The ultrastructural localization of IgA in skin of a patient with mixed form of dermatitis herpetiformis and bullous pemphigoid.

A case with mixed features of dermatitis herpetiformis and bullous pemphigoid was investigated by immuno-electron microscopy. There were clinical, histological, and ultrastructural characteristics of both diseases, the response to sulfapyridine was dramatic at the beginning, but intestinal lesions were absent. Direct immunofluorescence tests were made 6 times in the 4 year period and demonstrated in all biopsies exclusively linear IgA deposits. The IgA deposits were shown to occupy the entire lamina lucida and to adhere to the basal cell membranes and lamina densa, very much like IgG deposits in bullous pemphigoid. Antibodies against the basement membrane zone could not be demonstrated in the serum.     

Dermatitis herpetiformis Duhring with linear deposits of IgA (linear IgA dermatosis)

Three patients with linear deposits of IgA along the epidermal basement membrane were studied. The clinical and histopathological picture as well as the response to dapsone were typical of dermatitis herpetiformis. Two of the three patients were HLA-B8/DR3-positive. By immunoelectron microscopy, the previously reported two types of linear IgA deposits were confirmed: in one patient, the IgA precipitates were localized below the basal lamina as in dermatitis herpetiformis, in the other two above the basal lamina in the lamina lucida as in bullous pemphigoid. The immunoelectron microscopic findings imply that in some patients with linear IgA dermatosis a pathomechanism different from that in classical dermatitis herpetiformis may be operative.     

Histology of linear IgA disease, dermatitis herpetiformis, and bullous pemphigoid

The histologic appearances of cutaneous biopsy specimens from 30 patients with linear IgA disease with a continuous band of IgA along the basement membrane, four patients with a linear pattern of granular IgA along the basement membrane, 26 patients with dermatitis herpetiformis who had IgA in the papillary dermis, and 23 patients with bullous pemphigoid who had IgG and/or C3 along the basement membrane were compared. Those with linear and granular IgA and dermatitis herpetiformis differed from those with bullous pemphigoid in five respects. Multiple microabscesses and fibrin at tips of papillae and leukocytoclasis were less common in bullous pemphigoid, whereas a dense infiltrate of eosinophils in and below bullae and a linear infiltrate of eosinophils along the basement membrane were more common in bullous pemphigoid. Also, multilocular bullae and acantholysis were more common in dermatitis herpetiformis than in bullous pemphigoid. Linear IgA disease differed from dermatitis herpetiformis in two respects. Acantholysis and fibrin at the tips of papillae and leukocytoclasis were more common in dermatitis herpetiformis. The specimens from patients with granular IgA did not differ significantly from those with linear IgA or dermatitis herpetiformis. The appearances of biopsy specimens of patch tests with potassium iodide taken from 11 patients with dermatitis herpetiformis and linear or granular IgA disease were similar to those taken from spontaneous lesions.     

IgA linear dermatosis of childhood (chronic Bullous disease of childhood)

Of twenty-seven cases of subepidermal blistering disease of children twelve corresponded clinically, histologically and immunologically to dermatitis herpetiforms of adults, six to bullous pemphigoid, and eight to chronic bullous disease of childhood (CBDC), i.e. IgA linear dermatosis. This latter disease seems to be a distinct entity, different from both dermatitis herpetiformis and bullous pemphigoid, and is characterized immunopathologically by linear IgA deposits at the basement membrane zone. These cases usually do not show intestinal involvement and respond well to combined treatment with sulphones and corticosteroids, whereas sulphones or sulphapyridine alone are, even in very high doses, not sufficient for full control of the disease. CBDC or IgA linear dermatosis of childhood may be regarded as a counterpart of IgA linear dermatosis of adults.     

Bullous pemphigoid and dermatitis herpetiformis: mixed bullous disease or coexistence of two separate entities?

We present a 73-year-old man with a 5-year history of dermatitis herpetiformis who developed lesions with the clinical, histologic, and immunologic features of bullous pemphigoid. Direct immunofluorescence testing of a skin biopsy demonstrated both granular deposition of IgA, predominantly in the papillary bodies, and linear deposition of IgG and C3 at the basement membrane zone. This mixed direct immunofluorescence pattern, typical for dermatitis herpetiformis in the type of IgA deposits, but also typical for pemphigoid in the linear localization of IgG and C3, is unusual. This case emphasizes that even after a specific diagnosis has been established, if the clinical morphology or response to therapy changes, repeat histologic and immunofluorescence studies may be indicated in diagnosis and management of patients with bullous disease.     

