Restriction of cicatricial pemphigoid antigens to the lamina densa: confirmation by indirect immunoelectron microscopy.

Circulating anti-basement membrane zone (BMZ) antibodies in a patient with cicatricial pemphigoid (CP) were examined using an indirect immunofluorescence test, indirect immunoperoxidase electron microscopy, and Western blot analysis. An indirect immunofluorescence test on salt-split skin revealed that the anti-BMZ antibodies reacted solely to the dermal side at the separating epidermal-dermal interface, and indirect immunoelectron microscopy on intact skin indicated localization of the corresponding antigens (CP antigens) over the lamina densa and within the lower half of the lamina lucida; there were no CP antigens beneath a melanocyte. Indirect immunoelectron microscopy on salt-split skin demonstrated that the CP antigens were partly dissociated from, but restricted to, the lamina densa. Western blot analysis showed no differences in molecular weight between the CP antigens and bullous pemphigoid (BP) antigens. CP antigens, as detected by this patient's serum, appear to be constituted of molecules quite similar to BP antigens, but with different epitopes. CP antigens may be shed from basal cells and locate in the area of anchoring filaments, where they play a role in connecting basal cells to the underlying lamina densa.     

A case of cicatricial pemphigoid with circulating IgA and IgG antibodies directed against 280 kD, 165 kD and 120-130 kD epidermal antigens

A case of subepidermal autoimmune blistering disease in an 86-year-old woman is reported. Clinical features were those of a cicatricial pemphigoid, with prominent mucosal involvement leading to conjunctival and nasal scarring. Direct immunofluorescence findings were consistent with either cicatricial pemphigoid or linear IgA dermatosis, since both IgG and IgA linear deposits were found at the basal membrane zone. Immunoelectron microscopy of perilesional skin revealed IgA deposits within the lamina lucida and immunoblotting of the patient's serum disclosed IgA and IgG antibodies directed against epidermal antigens of 280, 165 and 120-130 kD.     

Identification of cicatricial pemphigoid antigens.

The nature of skin antigens defined by antibodies in patients with cicatricial pemphigoid was studied with use of the 1 mol/L of sodium chloride split skin technique and Western immunoblot analysis. Antibodies in the serum samples of three of seven patients with cicatricial pemphigoid reacted to the epidermal side of 1 mol/L of sodium chloride split skin, and antibodies in the serum sample of one patient reacted to the dermal side. With Western immunoblot analysis, three patients had antibodies to antigens in the epidermal extracts of skin. The antibodies reacted in all patients to a 160-kd antigen and in one patient to an additional 230-kd antigen. These two antigens are similar in molecular weight to the 230-kd major bullous pemphigoid antigen and to the 160-kd minor bullous pemphigoid antigen. However, while the basement membrane zone antibodies present in cicatricial pemphigoid were most often directed to the 160-kd antigen, those present in 38 patients with bullous pemphigoid reacted most often (in 34 patients [89%]) to the 230-kd antigen. None of the serum samples reacted to antigens in dermal extracts that contained the epidermolysis bullosa acquisita antigen. These results indicate that the basement zone membrane antibodies present in cicatricial pemphigoid are directed in part to epidermal antigens that are similar in molecular weight to bullous pemphigoid antigens. However, the frequency of reactions to different basement membrane zone antigens differs in the two diseases, which may account for the clinical differences between the two conditions.     

Disseminated cicatricial pemphigoid in a child and in an adult. Ultrastructural diagnostic criteria and differential diagnosis with special reference to acquired epidermolysis bullosa

Summary The first case of an infant affected with a rare, disseminated variant of benign cicatricial pemphigoid is described, showing the same ultrastructural features of initial blister formation as an adult patient. These consist in edematous changes within the superficial dermis caused by vesiculation or dissolution of cellular and noncellular connective tissue elements, coalescing into subepidermal blisters. Differential diagnosis excludes other nonhereditary bullous disorders because of the ultrastructure of the dermo-epidermal junction in nascent blisters and in perilesional skin. In spite of evident clinical, histological, and immunohistological similarities as well as controversial and confusing immunological studies, acquired epidermolysis bullosa can be clearly separated from our case by a diagnostic hallmark on the electron-microscopical level, i.e., band-like IgG depositions beneath the basal lamina. This is demonstrated in comparing the two cases of disseminated cicatricial pemphigoid with three patients suffering from acquired epidermolysis bullosa, thus providing evidence that disseminated cicatricial pemphigoid and acquired epidermolysis bullosa are two distinct nosologic entities.     

