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PubMed1992

Molecular biology and pathology of type VII collagen.

Type VII collagen is a genetically distinct member of the collagen family of proteins. Type VII collagen has been shown to be the major component of anchoring fibrils, attachment complexes which secure the cutaneous basement membrane of the skin to the underlying dermis. Understanding of the structure of type VII collagen has been advanced by recent cloning of the corresponding gene. Chromosomal mapping of the gene to the short arm of chromosome 3 and identification of intragenic polymorphic markers have allowed demonstration of strong genetic linkage between the type VII collagen locus and the dystrophic forms of EB (epidermolysis bullosa). This overview summarizes the progress made in the molecular genetics of type VII collagen.

Amino Acid Sequence↗

PubMed1998

Equine laminitis basement membrane pathology: loss of type IV collagen, type VII collagen and laminin immunostaining.

Disintegration of the basement membrane (BM) of the equine hoof lamellae and failure of the BM to remain attached to the basal cells of the secondary epidermal lamellae (SEL) is one of the earliest pathological events to occur in acute laminitis. Changes in the lamellar basement membrane were investigated by immunolabelling the key structural components of the BM, type IV collagen, type VII collagen and laminin in the lamellar BM of horses 48 h after the induction of laminitis. Lamellar tissues were harvested from 2 normal horses and 2 horses with acute laminitis. Immunostaining with antibody raised against human epitopes for type IV collagen, type VII collagen and laminin successfully stained the basement membranes of horse hoof lamellar tissues. Vascular tissue did not immunostain with type VII collagen antibody. Normal BM stained as a fine dark brown line and the lamellar BM was adhered to the basal cells of the SELs with no evidence of lamellar separation. At least 2 changes to the lamellar BM occurred in acute laminitis: loss of attachment of lamellar epidermal basal cells to their underlying BM and disintegration of the lamellar BM. In some sections from feet affected by acute laminitis, there was widespread separation of the SELs from their BM without loss of BM immunostaining and in others there was extensive loss of BM immunostaining. In lesions characterised by lamellar separation, the epidermal basal cells at the tips of the primary epidermal lamellae appeared to have slipped away from their BM and were an amorphous clump of epidermal cells devoid of immunostained BM. The BM from which they had separated remained in its original position in the dermis and was clearly outlined by all 3 antibodies. In other areas, however, virtually all the BM immunoreactivity at the PEL tips was absent. Only the occasional distorted SEL tip and fragments of BM retained sufficient immunostaining to allow anatomical identification. Numerous polymorphonuclear leucocytes (PMNs) invariably surrounded the tips of lamellae showing large scale loss of immunoreactivity and many PMNs had penetrated the lamellar BM and were within the epidermal compartments. PMNs were less frequent in the midlamellar region. Immunostaining of the BM of many SELs was absent in the midlamellar region. In some lamellae loss of BM immunostaining had occurred only at the bases of the SELs and fragments of immunostained BM were present in the zones of lysed BM suggesting that BM lysis was incomplete at the time of tissue fixation. In other lamellae, lysis of the BM was complete; there was no immunostained BM between SELs and the bulk of the epidermal cells of each PEL were an amorphous column of cells on either side of the central keratinised axis of the PEL. The lamellar BM which remained appeared as immunostained strands of unattached BM along the edges of the PDLs. Activation of BM degrading metalloproteinases (MMPs) occurs in acute laminitis and it seems likely that uncontrolled MMP activity is responsible for the loss and disorganisation of lamellar BM demonstrated in this study.

Acute Disease↗

PubMed1994

The epitope for anti-type VII collagen monoclonal antibody (LH7:2) locates at the central region of the N-terminal non-collagenous domain of type VII collagen.

The monoclonal antibody LH7:2, which recognizes type VII collagen, is now used in the diagnosis and prenatal diagnosis of epidermolysis bullosa dystrophica. We constructed the expression vector which contains the cDNA fragment of type VII collagen. Western blot with LH7:2 was carried out with the resultant fusion proteins which overlap each other, and we found that reactivity is located in the central region of the N-terminal non-collagenous domain of type VII collagen, at a position 81 kDa upstream from the collagenous domain. This epitope mapping for LH7:2 may be useful in studying the role of type VII collagen in epidermolysis bullosa dystrophica.