Circulating IgA anti-basement membrane antibodies in linear dermatitis herpetiformis (Duhring): immunofluorescence and immunoelectronmicroscopic studies.

IgA deposits were observed by direct immunofluorescence in linear distribution along the basement membrane zone in a case of dermatitis herpetiformis (Duhring). In addition, in the serum of the same patient circulating IgA antibasement membrane zone antibodies were detected by indirect immunofluorescence, utilizing normal human skin and monkey esophagus as substrates. The ultrastructural localization of in vivo-bound IgA and circulating IgA antibasement membrane zone antibodies fixed to substrate tissue in vitro was found to be in the uppermost strata of the dermis below the basal lamina.     

Chronic bullous disease of childhood and linear IgA disease of adults are IgA1-mediated diseases

Linear IgA disease is characterized by the presence of linear IgA deposits at the basement membrane zone of the skin, and in some cases by circulating basement membrane zone antibodies. The disease occurs in both adults and children, and is designated adult linear IgA disease in the former and chronic bullous disease of childhood in the latter. The subclass distribution of the circulating and bound basement membrane zone antibodies was studied in 32 children and eight adults. The results were compared with five dermatitis herpetiformis patients and five normal controls. The circulating antibodies (39 patients) and the cutaneous deposits (39 patients) were IgA1 in all 40 patients with linear IgA disease. The cutaneous deposits in dermatitis herpetiformis were also all IgA1, and no circulating antibodies were detected. The controls were all negative. This large series of children and adults with linear IgA disease demonstrates that the circulating and cutaneous basement membrane zone deposits are all IgA1, and suggests that linear IgA disease is an IgA1-mediated disease.     

Linear arrangement of neutrophils along the Basal layer in bullous pemphigoid: a unique histological finding

Bullous pemphigoid is an inflammatory autoimmune subepidermal bullous disease with distinct immunohistological features. We report an unusual case of a 59-year-old woman with a bullous eruption whose lesional skin biopsy showed a subepidermal blister with a linear arrangement of neutrophils, mimicking linear IgA bullous dermatosis. However, direct immunofluorescence studies demonstrated IgG and C3 linear deposition along the basement membrane zone, compatible with bullous pemphigoid. We suggest that bullous pemphigoid should therefore be considered in the differential diagnosis of neutrophil-rich subepidermal bullous diseases along with dermatitis herpetiformis and linear IgA.     

IgA bullous pemphigoid: a distinct blistering disorder

We report a patient with an eccrine carcinoma who developed localized blistering which clinically resembled pemphigoid, histologically showed subepidermal blistering with features of both dermatitis herpetiformis and bullous pemphigoid, responded to dapsone and exhibited linear IgA deposition on direct immunofluorescence. The nosological position of patients with linear IgA deposition and subepidermal blistering is not clear. A review of the literature reveals that in adults linear IgA deposition may occur in three separate situations: dermatitis herpetiformis, bullous pemphigoid and a third condition of which our case is an example which is best termed IgA bullous pemphigoid. This condition is distinguished from cases of dermatitis herpetiformis with linear IgA by the clinical features and the site of IgA deposition on immunoelectronmicroscopy. It is distinguished from cases of bullous pemphigoid with linear IgA by the absence of circulating IgG antibasement membrane zone antibody, the therapeutic response to dapsone and the frequent occurrence of circulating IgA antibasement membrane zone antibody. IgA bullous pemphigoid has not previously been reported with a carcinoma but the association lends further support to the concept that this eruption represents a variant of pemphigoid.     

Double immunofluorescence microscopy: a method for localizing immune deposits in skin diseases associated with linear basement membrane zone immunofluorescence

Direct immunofluorescence microscopy has shown that a linear pattern of immunoglobulin and/or complement deposition at the cutaneous basement membrane zone is a characteristic feature in a number of acquired bullous diseases and is occasionally observed in systemic lupus erythematosus. Immunoelectron microscopy has shown the linear pattern of immunofluorescence may be produced by immune deposits located either above the basal lamina (in the lamina lucida) or below the basal lamina (in the upper dermis). Distinguishing between these sites of immune reactant deposition may be of value in differential diagnosis. In this study we report a double immunofluorescent method by which skin biopsies with linear IgG immunofluorescence due to deposits above the basal lamina (bullous pemphigoid) could be distinguished from biopsies with deposits beneath the basal lamina (bullous systemic lupus erythematosus and epidermolysis bullosa acquisita). When skin sections were treated sequentially with rhodamine-labeled anti-human IgG followed by fluorescein-labeled antilamina lucida (pemphigoid) antibody and examined by fluorescence microscopy, the following results were obtained. In biopsies with IgG deposits in the lamina lucida, a single green fluorescent band was observed. In tissues with subbasal lamina deposits, either parallel and contiguous bands of green and yellow-orange fluorescence or a single band of yellow-orange fluorescence was observed. The method is simpler, quicker, and less expensive than immunoelectron microscopy and should be a useful technique for evaluating skin diseases with linear immunofluorescence at the basement membrane zone.     