Lichen planus pemphigoides is a heterogeneous disease: a report of five cases studied by immunoelectron microscopy

Lichen planus pemphigoides (LPP) is a rare and controversial disease. It is characterized by bullae arising on lichen planus papules and on uninvolved skin, subepidermal bullae in histology, and linear deposits of IgG and C3 along the basal membrane zone on immunofluorescence of peribullous skin. Our goal was to identify the localization of the target antigen in cases of LPP. Five patients diagnosed with LPP on clinical, histological and immunofluorescence criteria were explored by immunoelectron microscopy and immunoblot. Our results show that the target antigen in LPP is not unique. The localization of the immune deposits was consistent with a diagnosis of bullous pemphigoid in two cases, of cicatricial pemphigoid in two cases and of epidermolysis bullosa acquisita in one case. Our study supports the view that LPP is a heterogeneous condition in which lichen planus may induce different subepidermal acquired bullous dermatoses.     

(11) Oesophageal strictures in cicatricial pemphigoid

Cicatricial pemphigoid is a rare disease affecting the skin and mucous membranes. It is a disorder characterized by sub-epidermal blisters which heal with fibrosis and scarring. The diagnosis is confirmed by demonstration of immunoglobulins along the basement membrane of perilesional tissue using immunofluorescence. Ten patients with cicatricial pemphigoid who complained of dysphagia were investigated by barium swallow. An upper oesophageal stricture was demonstrated in eight of these. In the remaining two patients indirect laryngoscopy showed hypopharyngeal ulcers which could account for the dysphagia. A benign stricture of the upper third of the oesophagus is a rare finding and cicatricial pemphigoid should be recognized as a possible cause. The other clinical manifestations of cicatricial pemphigoid may be subtle. However, they can be seen on careful examination of the skin and mucous membranes which will enable the diagnosis to be made.     

Antiepiligrin cicatricial pemphigoid: an underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases?

BACKGROUND: Antiepiligrin cicatricial pemphigoid (AECP) is a chronic autoimmune subepidermal blistering disease characterized by autoantibodies to laminin 5 and clinical features of cicatricial pemphigoid. Only a few patients with AECP have been described to date. The aim of the present study was to analyze the relative frequency of AECP among patients with the clinical phenotype of cicatricial pemphigoid. OBSERVATIONS: Serum from 16 consecutive patients with the clinical phenotype of cicatricial pemphigoid were included in this study. Nine patients had circulating IgG autoantibodies by indirect immunofluorescence on sodium chloride-split skin; patients' IgG bound to the epidermal side (n = 2), dermal side (n = 5), or both sides (n = 2) of this test substrate. Interestingly, all 5 cases with dermal binding immunoprecipitated laminin 5 from extracts and media of cultured keratinocytes, and 4 of these serum samples reacted with the alpha3 subunit of laminin 5 by immunoblotting. None of the patients with dermal binding of IgG demonstrated autoantibodies to type VII collagen. CONCLUSION: Our data suggest that, among patients with the clinical phenotype of cicatricial pemphigoid, AECP may be more frequent than previously assumed.     

Acquired skin disease of hemidesmosomes.

