The vWFA2 domain of type VII collagen is responsible for collagen binding

Wegener, Henrik; Leineweber, Sarah; Seeger, Karsten

doi:10.1016/j.bbrc.2012.11.119

Cited by 18 publications

(30 citation statements)

References 21 publications

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“…In an attempt to reproduce also the findings in the mechanobullous variant of EBA (14,36), we immunized rabbits of the vWFA2 domain. This domain had been shown to be important for the interaction of COL7 with type I collagen (37), with the fibronectin 3-like domain 9 of COL7 (22) and the cysteine-knot located between the NC-1 and collagenous domain of COL7 (38). In this study, we show that Abs to the vWFA2 domain induce frank blistering when injected into wild-type mice.…”

Section: Discussionsupporting

confidence: 49%

Radiosensitive Hematopoietic Cells Determine the Extent of Skin Inflammation in Experimental Epidermolysis Bullosa Acquisita

Iwata

Witte

Samavedam

et al. 2015

The Journal of Immunology

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Animal models have enhanced our understanding of the pathogenesis of autoimmune diseases. For these models, genetically identical, inbred mice have commonly been used. Different inbred mouse strains, however, show a high variability in disease manifestation. Identifying the factors that influence this disease variability could provide unrecognized insights into pathogenesis. We established a novel Ab transfer-induced model of epidermolysis bullosa acquisita (EBA), an autoimmune disease characterized by (muco)-cutaneous blistering caused by anti-type VII collagen (COL7) autoantibodies. Blistering after anti-COL7 IgG (directed against the von Willebrand factor A–like domain 2) transfer showed clear variability among inbred mouse strains, that is, severe cutaneous blistering and inflammation in C57BL/6J and absence of skin lesions in MRL/MpJ mice. The transfer of anti-COL7 IgG into irradiated, EBA-resistant MRL/MpJ mice, rescued by transplantation with bone marrow from EBA-susceptible B6.AK-H2k mice, induced blistering. To the contrary, irradiated EBA-susceptible B6.AK-H2k mice that were rescued using MRL/MpJ bone marrow were devoid of blistering. In vitro, immune complex activation of neutrophils from C57BL/6J or MRL/MpJ mice showed an impaired reactive oxygen species release from the latter, whereas no differences were observed after PMA activation. This finding was paralleled by divergent expression profiles of immune complex–activated neutrophils from either C57BL/6J or MRL/MpJ mice. Collectively, we demonstrate that radiosensitive cells determine the varying extent of skin inflammation and blistering in the end-stage effector phase of EBA.

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Section: Discussionsupporting

confidence: 49%

Radiosensitive Hematopoietic Cells Determine the Extent of Skin Inflammation in Experimental Epidermolysis Bullosa Acquisita

Iwata

Witte

Samavedam

et al. 2015

The Journal of Immunology

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“…The C-terminal subdomain of NC1 shows high homology with von Willebrand factor A and was therefore termed von Willebrand factor A-like domain 2 (vWFA2) (29). This domain has been shown to interact with type I collagen (30,31) and was demonstrated to be targeted by a significant number of patients' sera (32).…”

mentioning

confidence: 99%

“…We therefore aimed at developing a novel immunization-induced EBA mouse model in which the disease develops independent of an immune response to proteins other than COL7. Because the vWFA2 domain had been demonstrated as an immunodominant site on COL7 (32) and represents the interaction site between type I collagen and COL7 (30,31), we used in this article the murine vWFA2 protein for immunization of mice.…”

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confidence: 99%

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

Iwata

Bieber

Tiburzy

et al. 2013

The Journal of Immunology

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In autoimmune bullous dermatoses (AIBD), autoantibodies induce blisters on skin or mucous membranes, or both. Mechanisms of continued autoantibody production and blistering have been well characterized using AIBD animal models. Mechanisms leading to the initial autoantibody production, however, have not been investigated in detail. Epidermolysis bullosa acquisita (EBA) is an AIBD associated with autoantibodies to type VII collagen (COL7). The majority of EBA patients’ sera recognize the noncollagenous domain 1, including the von Willebrand factor A–like domain 2 (vWFA2). In experimental EBA induced by immunization with GST-COL7, disease manifestation depended on the genetic background, a Th1 polarization, and the GST-tag. In this model, nude mice neither produced autoantibodies nor blisters. It has remained uncertain which APC and T cell subsets are required for EBA induction. We established a novel EBA model by immunization with vWFA2 fused to intein (lacking the GST-tag). All tested mouse strains developed autoantibodies, but blisters were exclusively observed in mice carrying H2s. In immunized mice, CD4 T cells specific for vWFA2 were detected, and their induction required presence of B cells, dendritic cells, and macrophages. Anti-vWFA2 autoantibodies located at the lamina densa bound to the dermal side of salt-split skin and induced blisters when transferred into healthy mice. Absence of CD8 T cells at time of immunization had no effect, whereas depletion of CD4 T cells during the same time period delayed autoantibody production and blisters. Collectively, we demonstrate the pathogenic relevance of Abs targeting the vWFA2 domain of COL7 and show the requirement of APC-induced CD4 T cells to induce experimental EBA.

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“…Resonance assignment was performed using the following spectra: 1 H, 1 H TOCSY (total correlation spectroscopy), 1 H, 1 H COSY, 1 H, 13 C HSQC (heteronuclear single quantum correlation), and 1 H, 13 C HMBC (heteronuclear multiple bond correlation) using standard Bruker pulse sequences at 281.2 K (8°C). Peptide concentrations varied between 1.3 and 0.03 mM and were determined by UV absorbance of the tyrosine.…”

Section: Design Of Col7-thc Peptide and Cloning Of Cysvwfa2-thcmentioning

confidence: 99%

“…The large central collagenous domain is flanked by two noncollagenous domains (NC). The subdomains of the NC1 domain have homology to the von Willebrand factor A (vWFA) or fibronectin III and mediate interactions with other extracellular proteins such as laminin-332 (10 -12) and type I and IV collagen (10,(12)(13)(14), but interactions between neighboring Col7 domains have also been observed (15). Important for the function of Col7 is the formation of anchoring fibrils.…”

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confidence: 99%

The Cysteine-rich Region of Type VII Collagen Is a Cystine Knot with a New Topology

Wegener

Paulsen

Seeger

2014

Journal of Biological Chemistry

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Background: Type VII collagen is essential for skin stability as highlighted by related skin blistering diseases. Results: A fusion protein comprising the cysteine-rich region and parts of the flanking domains forms a trimer upon oxidization. Conclusion:The cysteine-rich region is an N-terminal cystine knot with novel topology. Significance: The cystine knot is also found in type IX collagen, indicating a general principle.

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The vWFA2 domain of type VII collagen is responsible for collagen binding

Cited by 18 publications

References 21 publications

Radiosensitive Hematopoietic Cells Determine the Extent of Skin Inflammation in Experimental Epidermolysis Bullosa Acquisita

Radiosensitive Hematopoietic Cells Determine the Extent of Skin Inflammation in Experimental Epidermolysis Bullosa Acquisita

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

The Cysteine-rich Region of Type VII Collagen Is a Cystine Knot with a New Topology

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