Antibodies, Monoclonal↗

PubMed1992

Molecular cloning and characterization of type VII collagen cDNA.

Type VII collagen, located in human epidermal basement membrane, is the primary pathogenic target molecule in epidermolysis bullosa acquisita and epidermolysis bullosa dystrophica. Using a monoclonal antibody against the non-collagenous domain of type VII collagen, approximately 1 Kb cDNA was isolated from human keratinocyte library. The deduced primary structure of this clone thus reflects the non-collagenous domain of type VII collagen that may be involved in cell attachment. This region shows a weak homology (approximately 23%) to the cell attachment domain of fibronectin. Northern blot revealed approximately 9.5 Kb single band.

Amino Acid Sequence↗

PubMed1989

Cleavage of type VII collagen by interstitial collagenase and type IV collagenase (gelatinase) derived from human skin.

Type VII collagen is the major structural protein of anchoring fibrils, which are believed to be critical for epidermal-dermal adhesion in the basement membrane zone of the skin. To elucidate possible mechanisms for the turnover of this protein, we examined the capacities of two proteases, human skin collagenase, which degrades interstitial collagens, and a protease with gelatinolytic and type IV collagenase activities, to cleave type VII collagen. At temperatures below the denaturation temperature, pepsin cleaves type VII collagen into products of approximately 95 and approximately 75 kDa. Human skin collagenase cleaved type VII collagen into two stable fragments of approximately 83 and approximately 80 kDa, and the type IV collagenase (gelatinase) produced a broad band of approximately 80 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cleavage of type VII collagen was linear with time and enzyme concentration for both enzymes. Although the Km values were similar for both enzymes, the catalytic rate of cleavage by type IV collagenase is much faster than by interstitial collagenase, and shows a greater rate of increase with increasing temperature. Sequence analysis of the cleavage products from both enzymes showed typical collagenous sequences, indicating a relaxation in the helical part of the type VII collagen molecule at physiological temperature which makes it susceptible to gelatinolytic degradation. Interstitial collagenase from both normal skin cells and cells from patients with recessive dystrophic epidermolysis bullosa, a severe hereditary blistering disease in which both an anchoring fibril defect and excessive production of collagenase can be observed, produced identical cleavage products from type VII collagen. These data suggest a pathophysiological link between increased enzyme levels and the observed decrease or absence of anchoring fibrils.

Amino Acid Sequence↗

PubMed2002

The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with crohn's disease have autoantibodies to type VII collagen.

Epidermolysis bullosa acquisita is an autoimmune blistering disease of the skin characterized by IgG autoantibodies against type VII collagen. Systemic diseases are often associated with epidermolysis bullosa acquisita, Crohn's disease being the most frequent. This study sought to determine if type VII collagen, the epidermolysis bullosa acquisita autoantigen, was present in normal human colon by western blotting and immunofluorescence. The 290 kDa type VII collagen alpha chain was demonstrated by western blotting in four normal intraoperative colon specimens. Antibodies to type VII collagen labeled the junction between the intestinal epithelium and the lamina propria. We also used an enzyme-linked immunosorbent assay to test sera from patients with Crohn's disease (n = 19), ulcerative colitis (n = 31), celiac disease (n = 17), rheumatoid arthritis (n = 15), and normal controls (n = 16). It was found that 13 of 19 patients with Crohn's disease and four of 31 patients with ulcerative colitis demonstrated reactivity to type VII collagen. Sera from control subjects, patients with celiac disease or rheumatoid arthritis were negative. The sera from Crohn's disease patients also reacted with type VII collagen by immunoblot analysis. It was concluded that patients with inflammatory bowel disease may have IgG autoantibodies to type VII collagen, which exists in both the skin and the gut.

