Identification of the Skin Basement-Membrane Autoantigen in Epidermolysis Bullosa Acquisita

Woodley, David T.; Briggaman, Robert A.; O’Keefe, Edward J.; Inman, Alfred O.; Queen, Laurinda L.; Gammon, W. Ray

doi:10.1056/nejm198404193101602

Cited by 484 publications

(286 citation statements)

References 30 publications

Supporting

Mentioning

272

Contrasting

Unclassified

Order By: Relevance

“…The completeness of digestion was assessed by IIF on mouse skin substrate. The purified F(abЈ) 2 preparations showed reactivity only with a fluorescein isothiocyanate (FITC)-labeled goat anti-human-F(abЈ) 2 but not with a FITC-labeled goat anti-human-Fc secondary antibodies.…”

Section: Preparation Of F(abј) 2 Fragmentsmentioning

confidence: 99%

“…Both lesional and perilesional tissues were subjected to DIF staining as previously described. 2,24 Monospecific FITC-conjugated sera were obtained commercially: goat anti-human IgG (Sigma), monospecific goat anti-mouse C3 (Cappel Laboratories, Durham, NC), goat anti-mouse neutrophils (Cedarlane, Ontario, ON, Canada), and goat anti-human F(abЈ) 2 and Fc (Cappel Laboratories). Photographs of immunolabeled tissues were obtained with a Zeiss Axioplan fluorescence microscope equipped with a Zeiss Axiocam MRM digital camera system (Carl Zeiss, Thornwood, NY).…”

Section: Administration Of Eba Antibodies Animal Evaluation and Chamentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Preparation Of F(abј) 2 Fragmentsmentioning

confidence: 99%

Section: Administration Of Eba Antibodies Animal Evaluation and Chamentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…We selected epidermolysis bullosa acquisita (EBA) as a model, because the pathogenic relevance of autoantibodies in this disease has been clearly demonstrated (23)(24)(25), and induction of EBA has been described in a patient treated with GM-CSF (26). These autoantibodies are directed to type VII collagen (COL7), a major component of the hemidesmosomal adhesion complex of the dermal-epidermal junction (DEJ) (27,28). After binding to their target Ag in the skin, a proinflammatory milieu is generated, leading to both neutrophil extravasation and activation.…”

mentioning

confidence: 99%

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

Samavedam

Iwata

Müller

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates disease activity in models of chronic inflammatory disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF−/− mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF−/− mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, disease was induced by transfer of anti–type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti–GM-CSF had a beneficial effect on established disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical organ-specific autoimmune disease.

show abstract

“…Three collagen types have been shown thus far to be the target of autoimmune response in human pathologies: (i) the NC1 domain of ␣3 chain of type IV collagen in Goodpasture syndrome (2), (ii) the NC1 domain of type VII collagen in epidermolysis bullosa acquisita (EBA) 1 (3), and (iii) a noncollagenous segment of type XVII collagen in bullous pemphigoid (BP) (4). The ␣3(IV) collagen chain, present in glomerular and alveolar basement membranes, is the target antigen in Goodpasture syndrome, a lethal form of autoimmune disease characterized by glomerulonephritis and pulmonary hemorrhage.…”

mentioning

confidence: 99%

The α5 Chain of Type IV Collagen Is the Target of IgG Autoantibodies in a Novel Autoimmune Disease with Subepidermal Blisters and Renal Insufficiency

Ghohestani¹,

Hudson²,

Claudy³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

We describe a novel autoimmune disease characterized by severe subepidermal bullous eruptions and renal insufficiency with IgG autoantibodies directed against the NC1 domain of the ␣5(IV) collagen chain. In vivo deposits of IgG and C3 were found along the dermal-epidermal junction of skin lesions. The identity of the target antigen was determined by immunochemical analyses of candidate antigens using the patients' autoantibodies. The patients' IgG autoantibodies reacted with a 185-kDa polypeptide that was distinguished from the known autoantigens of the extracellular matrix including type XVII collagen, type VII collagen, or the ␣3, ␤3, and ␥2 chains of laminin 5. Preincubation of the serum with recombinant ␣5(IV)NC1 domain of type IV collagen abolished immunoreactivity with the 185-kDa antigen. The serum reacted specifically with the ␣5(IV)NC1, among the six NC1 domains of type IV collagen, by Western blot and enzyme-linked immunosorbent assay analyses. The patients' autoantibodies reacted with normal skin and renal glomerulus but not with skin and glomerulus of a patient with Alport syndrome in which the basement membranes are devoid of the ␣5(IV) collagen chain. This study provided for the first time unambiguous evidence for the ␣5(IV) collagen chain as the target antigen in a novel autoimmune disease characterized by skin and renal involvement.

show abstract

Identification of the Skin Basement-Membrane Autoantigen in Epidermolysis Bullosa Acquisita

Cited by 484 publications

References 30 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

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

The α5 Chain of Type IV Collagen Is the Target of IgG Autoantibodies in a Novel Autoimmune Disease with Subepidermal Blisters and Renal Insufficiency

Contact Info

Product

Resources

About