Epithelial Basement Membrane Zone Research Articles

Oral Lesions in Autoimmune Bullous Diseases: An Overview of Clinical Characteristics and Diagnostic Algorithm

Autoimmune bullous diseases are a group of chronic inflammatory disorders caused by autoantibodies targeted against structural proteins of the desmosomal and hemidesmosomal plaques in the skin and mucosa, leading to intra-epithelial or subepithelial blistering. The oral mucosa is frequently affected in these diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus. The clinical symptoms are heterogeneous and may present with erythema, blisters, erosions, and ulcers localized anywhere on the oral mucosa, and lead to severe complaints for the patients including pain, dysphagia, and foetor. Therefore, a quick and proper diagnosis with adequate treatment is needed. Clinical presentations of autoimmune bullous diseases often overlap and diagnosis cannot be made based on clinical features alone. Immunodiagnostic tests are of great importance in differentiating between the different diseases. Direct immunofluorescence microscopy shows depositions of autoantibodies along the epithelial basement membrane zone in mucous membrane pemphigoid subtypes, or depositions on the epithelial cell surface in pemphigus variants. Additional immunoserological tests are useful to discriminate between the different subtypes of pemphigoid, and are essential to differentiate between pemphigus and paraneoplastic pemphigus. This review gives an overview of the clinical characteristics of oral lesions and the diagnostic procedures in autoimmune blistering diseases, and provides a diagnostic algorithm for daily practice.

Ocular Manifestations and Management of Autoimmune Bullous Diseases.

Autoimmune bullous diseases with ocular involvement consist of a group of systemic entities that are characterized by formation of autoantibodies against the proteins of the epithelial basement membrane zone of the conjunctiva. Mostly, the elderly are affected by these diseases. The characteristic patterns of mucocutaneous involvement and the specific tissue components targeted by these autoantibodies are differentiating features of these diseases. Ocular pemphigus vulgaris exhibits intraepithelial activity, whereas the autoimmune activity in linear immunoglobulin A disease, mucous membrane pemphigoid, and epidermolysis bullosa acquisita occurs at a subepithelial location. Given the increased risk for blindness with delays in diagnosis and management, early detection of ocular manifestations in these diseases is vital. The precise diagnosis of these autoimmune blistering diseases, which is essential for proper treatment, is based on clinical, histological, and immunological evaluation. Management usually includes anti-inflammatory and immunosuppressive medications. Inappropriate treatment results in high morbidity and even potential mortality.

A subset of patients with pemphigoid (herpes) gestationis has serological evidence of celiac disease.

Pemphigoid (herpes) gestationis (PG) is an uncommon, self-limited disease with other autoimmune associations; however, celiac disease (CD) is not recognized as one. From 71 patients' sera submitted for herpes gestationis factor (HGF) testing over a 5-year period, 12 were consistent with PG demonstrating HGF and increased IgG BP180 antibody levels; these sera were tested for IgA and IgG endomysial antibodies (EMA), epithelial basement membrane zone and cell surface antibodies by indirect immunofluorescence, and for IgA and IgG tissue transglutaminase (transglutaminase 2 or TG2) antibodies, IgA epidermal transglutaminase (transglutaminase 3 or TG3) antibodies, IgG BP230, and IgG desmoglein 1 and desmoglein 3 antibodies by enzyme-linked immunosorbent assays (ELISAs). Three of 12 patients' sera with PG (25%) had CD antibodies with positive IgA EMA and increased IgA TG2 antibody levels; two of these had positive IgG EMA, and one other had an increased IgA TG3 antibody level. A subset of patients with serological findings of PG also has serological evidence of CD, which may have implications in the etiopathogenesis of PG and which reveals important information about the mother's, and possibly her infant's, health.

Is chronic ulcerative stomatitis a variant of lichen planus, or a distinct disease?