Animals↗

PubMed1992

The large non-collagenous domain (NC-1) of type VII collagen is amino-terminal and chimeric. Homology to cartilage matrix protein, the type III domains of fibronectin and the A domains of von Willebrand factor.

Type VII collagen, the major component of anchoring fibrils, consists of a central collagenous triple-helical segment flanked by non-collagenous domains, NC-1 and NC-2. In this study, we examined the domain organization of human type VII collagen through analysis of deduced amino acid sequences derived from cloned complementary and genomic DNAs, as compared to peptide segments derived from amniotic membrane type VII collagen. The results revealed that the peptide segments derived from the NC-1 domain of type VII collagen could be assigned to the 5' portion of the composite cDNA, indicating that NC-1 resides at the amino terminal end of the molecule. Several sub-domains with homology to adhesive molecules were also identified within NC-1. These protein domains may confer adhesive properties to NC-1, thereby facilitating the binding of type VII collagen to the lamina densa in the cutaneous basement membrane and the anchoring plaques within the dermis.

Amino Acid Sequence↗

PubMed1992

Laminin and type VII collagen distribution in different types of human lung carcinoma: correlation with expression of keratins 14, 16, 17 and 18.

The expression patterns of basement membrane components and keratin intermediate filament proteins were studied in normal human bronchial epithelium and 56 lung carcinomas using monoclonal antibodies to laminin, type VII collagen and the individual keratins 14, 16, 17 and 18. In normal lung, laminin and type VII collagen were present between the epithelium and the lamina propria of bronchi and bronchioles. Keratin 14 was expressed in the basal cells, keratin 17 in the basal and some suprabasal cells and keratin 18 in the columnar cells of the bronchi and bronchioles. Keratin 16 was not present in normal bronchial epithelium. Laminin was found in all subtypes of lung carcinoma, but type VII collagen was present only in squamous cell carcinomas, where it showed a reduction in expression with decreasing differentiation. Type VII collagen was not identified in adenocarcinomas, small cell carcinomas or carcinoids. Antibodies to basal cell keratins 14 and 17 also displayed positivity only in squamous cell carcinomas, although no correlation with the degree of differentiation could be observed. Keratin 16 appeared to be a marker of the squamous phenotype, rather than of hyperproliferation. The keratin 18 marker for columnar epithelial cells showed a reaction pattern opposite to that of the basal cell keratins, being extensively present in adenocarcinomas, small cell carcinomas and carcinoids, with less expression in squamous cell carcinomas. This study shows a correlation between the presence of type VII collagen and the basal cell keratins 14 and 17, and a negative correlation between these components and keratin 18. These findings are likely to be useful in identifying lung cancer subtypes.

Adenocarcinoma↗

PubMed2003

Normal and gene-corrected dystrophic epidermolysis bullosa fibroblasts alone can produce type VII collagen at the basement membrane zone.

Type VII collagen is synthesized and secreted by both human keratinocytes and fibroblasts. Although both cell types can secrete type VII collagen, it is thought that keratinocytes account for type VII collagen at the dermal-epidermal junction (DEJ). In this study, we examined if type VII collagen secreted solely by dermal fibroblasts could be transported to the DEJ. We established organotypic, skin-equivalent cultures composed of keratinocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB) and normal dermal fibroblasts. Immuno-labeling of skin equivalent sections with the anti-type VII collagen antibody revealed tight linear staining at the DEJ. RDEB fibroblasts, were gene-corrected to make type VII collagen and used to regenerate human skin on immune-deficient mice. The human skin generated by gene-corrected RDEB fibroblasts or normal human fibroblasts combined with RDEB keratinocytes restored type VII collagen expression at the DEJ in vivo. Further, intradermal injection of normal human or gene-corrected RDEB fibroblasts into mouse skin resulted in the stable expression of human type VII collagen at the mouse DEJ. These data demonstrate that human dermal fibroblasts alone are capable of producing type VII collagen at the DEJ, and it is possible to restore type VII collagen gene expression in RDEB skin in vivo by direct intradermal injection of fibroblasts.