The hemidesmosome is a membrane-associated supramolecular dermal epidermal complex linking the cytoskeleton of the basal keratinocyte to structures within the papillary dermis. Different components of this complex have been identified as autoantigens in autoimmune bullous skin diseases. Some of the autoantigens have been characterized at the molecular level. Little is known, however, about the factors that initiate the production of autoantibodies. By histopathology, acquired skin diseases of hemidesmosomes show subepidermal blisters and by direct immunofluorescence, linear deposits of IgG, C3 or IgA at the dermal epidermal junction. Bullous pemphigoid (BP) is the most common acquired disease of hemidesmosomes. Two proteins, BP180 and BP230, have been identified as primary targets of autoantibodies in BP. In addition, pemphigoid/herpes gestationis, lichen planus pemphigoides, cicatricial pemphigoid and linear IgA disease are characterized by an immune response to BP180. Laminin 5 is another well-characterized anchoring filament-lamina densa component of hemidesmosomes. Patients with autoantibodies to laminin 5 show the clinical phenotype of cicatricial pemphigoid. Other acquired skin diseases of the hemidesmosomes reveal autoantibodies to a plectin-like protein, the beta4 subunit of alpha6beta4 integrin, uncein and a not yet characterized 168 kDa protein. Recently, diseases with autoantibodies to 105 and 200 kDa proteins of the lower lamina lucida have been reported. The association of these autoantigens with hemidesmosomes still needs to be demonstrated. Finally, anchoring fibrils associate with the dermal epidermal anchoring complex. The major structural component of anchoring fibrils is type VII collagen, the autoantigen of epidermolysis bullosa acquisita.     

Immunofluorescent studies in ocular cicatricial pemphigoid

Twenty nine patients with cicatrizing conjunctivitis were studied; 17 with a clinical diagnosis of cicatricial pemphigoid, five with a clinical diagnosis of pseudopemphigoid caused by long-term application of topical medication and seven who had a cicatrizing conjunctivitis from other causes. Biopsies from clinically uninvolved bulbar conjunctiva were taken for direct immunofluorescence and blood was taken for indirect immunofluorescence using normal human conjunctiva, oral mucosa and skin as substrates. On direct immunofluorescence, in vivo bound immunoglobulins were found along the basement membrane in 10 of the 17 patients with cicatricial pemphigoid, one of the five with pseudopemphigoid and two of the seven with a cicatrizing conjunctivitis associated with other diseases. Circulating anti-basement membrane zone antibodies were found only when conjunctiva was used as a substrate. These were present in seven of the patients with cicatricial pemphigoid, three of those with pseudopemphigoid and two of those with a cicatrizing conjunctivitis caused by other diseases. These results indicate that direct immunofluorescence is a useful, but not absolute diagnostic marker for ocular cicatricial pemphigoid. The results in the pseudopemphigoid group argue that this is an immunologically mediated disorder indistinguishable from spontaneous cicatricial pemphigoid and probably triggered by the drugs. The presence of circulating antibodies should allow for precise identification of the antigen involved in cicatricial pemphigoid using SDS electrophoresis and Western blot analysis.     

Epidermolysis bullosa acquisita with combined features of bullous pemphigoid and cicatricial pemphigoid.

Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. The classical or mechanobullous form of EBA is characterized by skin fragility, trauma-induced blisters and erosions with mild mucous membrane involvement and healing with scars. Furthermore, bullous-pemphigoid-like and cicatricial pemphigoid-like features have been described. We report a patient who developed a bullous skin disease with upper airway obstruction requiring tracheotomy. The diagnosis of EBA was established by immunoblot, showing a band at 290 kD (collagen VII), and NaCl-split skin immunofluorescence (IgG deposition at the floor of the split). This case presented with clinical features of both bullous pemphigoid and cicatricial pemphigoid which to our knowledge is the first report of such a combination in EBA. The patient also presented tracheal involvement that has never been described either.     

The use of chemically split tissue in the detection of circulating anti-basement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid

Human skin and mucous membranes were used to detect circulating auto-antibodies by indirect immunofluorescence in 20 patients with bullous pemphigoid and eight with cicatricial pemphigoid. The tissue substrate was used intact and after chemical separation through the basement membrane zone (BMZ) by incubation with I M NaCl. Chemically split skin and oral mucosa provided a more sensitive assay for demonstrating circulating anti BMZ antibodies. Use of a battery of substrates increased the number of positives in bullous pemphigoid from 30% detected on monkey oesophagus to 100% (tissue battery). In cicatricial pemphigoid there was an increase in the proportion of positive sera from 13% (monkey oesophagus) to 88% (tissue battery). In addition, a different class of antibody was frequently detected on split tissue substrate suggesting that new antigens are exposed by this procedure.     