Chronic ulcerative stomatitis is an immune-mediated mucocutaneous disorder characterized clinically by erosions or ulcers. Most cases are limited to the mouth. The histopathological features are non-specific or mimic those of oral lichen planus, and studies by immunofluorescent microscopy are essential for definitive diagnosis. The defining immunopathogenic mechanism is the binding of IgG to the nuclear protein deltaNp63alpha of keratinocytes in the basal and parabasal cell layers of the oral stratified epithelium. DeltaNp63alpha functions as a regulator of epithelial stem cell activity and as an antiapoptotic agent and regulates the expression of cell-to-cell and cell-to-basement membrane adhesion molecules. The autoimmune IgG-deltaNp63alpha interaction is thought to result in damage to the structural attachment of keratinocytes to one another and to the epithelial basement membrane zone and in dysregulation of the cell cycle and apoptosis of basal keratinocytes with the development of erosions or ulcers. The aims of treatment are to suppress the pathogenic immunoinflammatory responses, to prevent local infection and to promote healing. The purpose of this article is to provide a succinct review of the diagnostic, clinical and etiopathogenic features of, and treatment guidelines for chronic ulcerative stomatitis, and to argue that this disease should be regarded as a variant of oral lichen planus, rather than as a distinct entity.

IgM ocular cicatricial pemphigoid: a unique insight into the immune system

A 42-year-old man with ocular erythema and scarring had a conjunctival biopsy revealing depostion of IgM and C3 without IgG at the epithelial basement membrane zone. Treatment with doxycyline, dapsone, and mycophenolate mofetil was unsuccessful and treatment with rituximab has led to partial remission of the conjunctival inflammation. He has undergone 4 cycles of rituximab treatment at intervals of 12 to 18 months.

Mucous Membrane Pemphigoid: Diagnosis and Sequel

Introduction: Mucous membrane pemphigoid is a disease characterized by subepidermal bullae primarily involving the oral and ocular mucous membranes. In its pathogenesis there is linear deposition of IgG, IgA, and C3 along the epithelial basement membrane zone. Its prevalence is estimated between 1/12,000 and 1/20,000 in general population and its clinical manifestations are varied, being invasive and aggressive.

In vivo confocal microscopy of mucous membrane pemphigoid, a new tool for the diagnosis. Reporting 6 cases

AbstractPurpose Mucous membrane pemphigoid (MMP), previously known as cicatricial pemphigoid, is an autoimmune disease characterized by linear deposition of IgG and IgA along the epithelial basement membrane zone in direct immunofluorescence (DIF). DIF requires mucosal biopsy, which can worsen the condition by triggering an inflammatory response of the mucosa, especially the conjunctiva. We assess in vivo confocal microscopy (IVCM) for the detection of the pathognomonic basement membrane cleavage zone (BMCZ) in MMPMethods Six patients (4 M, 2 W), suffering from ocular and/or oral MMP were tested with IVCM, using the handheld Vivascope 3000. Three patients had ocular involvement, 2 oral involvement, and 1 had both.Results Mean age was 76 years old. Out of the 4 patients with ocular involvement, 2 patients had active conjunctivitis and 2 patients had cicatricial lesions. A BMCZ was identified in both patients with active conjunctivitis, while none was observed in those with cicatricial lesions. All 3 patients with oral involvement had desquamative gingivitis with marked BMCZ.Conclusion IVCM is non‐invasive and reliable for the diagnosis of MMP. Conjunctival fornix biopsy is at high risk of symblepharon. These biopsies are often performed blindly as the pathological zones are barely visible clinically. IVCM enables the observation of the whole inflammatory surface of the conjunctiva and gum. To our knowledge, these are the first 2 cases of patients with conjunctival BMCZ clearly identified with IVCM.

Low-level laser therapy for oral mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) describes a group of chronic, inflammatory, sub epithelial blistering diseases that manifest a heterogeneous pattern of oral, ocular, skin, genital, nasopharyngeal, oesophageal, and laryngeal lesions. MMP is histologically characterizedby lineardepositionof IgG, IgA,or C3 along the epithelial basement membrane zone (BMZ). Autoantibodies against various epithelial BMZ components probablyplaya role in thepathogenesisof thisgroupofdiseases [1, 2].MMPdoesnothaveapredictablenatural history. In some patients, the disease is localized and has a slowly progressive course without complications; in others, it is devastating, with severe morbidity. There have been no large-scale, wellcontrolled studies regarding therapy for MMP and most of the therapeutic experience is from studies on cutaneous bullous pemphigoid [3].The choice of agents for its treatment ismainly based upon the sites of involvement, clinical severity, and disease progression [3].Usually, limited oral lesions are treated with topical immunosuppressive drugs. Low-level laser therapy (LLLT) is a novel approach increasingly used in medicine, which has potential biostimulating effects when applied to oral tissues thus improving wound healing [4, 5]. The basic principle of LLLT is based upon the biostimulation or the biomodulation effect: irradiation at a specific wavelength is able to alter cellular behavior. Laser biostimulationcanobtaindifferent intracellular biological reactions to stimulate regenerative abilities, without undesired adverse effects, reducing also the pharmacological support [6–8]. To date, two MMP cases have been described in literature to have been successfully treated with LLLT but in addiction with systemic [9] and topical [10] immunosuppressive therapy. We have reviewed our experience of treating three patients with MMP using only LLLT.