Animals↗

PubMed1994

Type VII collagen specifically binds fibronectin via a unique subdomain within the collagenous triple helix.

Type VII collagen is the major component of anchoring fibrils, structures within basement membranes beneath stratified squamous epithelium thought to mediate the adherence of the epidermis to the dermis of human skin. Type VII collagen has affinity for fibronectin. The interaction between type VII collagen and fibronectin is mediated through the collagen-binding domain on the amino terminus of fibronectin. Heretofore, the domain on the type VII collagen molecule that binds to fibronectin was not known. In this study, we mapped the binding site of fibronectin to a specific subdomain of the triple helical collagenous region of type VII collagen, immediately adjacent to the small carboxyl terminal non-collagenous domain. This fibronectin-binding site within the type VII collagen molecule lies between nucleotide residues 615 and 1161.

Amino Acid Sequence↗

PubMed2002

A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa.

Dystrophic epidermolysis bullosa pruriginosa, a subtype of epidermolysis bullosa dystrophica and a heterogeneous inherited disease, is characterized by pruritus, excoriated nodular prurigo-like lesions, skin fragility, altered anchoring fibrils and loss of dermal-epidermal adhesion. Mutation in type VII collagen gene (COL7A1) is thought to be implicated in the underlying change for dystrophic epidermolysis bullosa pruriginosa. We report here a large family of dominant dystrophic epidermolysis bullosa pruriginosa. Mutation analysis using polymerase chain reaction and direct sequencing demonstrated a novel nucleotide substitution of 6899A-->G in exon 87 in one COL7A1 allele of the proband and 18 affected family members. This substitution was not found in 100 normal alleles. Polymerase chain reaction and sequencing of the cDNA, reverse transcribed from the proband's peripheral lymphocyte RNA, suggest that this mutation causes aberrant COL7A1 mRNA splicing of exon 87 skipping. Clinical features and pedigree analysis suggest that 6899A-->G substitution is a mutation with full penetrance and variable expressivity.

Adolescent↗

PubMed1997

Ultraviolet A irradiation upregulates type VII collagen expression in human dermal fibroblasts.

Type VII collagen, a major component of skin-anchoring fibrils, is synthesized by both fibroblasts and keratinocytes, the two principal cell types in the skin. In this study, we examined the effects of ultraviolet A (UVA) irradiation on the expression of type VII collagen in human fibroblasts. UVA irradiation (0-15 J/cm2) caused a dose-dependent increase (5- to 10-fold) in type VII collagen mRNA levels as detected by northern blot analysis. The UVA-induced enhancement of type VII collagen gene expression correlated with an increase in its protein level by immunoblot analysis of proteins secreted into the conditioned medium. The effect of UVA was observed at 12 h and reached its maximum by 18 h. Under these conditions, however, the expression of fibronectin, a major dermal matrix protein, remained unchanged, suggesting that the induction of type VII collagen expression was selective. Actinomycin D, a transcription inhibitor, blocked the UVA-mediated induction of type VII collagen gene expression, whereas cycloheximide, a protein synthesis inhibitor, superinduced the expression of type VII collagen, suggesting that de novo protein synthesis was not required for the action of UVA. Interestingly, in contrast to the increased type VII collagen expression in fibroblasts in response to UVA, a slight decrease in type VII collagen mRNA level was observed in the UVA-irradiated keratinocytes, suggesting that the effect of UVA on the type VII collagen expression is cell type specific.

Adult↗

PubMed1994

Epitope mapping for epidermolysis bullosa acquisita autoantibody by molecularly cloned cDNA for type VII collagen.

