

Bandyopadhyay

et al. 2007

The American Journal of Pathology

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“…Antibodies from the sera offive patients with EBA were used. These sera have been shown previously to label the dermal-epidermal junction of human skin by indirect immunofluorescence, the lamina densa and sub-lamina densa regions of the basement membrane within the dermal-epidermal junction ofskin by indirect immunoelectron microscopy, and the 290-and 145-kD EBA antigen chains by Western blot analysis of urea extracts of human skin basement membrane (5,6,8). A new MAb, EBA-1, with properties identical to those of antibodies in the serum of patients (13) was also used and compared with a well-characterized MAb to the carboxyl terminus of type VII procollagen (14).…”

Section: Methodsmentioning

confidence: 96%

Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen.

Woodley¹,

Burgeson²,

Lunstrum³

et al. 1988

J. Clin. Invest.

321

143

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Epidermolysis bullosa acquisita (EBA) is a severe, chronic blistering disease of the skin. EBA patients have circulating and tissue-bound autoantibodies to a large (M, = 290,000) macromolecule that is localized within the basement membrane zone between the epidermis and dermis of skin, the site of blister formation. The "EBA antigen" is known to be distinct from laminin, heparan sulfate proteoglycan, fibronectin, the bullous pemphigoid antigen, elastin, and collagen types I, II, III, IV, and V. Sera from patients with EBA, two monoclonal antibodies to the EBA antigen, and a monoclonal antibody to the carboxyl terminus of type VII procollagen identically label human amnion and skin by immunofluorescent and immunoelectron microscopy. Western immunoblots of the EBA antigen extracted from skin and of type VII procollagen labeled with the above sera and antibodies are identical. None of the sera or antibodies labels Western blots of pepsinized type VII collagen which is missing the globular amino and carboxyl terminal domains. These data show that the EBA antigen is the carboxyl terminus of type VII procollagen.

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“…In case of clinical suspicion of EBA, diagnosis needs to be based on different approaches schematically shown in Figure 12. Traditionally, the diagnostic gold standard has been direct immunogold electron microscopy [108]. At present, in nearly all patients, diagnosis can be made by serration pattern …”

Section: Diagnostic Methodsmentioning

confidence: 99%

“…Subsequently, direct immunogold electron microscopy became the diagnostic gold standard for EBA [85,108,[118][119][120][121]. Unfortunately, this technique is available for the diagnosis of autoimmune blistering diseases in only a handful of laboratories.…”

Section: Immunoelectron Microscopymentioning

confidence: 99%

Clinical features and diagnosis of epidermolysis bullosa acquisita

Vorobyev

Ludwig

Schmidt

2016

Expert Review of Clinical Immunology

100

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Introduction: Epidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disease of skin and mucous membranes. EBA is caused by autoantibodies against type VII collagen, which is a major component of anchoring fibrils, attaching epidermis to dermis. Binding of autoantibodies to type VII collagen leads to skin fragility and, finally, blister formation. The clinical picture of EBA is polymorphic, with several distinct phenotypes being described. Despite recent progress in understanding the pathophysiology of EBA, its diagnosis is still challenging. Areas covered: This review provides an update on the clinical manifestations and diagnostic methods of EBA. We searched PubMed using the terms 'epidermolysis bullosa acquisita' covering articles in English between 1 January 2005 and 31 May 2016. Relevant older publications were retrieved form cited literature. Expert commentary: While the clinical picture is highly variable, diagnosis relies on direct immunofluorescence (IF) microscopy of a perilesional skin biopsy. Linear deposits of IgG, IgA and/or C3 along the dermal-epidermal junction with an u-serrated pattern are diagnostic for EBA alike the detection of serum autoantibodies against type VII collagen. Several test systems for the serological diagnosis of EBA have recently become widely available. In some patients, sophisticated diagnostic approaches only available in specialized centers are required. ARTICLE HISTORY

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Epidermolysis Bullosa Acquisita: Ultrastructural and Immunological Studies

Cited by 249 publications

References 9 publications

The Cartilage Matrix Protein Subdomain of Type VII Collagen Is Pathogenic for Epidermolysis Bullosa Acquisita

The Cartilage Matrix Protein Subdomain of Type VII Collagen Is Pathogenic for Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen.

Clinical features and diagnosis of epidermolysis bullosa acquisita

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