Immunohistochemical Differences Between Normal and Chronically Inflamed Conjunctiva: Diagnostic Features

There is widespread misinterpretation of normal conjunctival fibrinogen. In differentiating between normal conjunctiva and cicatrizing conjunctivitis, including ocular cicatricial pemphigoid, atopic keratoconjunctivitis, and lichen planus, it is important to properly evaluate and characterize the histologic appearance of the structures seen and not base a diagnosis on just the presence or absence of certain features. One feature of conjunctival histology prone to misinterpretation and misdiagnosis is the presence of subepithelial fibrinogen, particularly when the diagnosis of lichen planus is being considered. Although the presence of subepithelial fibrinogen in oral mucous membranes and in skin can be indicative of lichen planus, such is not the case for conjunctiva. An erroneous diagnosis of lichen planus based on the presence of conjunctival subepithelial fibrinogen can initiate prolonged treatment with topical steroids leading to avoidable, blinding, complication, and further, delay therapy for the real cause of the conjunctivitis. We conducted a cross sectional, controlled, blinded and prospective Institutional Review Board-approved study on the occurrence and pattern of fibrinogen at the epithelial basement membrane zone (BMZ) of normal and inflamed conjunctiva. Bulbar conjunctiva was obtained from 10 cases of undiagnosed chronic conjunctivitis of at least 6 months duration and 8 patients with normal conjunctiva. Immunofluorescent staining with antifibrinogen antibodies, periodic acid-schiff stain (PAS), and Giemsa staining were performed. BMZ fibrinogen was found in all cases. This layer was linear, smooth, and continuous in normal conjunctiva and 7 cases of chronic conjunctivitis. It was fragmented and lumpy in 1 case of ocular cicatricial pemphigoid (OCP) and showed spikes and spurs in 2 cases of lichen planus. BMZ fibrinogen is a normal component of the conjunctiva and its morphological features rather than its mere presence should be assessed as a diagnostic tool.

Lúpus eritematoso sistêmico bolhoso: diagnóstico diferencial com dermatite herpetiforme

Bullous systemic lupus erythematosus is a rare subset of systemic lupus erythematosus that is even rarer in pediatric patients. We report a case of a 12-year-old girl who presented with a vesiculobullous eruption on her face, neck, trunk and genital and oral mucosa, as well as anemia, sterile pyuria, ANA (1:1280, speckled pattern) and positive anti-Sm and anti-RNP. Pathological examination suggested dermatitis herpetiformis, and direct immunofluorescence revealed IgG, IgA and fibrin in the epithelial basement membrane zone. We present a typical case of bullous systemic lupus erythematosus and emphasize the importance of clinical and histopathological differential diagnosis with dermatitis herpetiformis.

Conjunctival Interleukin-13 Expression in Mucous Membrane Pemphigoid and Functional Effects of Interleukin-13 on Conjunctival Fibroblasts in Vitro

Interleukin-13 (IL-13) is the dominant effector cytokine of fibrosis in pulmonary and liver disease. Excessive conjunctival fibrosis in the immunobullous disease ocular mucous membrane pemphigoid (MMP) causes blindness; the pathogenesis of scarring in this disease is incompletely understood. To determine whether IL-13 is involved in conjunctival fibrosis in MMP, we studied the expression of IL-13 in ocular MMP patients before and after systemic immunosuppression and examined the effects of IL-13 on normal human conjunctival fibroblasts. We found high stromal cell expression of IL-13 in active ocular MMP by immunohistochemistry; 80% of these cells were CD3-positive T cells. Following immunosuppression, in clinically uninflamed, treated, ocular MMP patients, the number of IL-13 positive cells was significantly reduced, but this was still fourfold greater than in normal conjunctiva. IL-13 stimulated collagen lattice contraction and migration, and decreased production of mmp-3 and mmp-10 by human conjunctival fibroblasts. The addition of T cell culture supernatant to IL-13 synergistically augmented fibroblast migration. IL-13 also up-regulated surface expression of HLA-DR, CD80, CD40, and CD154 by conjunctival fibroblasts, suggesting a potential mechanism for fibroblast-T cell cross talk, via which fibroblasts may actively engage in perpetuating chronic inflammation and continued fibrosis. Together, these findings suggest that IL-13 is involved in conjunctival fibrosis in MMP, and that IL-13 has both profibrotic and pro-inflammatory effects on human conjunctival fibroblasts.