Cicatricial pemphigoid (Brunsting-Perry type). Case report and immunofluorescence findings.

We describe clinical and immunofluorescence findings of a patient with Brunsting-Perry-type cicatricial pemphigoid. Direct immunofluorescence showed tissue-fixed basement membrane zone antibodies similar to those characteristic of bullous pemphigoid. Circulating antibodies to the basement membrane zone were not found. Brunsting-Perry-type cicatricial pemphigoid probably represents a clinical variation midway in the cicatricial pemphigoid-bullous pemphigoid spectrum of disease. Management with intralesional corticosteroids was successful in controlling the skin lesions.     

A case of anti-epiligrin cicatricial pemphigoid associated with lung carcinoma and severe laryngeal stenosis: review of Japanese cases and evaluation of risk for internal malignancy

A 68-year-old Japanese male with a five-year-history of lung carcinoma showed recurrent blisters and erosions on the oral and genital mucosae and the skin. The patient complained of dyspnea due to severe laryngeal stenosis and underwent a tracheostomy. A skin biopsy specimen showed a subepidermal blister and linear deposits of IgG and C3 at the basement membrane zone of the epidermis. Indirect immunofluorescence examination demonstrated circulating IgG anti-basement membrane zone autoantibodies that reacted to epiligrin on immunoblotting. Based on a diagnosis of anti-epiligrin cicatricial pemphigoid, he was treated with prednisolone, minocycline hydrochloride and nicotinamide. Although no new skin lesions appeared, he died of lung carcinoma five months after the tracheostomy. A review of reported cases with anti-epiligrin cicatricial pemphigoid in Japan disclosed that 5 of 16 cases (31.2%) were complicated by internal malignancies.     

Cicatricial pemphigoid with linear IgA deposit

A Japanese woman with typical clinical and histological manifestations of cicatricial pemphigoid was presented. Direct immunofluorescent (IF) investigation of perilesional skin revealed in vivo deposits of IgA but not of IgG, IgM, or C3. Indirect IF study revealed that this patient had circulating antibody against epidermal basement membrane zone of the IgA class. We would like to classify this case as cicatricial pemphigoid with IgA deposits rather than as a cicatricial variant of linear IgA bullous dermatosis.     

Immunofluorescence and immunoelectron microscopic studies in cicatricial pemphigoid

We have studied various tissues from 10 patients with cicatricial pemphigoid using direct and indirect immunofluorescence, mechanical suction blister induction, and immunoelectron microscopy. In 8 of the 10 patients, direct immunofluorescence of buccal mucosa showed a linear deposition of immunoreactants, IgG and C3 being those most commonly detected. Direct immunofluorescence of skin was positive in only 4 patients. Only 1 patient had a detectable circulating anti-basement membrane zone antibody. Substitution of normal human oral mucosa for adult skin as the tissue substrate for indirect immunofluorescence did not prove useful in the detection of circulating autoantibodies. Immunoelectron microscopy was performed in the skin or mucosa (buccal or ocular) of 6 patients, revealing lamina lucida localization of in vivo-bound immunoreactants. Indirect immunofluorescence studies on mechanically induced suction blisters in skin of 2 patients with in vivo-bound IgG suggest that the lamina lucida antigen involved in cicatricial pemphigoid may be distinct from the bullous pemphigoid antigen.     

Complement activation in bullous skin diseases.

Pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, and herpes gestationis are members of the chronic vesiculobullous skin diseases of man. The complement system, including both the classical and alternative pathways, may be important in the pathogenesis of these diseases. In pemphigus, early complement components (C1, C4, and C2) appear to be activated in addition to later components (C3 and C5), suggestive of classical pathway activation. Participation of properdin in addition to early complement components suggests local activation of both complement pathways in bullous pemphigoid and cicatricial pemphigoid. Herpes gestationis and dermatitis herpetiformis may be bullous skin diseases entirely mediated by the alternate or properdin pathway. The specific immunopathologic findings in these diseases are discussed.     

Anti-epiligrin cicatricial pemphigoid with IgG autoantibodies to the beta and gamma subunits of laminin 5

Anti-epiligrin cicatricial pemphigoid is an autoimmune subepithelial blistering disorder of mucous membranes and skin. By immunoblot analyses, sera of most patients with antiepiligrin cicatricial pemphigoid have been shown to react specifically with the alpha3 chain of laminin 5. We describe the first patient with anti-epiligrin cicatricial pemphigoid in whom circulating IgG autoantibodies directed against the beta3 and gamma2-chains of laminin 5 were detected. Treatment with oral prednisolone was beneficial in controlling the disease.     

Cicatricial pemphigoid disclosed by superficial desquamative gingivitis. Clinical and immuno-electron microscopic study of a case

Six months before consulting, a 71-year old man developed buccal and genital erosions which gradually became worse. Physical examination showed signs of superficial desquamative gingivitis, wide erosions on the bony palate, erythemato-erosive balanoposthitis and 7 bullae or skin erosions on the upper part of the back. At histopathological examination of a cutaneous bulla there was dermoepidermal cleavage and an inflammatory infiltrate without eosinophils. At direct immunofluorescence, linear deposits of IgG and C3 were present along the basement membrane. A search for anti-skin autoantibodies was negative at indirect immunofluorescence but positive at immunoblotting (240 Kd band). The cicatricial pemphigoid was treated with dapsone alone in doses of 100 mg/day. Treatment was continued for 6 months, resulting in complete cure of the mucosal and cutaneous lesions. An immunoelectromicroscopic study, performed according to the technique described by Prost et al., on a fragment of skin from around the bullae, showed deposits of granular IgG in the lamina lucida and the lamina densa and deposits of C3 in the lamina densa. This case of cicatricial pemphigoid exhibited 3 features which are not usually found in bullous pemphigoid. Clinically, the buccal lesions were located on the gums and on the hard palate, i.e. where the mucosa adheres to the underlying bone through the periosteum. This location is habitual in cicatricial pemphigoid and differs from that of the bullous pemphigoid lesions which affect the free mucosa lining the cheeks and the soft palate. Treatment with dapsone was dramatically successful in our patient whose lesions disappeared in 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoelectron microscopic findings in cicatricial pemphigoid: their significance in relation to epidermolysis bullosa acquisita

Immunoelectron microscopic studies in a patient with cicatricial pemphigoid revealed the deposition of IgG above the basal lamina. This location is distinctive for pemphigoid and differs from that found in epidermolysis bullosa acquisita.     

Antiepiligrin (laminin 5) cicatricial pemphigoid associated with an underlying gastric carcinoma producing laminin 5

Although bullous pemphigoid and cicatricial pemphigoid are sometimes associated with malignancy, it remains uncertain whether such an association is pathogenetically related or just a coincidence attributable to the advanced age of the patients. We report a 61-year-old patient with antiepiligrin (laminin 5) cicatricial pemphigoid (AeCP) associated with an advanced gastric carcinoma. The gastric carcinoma cells in this patient were shown to produce laminin 5 by immunofluorescence microscopy, and the patient's serum contained autoantibodies directed against laminin 5 on immunoprecipitation. Furthermore, the blistering symptoms and the titre of antibasement membrane zone antibodies coordinately changed with the resection and subsequent relapse of the gastric cancer. These observations suggest that the gastric carcinoma producing laminin 5 may have induced the production of autoantibodies to this laminin, which were pathogenic to the skin and mucous membranes in this patient. This report demonstrates a link between this autoimmune subepithelial blistering disease and malignancy. It is of interest and potential great importance to examine other cases of AeCP for such a potential association.