Epidermolysis bullosa acquisita is a subepidermal blistering disease in which patients have autoantibodies against the non-collagenous domain of type VII collagen. Starting with previously isolated 1-kilobase pair (Kb) cDNA for this autoantigen, we isolated overlapping cDNAs with a combined open reading frame of approximately 3.2 Kb, encoding most (approximately 115 kilodaltons [KDa]) of the N-terminal non-collagenous domain of type VII collagen. To localize immunogenic domains, we produced maltose-binding fusion proteins with cDNA encoding different portions of this autoantigen. These cDNA fragments scan from 5' to 3' of this non-collagenous domain and overlap each other. An immunoblot analysis of these fusion proteins with eight epidermolysis bullosa acquisita patient sera demonstrated that each patient serum binds to different regions of this molecule and that epitopes for these patient sera locate throughout this autoantigen. These data suggest that multiple epitopes on the N-terminal non-collagenous domain of type VII collagen are recognized by circulating autoantibodies in patients with epidermolysis bullosa acquisita.

Autoantibodies↗

PubMed1993

Type VII collagen gene expression in human umbilical tissue and cells.

BACKGROUND: Type VII collagen is a minor collagen found in anchoring fibrils. It is expressed predominantly by keratinocytes. In this study, we report the localization and spatial distribution of type VII collagen gene expression in the human umbilical cord, a fetal-derived tissue. EXPERIMENTAL DESIGN: Human umbilical cords were examined in indirect immunofluorescence studies, employing a mouse monoclonal anti-human type VII collagen antibody. Endothelial cells were cultured from the vein and grown on chamber slides for the detection of type VII collagen epitopes. In addition, cultured human umbilical vein cells were analyzed by Northern transfer analysis and by polymerase chain reaction for the expression of the corresponding gene. Fibroblast-like cells were isolated from the Wharton's jelly and were analyzed similarly for type VII collagen expression as well. RESULTS: We demonstrate that type VII collagen is expressed by human umbilical tissue and cells. Indirect immunofluorescence studies demonstrate the presence of type VII collagen epitopes in the epithelium surrounding a connective tissue region known as Wharton's jelly. In addition, there was low but detectable immunofluorescence signal associated with endothelial cells of blood vessels within the umbilical cord. In vitro, the fibroblast-like cells cultured from the Wharton's jelly showed prominent type VII collagen signal. This result was supported by the finding of high level of type VII collagen mRNA in these cells. The human endothelial cells from the vein demonstrated weak but detectable staining for type VII collagen, and the corresponding gene expression was shown by polymerase chain reaction analysis of the mRNA of the endothelial cells. CONCLUSIONS: The results show that umbilical tissue and cells, specifically those from the Wharton's jelly, are relatively enriched in type VII collagen. There is differential spatial localization of this collagen in the fetal tissue. The novel finding is that cells, other than epithelial cells such as keratinocytes, are able to express the type VII collagen gene.

Antibodies, Monoclonal↗

PubMed1995

Immunodominant autoepitopes of type VII collagen are short, paired peptide sequences within the fibronectin type III homology region of the noncollagenous (NC1) domain.

Autoantibodies to type VII collagen are associated with the blistering diseases epidermolysis bullosa acquisita and bullous systemic lupus erythematosus. We showed previously that these autoantibodies recognize epitopes within the noncollagenous (NC1) region of type VII collagen. That region is composed of fibronectin type III homology units that may contribute to intermolecular cross-linking and basement membrane adhesion functions of type VII collagen. In this study, we defined the specific amino acid sequences recognized by these autoantibodies. By fusion protein analysis, sera from patients with epidermolysis bullosa acquisita and bullous lupus were found to react with two regions within the fourth (E-1) and eighth (E-2) fibronectin homology repeats, each consisting of approximately 100 amino acids. Affinity purification studies showed E-1 and E-2 to be independent and non-cross-reactive epitope regions. These regions were probed further by enzyme-linked immunosorbent assay analysis of overlapping octapeptide sets derived from the amino acid sequences of E-1 and E-2. The results showed two reactive, closely associated octapeptide sequences within each region, both lying in amphipathic portions of fibronectin type III homology repeats. These studies identify short peptide sequences within the NC1 domain of type VII collagen that are targeted independently by autoantibodies. These sequences may play a direct role in determining the properties of type VII collagen that influence adhesion between this molecule and other basement membrane proteins, and their alteration by antibody binding may be the immunopathogenic event underlying epidermolysis bullosa acquisita and bullous lupus.