Alterations of epithelial adhesion molecules and basement membrane components in lattice corneal dystrophy (LCD)

The aim of the study was to investigate the histopathological and ultrastructural correlate of delayed epithelial healing in eyes with lattice corneal dystrophy (LCD). Corneal buttons from 4 patients with LCD (two with subepithelial, two with stromal amyloid deposits) and 2 control corneas were examined. Cell-matrix adhesion molecules and basement membrane components of the corneal epithelium were analyzed by immunohistochemistry and hemidesmosomes between epithelium and stroma were quantified by transmission electron microscopy (TEM). By TEM well-developed hemidesmosomes anchored the basal epithelial cells to the underlying basement membrane in all normal and LCD corneas. Hemidesmosome density was not significantly different in subepithelial (224.7 +/- 34.1/100 microm) and stromal (234.3 +/- 36.3/100 microm) LCD compared to controls (241.3 +/- 26.8/100 microm). The basement membrane was interrupted in subepithelial, but continuous in stromal LCD. Integrin alpha6 and beta4 staining formed a continuous line along the basal surface of the corneal epithelium in control corneas, whereas it appeared discontinuous and patchy both in subepithelial and stromal forms of LCD. Staining for alphaV integrin showed irregular staining patterns, i.e. enhanced labelling intensity in subepithelial and interrupted pattern in stromal LCD, respectively. Integrins alpha3, beta1, beta2, and beta5, dystroglycan, and plectin were not markedly different in dystrophic corneas. Type VII collagen showed a discontinuous staining in subepithelial forms of LCD. In stromal forms of LCD, type VII collagen staining occurred in additional patches underneath the epithelial basement membrane zone. Type XVII collagen staining was reduced in subepithelial LCD. Laminin-1, laminin-5 and laminin gamma2 showed variable irregular staining patterns in dystrophic corneas with focal interruptions, focal thickenings, and reduplications of basement membrane. Some irregularities in corneas with subepithelial amyloid were observed for collagen types IV, V, and XVIII, laminin alpha1, alpha3, and gamma1, nidogen-1 and -2, perlecan, fibrillin-1. Immunohistochemical and electron microscopic evidence of structural alterations was found in LCD compared to normal corneas concerning cell-matrix adhesion molecules and basement membrane components. These alterations were more pronounced in dystrophic corneas with subepithelial amyloid deposits than in those with stromal deposits. Histopathological findings may correspond to reduced cell-matrix interactions and partly explain delayed epithelial healing in patients with lattice corneal dystrophy.

Cicatrising conjunctivitis with anti-basement membrane autoantibodies in ectodermal dysplasia

Aims:To report circulating and mucosa-deposited anti-basement membrane zone autoantibodies in a series of six ectodermal dysplasia patients with severe bilateral cicatrising conjunctivitis and blindness due to both corneal disease and...

Lúpus eritematoso sistêmico bolhoso na infância: relato de caso

É apresentado caso de lúpus eritematoso bolhoso na infância. Doente do sexo feminino, com nove anos, apresentava erupção vesicobolhosa no tronco, região cervical, genital e membros. O exame anatomopatológico mostrou bolha subepidérmica com neutrófilos, a imunofluorescência direta revelou depósito linear de IgA, IgM, IgG e C3 na zona da membrana basal, e a indireta foi negativa. Os anticorpos antinucleares e o anti-Sm estavam positivos. Houve regressão do quadro com dapsona e prednisona. Trata-se de caso raro de lúpus eritematoso sistêmico (LES) na infância que se iniciou com bolhas disseminadas. O LES bolhoso deve ser incluído no diagnóstico diferencial das erupções bolhosas na infância.

Chronic Cicatrizing Conjunctivitis in a Patient With Epidermolysis Bullosa Acquisita

To describe a nonconventional diagnostic technique used to diagnose a case of cicatrizing conjunctivitis associated with epidermolysis bullosa acquisita. Direct immunofluorescence of a biopsy specimen of the patient's conjunctiva was performed using fluorescein-conjugated rabbit antihuman antibodies against IgA, IgG, and IgM; complement C3; and fibrinogen. Immunoblot assay using healthy human skin as substrate was performed to investigate for the presence of antibodies in the patient's serum. After the diagnosis of systemic autoimmune disease was established, intravenous immunoglobulin therapy was administered. Direct immunofluorescence of the conjunctiva revealed linear deposition of IgA and IgG, and C3 at the epithelial basement membrane zone. Immunoblot analysis demonstrated the presence of IgG antibodies in patient serum directed against a 290-kDa protein in human skin. A diagnosis of epidermolysis bullosa acquisita was established. All signs and symptoms improved dramatically 4 months after initiation of intravenous immunoglobulin therapy and remained stable during follow-up. Epidermolysis bullosa acquisita can manifest in the eye as chronic cicatrizing conjunctivitis indistinguishable from ocular cicatricial pemphigoid. A nonconventional diagnostic tool (immunoblot assay) might be helpful in establishing the diagnosis of an underlying systemic autoimmune disease in patients with chronic cicatrizing conjunctivitis. Intravenous immunoglobulin therapy was effective against chronic cicatrizing conjunctivitis associated with epidermolysis bullosa acquisita.

Confocal Microscopy of Subepithelial Infiltrates Occurring After Epidemic Keratoconjunctivitis

To describe the confocal microscopic findings in subepithelial infiltrates associated with epidemic keratoconjunctivitis (EKC). Observational case report. A 14-year-old Saudi girl with keratoconus developed subepithelial infiltrates (SEIs) after the onset of bilateral EKC. Confocal microscopy of the left cornea 8 weeks after the onset of EKC showed many highly reflective dendritic cells at the level of basal epithelium, epithelial basement membrane zone, and anterior stroma, as well as many highly reflective fusiform and round cells within the anterior stroma, with deceasing density in progressively deeper layers of the stroma. These findings were not present on confocal microscopy that had been performed 2 weeks before the onset of EKC. Confocal microscopic examination of SEIs after EKC provides evidence of an inflammatory response localized to the basal epithelium and anterior stroma of the central cornea.

Confocal Microscopy of Subepithelial Infiltrates Occurring After Epidemic Keratoconjunctivitis

To describe the confocal microscopic findings in subepithelial infiltrates (SEIs) associated with epidemic keratoconjunctivitis (EKC). Observational case report. A 14-year-old Saudi girl with keratoconus developed SEIs after the onset of bilateral EKC. Confocal microscopy of the left cornea 8 weeks after the onset of EKC showed many highly reflective dendritic cells at the level of basal epithelium, epithelial basement membrane zone, and anterior stroma, as well as many highly reflective fusiform and round cells within the anterior stroma, with decreasing density in progressively deeper layers of the stroma. These findings were not present on confocal microscopy that had been performed 2 weeks before the onset of EKC. Confocal microscopic examination of SEIs after EKC provides evidence of an inflammatory response localized to the basal epithelium and anterior stroma of the central cornea.

Colocalization of the collagen‐binding proteoglycans decorin, biglycan, fibromodulin and lumican with different cells in human gingiva

Decorin, biglycan, fibromodulin and lumican are structurally related molecules that belong to the family of small leucine-rich proteoglycans (SLRPs). These SLRPs are secreted extracellular matrix molecules that interact with type I collagen and regulate collagen fibrillogenesis. They may also modulate cell functions that are important in maintenance of connective tissue structure. The aim of this study was to localize decorin, biglycan, fibromodulin and lumican in human gingiva. Localization of decorin and its proform (prodecorin), biglycan, fibromodulin and lumican and mature and proform of type I collagen was studied by immunohistochemical staining of frozen tissue sections from healthy human attached gingiva. Double immunostaining with anti-SLRP or anti-type I procollagen antibodies and specific markers for different connective tissue cells was used to study association of these molecules with cells. The mature and proforms of decorin and collagen and biglycan, fibromodulin and lumican showed distinct localization in the extracellular matrix, where they associated with type I collagen fiber bundles. Prodecorin also localized to the epithelial basement membrane zone. Fibroblasts, myofibroblasts, endothelial cells and pericytes showed immunoreactivity for procollagen, prodecorin, biglycan and fibromodulin, whereas lumican associated with fibroblasts and myofibroblasts only. Biglycan and fibromodulin were also associated with macrophages. Basal epithelial cells of the gingival epithelium showed immunoreactivity for biglycan, fibromodulin and lumican. Decorin, biglycan, fibromodulin and lumican associate with type I collagen and may collaborate to regulate collagen fibrillogenesis in human gingiva. Each of the SLRPs showed a distinct association with different connective tissue cells, suggesting that the cells produce these molecules and/or that the cells interact with them. Localization of biglycan, fibromodulin and lumican at the epithelial cells suggests novel functions for these SLRPs in human gingival epithelium.