Amino Acid Sequence↗

PubMed1987

Type VII collagen forms an extended network of anchoring fibrils.

Type VII collagen is one of the newly identified members of the collagen family. A variety of evidence, including ultrastructural immunolocalization, has previously shown that type VII collagen is a major structural component of anchoring fibrils, found immediately beneath the lamina densa of many epithelia. In the present study, ultrastructural immunolocalization with monoclonal and monospecific polyclonal antibodies to type VII collagen and with a monoclonal antibody to type IV collagen indicates that amorphous electron-dense structures which we term "anchoring plaques" are normal features of the basement membrane zone of skin and cornea. These plaques contain type IV collagen and the carboxyl-terminal domain of type VII collagen. Banded anchoring fibrils extend from both the lamina densa and from these plaques, and can be seen bridging the plaques with the lamina densa and with other anchoring plaques. These observations lead to the postulation of a multilayered network of anchoring fibrils and anchoring plaques which underlies the basal lamina of several anchoring fibril-containing tissues. This extended network is capable of entrapping a large number of banded collagen fibers, microfibrils, and other stromal matrix components. These observations support the hypothesis that anchoring fibrils provide additional adhesion of the lamina densa to its underlying stroma.

Antibodies↗

PubMed1994

Differential cytokine regulation of type I and type VII collagen gene expression in cultured human dermal fibroblasts.

Type VII collagen is the major component of anchoring fibrils in the cutaneous basement membrane zone. In this study, we have examined the effects of various cytokines on the expression of types I and VII collagen genes in dermal fibroblasts in culture. The pro-inflammatory cytokines, interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and leukoregulin (LR) strongly elevated (approximately 5-9-fold) type VII collagen mRNA levels, as measured by Northern blot hybridizations. These effects were also observed at the protein level by indirect immunofluorescence using a monoclonal antibody specific for type VII collagen. By contrast, IL-1 beta had only a slight stimulatory effect (approximately 2-fold) on type I collagen gene expression, while TNF-alpha and LR markedly reduced type I collagen mRNA steady-state levels. Interestingly, IL-1, TNF-alpha and LR had additive effects with transforming growth factor-beta (TGF-beta) on type VII collagen gene expression, whereas they counteracted the up-regulatory effect of TGF-beta on type I collagen gene expression. Thus, our data indicate that the modulation of type I and type VII collagen gene expression by cytokines involves different regulatory pathways.

Adult↗

PubMed1989

The carboxyl-terminal domain of type VII collagen is present at the basement membrane in recessive dystrophic epidermolysis bullosa.

Recent studies showing that type VII collagen is a component of anchoring fibrils suggests that the absence of anchoring fibrils in recessive dystrophic epidermolysis bullosa may be due to a defect in the synthesis, secretion, and deposition of type VII collagen. That hypothesis is further supported by recent studies suggesting that monoclonal antibodies to type VII collagen do not react with the basement membrane in most patients. To investigate further, we examined skin from 12 patients by electron microscopy and by immunohistology and immunoelectron microscopy using a concentrated and purified monoclonal antibody to the carboxy-terminal domain of Type VII collagen. Although anchoring fibrils were not detected by electron microscopy, the results of immunohistology showed definite, but reduced, binding of the monoclonal antibody to type VII collagen at the basement membrane in a linear pattern in 11 of 12 patients. By immunoelectron microscopy, reduced deposition of anti-type VII collagen antibody was detected beneath the lamina densa. The results of this study show that the carboxyl-terminal domain of type VII collagen is synthesized, secreted, and deposited at the basement membrane zone in 11 of 12 patients with recessive dystrophic epidermolysis bullosa and suggest that the absence of anchoring fibrils may be due either to deposition of abnormal type VII collagen, reduced levels of normal type VII collagen, defective assembly of type VII collagen into anchoring fibrils, or destruction of the collagenous domain of type VII collagen.

Antibodies, Monoclonal↗