Ocular Cicatricial Pemphigoid, Keratomycosis, and Intravenous Immunoglobulin Therapy

To report the case of a patient developing fungal keratitis in the context of uncontrolled ocular cicatricial pemphigoid (OCP), which, despite intravenous immunoglobulin (IVIg) and other immunomodulatory therapy, progressed to end-stage pemphigoid, with corneal opacification, ankyloblepharon, and xerosis. Keratoprosthesis (KPro) restored functional vision for the patient. A 39-year-old man presented with uncontrolled CP and corneal ulcer in the left eye. Conjunctival biopsy diagnosed OCP; corneal scraping and biopsy diagnosed the cause of the corneal ulcer. OCP was treated with systemic steroids, immunosuppressive drugs, and IVIg. Visual rehabilitation was accomplished with Ahmed valve and a type II Dohlman KPro. Immunohistology of the biopsied conjunctiva showed IgG at the epithelial basement membrane zone, confirming the clinical diagnosis of OCP. Microbiologic studies of the corneal biopsy specimen were negative for Acanthamoeba and herpes but positive for Aspergillus niger. The patient's keratomycosis resolved with topical antifungal therapy. Treatment with Dapsone, intravenous-pulse steroid, oral cyclophosphamide, and intravenous immunoglobulin (IVIg) failed to control the OCP, with resultant complete conjunctivization of the cornea. Keratoprosthesis improved the patient's visual acuity from hand movements to 20/20. Patients with uncontrolled OCP are at increased risk of corneal infection. The difficulty in diagnosing keratomycosis and the relatively rare occurrence of OCP explain the uniqueness of our reported case. OCP may progress to "end-stage" disease despite therapy. Keratoprosthesis can restore vision in selected otherwise seemingly hopeless cases.

Type XIX Collagen Purified from Human Umbilical Cord Is Characterized by Multiple Sharp Kinks Delineating Collagenous Subdomains and by Intermolecular Aggregates via Globular, Disulfide-linked, and Heparin-binding Amino Termini

Type XIX collagen was discovered from the sequence of rhabdomyosarcoma cDNA clones. The chain is composed of a 268-residue amino terminus, an 832-residue discontinuous collagenous region, and a 19-residue carboxyl peptide. Light microscopy immunohistochemistry of adult human tissues demonstrated that type XIX is localized in vascular, neuronal, mesenchymal, and some epithelial basement membrane zones. It also appears to be involved in events linked to skeletal myogenesis. In this report, we have presented the first direct evidence for the molecular structure of type XIX collagen. Using human umbilical cord, native type XIX was purified by neutral salt extraction and by ion exchange and antibody affinity chromatography. Type XIX was found to represent only approximately 10(-6)% of the dry weight of tissue, making it by far the least abundant collagen ever isolated. Transmission electron microscopy after rotary shadowing revealed the appearance of rodlike structures with multiple sharp bends, a small nodule at one end of the molecule, and a total length of 240 nm. Domain-specific antibodies were used to identify the nodule as the noncollagenous amino terminus, whereas the location of most kinks corresponds to major interruptions separating the five collagenous subdomains. More than half of the type XIX molecules observed were present in oligomers of different size and complexity, resulting from association of the amino-terminal domains. Biochemical analysis demonstrated that these supramolecular aggregates are dependent upon and/or stabilized by intermolecular disulfide cross-links and that the globular amino terminus contains a high affinity, heparin-binding site. The polymorphic conformational states of this rare collagen, and its ability to self-assemble into a higher order structure provide focal points for future determination of biologically significant functions in cell-cell and/or cell-matrix interactions.