Linear IgA bullous dermatosis of adults and children: an immunoelectron microscopic study

The ultrastructural localization of the IgA deposits in the skin of 15 patients with linear IgA bullous dermatosis of adults (LAD), 13 with chronic bullous dermatosis of childhood (CBDC) and three with childhood cicatricial pemphigoid (CCP) were studied. The site of the antigen was determined using sera from two LAD, 13 CBDC and two CCP patients. In all 31 patients the IgA was located predominantly below the lamina lucida (sublamina densa). Similarly, the indirect immunoelectron microscopic studies demonstrated the antigen to be present at the same site, below the lamina densa. This suggests that in linear IgA bullous dermatosis the antibody reacts with the antigen in the sublamina densa region of the basement membrane zone.     

A Case of Linear IgA Bullous Dermatosis with Atypical Clinical and Ultrastructural Manifestations

We report a case of linear IgA bullous dermatosis which presented with atypical clinical and ultrastructural findings. The patient initially manifested small, subepidermal blisters scattered only in the seborrheic region. On follow-up, grouped vesicles developed in a circular form similar to dermatitis herpetiformis. They subsided after treatment with diaminodiaphenyl sulphon. Immunofluorescent study showed predominant linear IgA deposits accompanied with IgG and C3 along the basement membrane zone. These deposits existed at the floor of the blister. Ultrastructurally, immunoreactants were demonstrated beneath the lamina densa while separation occurred at lamina lucida.     

Scarring linear IgA dermatosis in the adult

A 54-year-old woman had a six-months history of a scarring blistering disease with clinical signs of dermatitis herpetiformis and bullous pemphigoid. Direct immunofluorescence examination showed homogeneously linear deposits of IgA along the dermo-epidermal junction. Electron microscopic studies revealed blistering above and beneath the lamina densa. Referring to this new case of a scarring linear IgA disease we discuss some other forms of scarring bullous diseases in adults.     

IgA linear dermatosis (author's transl)]

Besides the typical forms of dermatitis herpetiformis (DH) and bullous pemphigoid (BP) of adults and children, there are cases combining clinical, histological and electronmicroscopic features of both. Linear continuous IgA deposits along basement membrane zone (BMZ) are a most characteristic finding. They differ from the granular IgA deposits in DH, even if these are also distributed along the BMZ (however, preserving as a rule their granular pattern). IgG circulating anti-BMZ antibodies are absent, whereas in some cases IgA anti-BMZ antibodies may be found. In contrast to DH, there is no gluten-sensitive enteropathy, and the gluten-free diet is ineffective. The recognition of this bullous disease as a distinct entity is of practical significance because these cases respond well to combined treatment with sulfones and corticosteroids, all in small doses. Because of diagnostic importance of linear IgA deposits at BMZ we have proposed the name IgA linear dermatosis. In children a counterpart of IgA linear dermatosis of adults is chronic bullous disease of childhood (CBDC), which we propose to call IgA linear dermatosis of childhood.     

IgA-lineare Dermatose im Erwachsenenalter mit klinischen Zeichen eines Stevens-Johnson-Syndroms

Immunohistologically linear IgA disease presents with unambiguous features, whereas clinical manifestations are variable. It sometimes shows similarity to other bullous dermatoses such as bullous pemphigoid and dermatitis herpetiformis. A 73 year old female patient was referred with the diagnosis of bullous pemphigoid. One day after admission clinical examination revealed the classical features of Stevens-Johnson syndrome (SJS): widespread confluent atypical target lesions, partly raised, partly flat with central blisters, and erythematous spots, but few typical targets, as well as blisters and large areas of skin detachment on her back and buttocks, accompanied by erosions of the oral and genital mucosa. Direct immunofluorescence performed on peri-lesional skin showed linear deposition of IgA along the basement membrane zone, leading to the diagnosis of linear IgA disease of adults. Our case report shows that linear IgA disease may present with the clinical pattern of SJS.     

Cutaneous IgA deposits in bullous diseases function as ligands to mediate adherence of activated neutrophils

Linear IgA bullous dermatosis and dermatitis herpetiformis are inflammatory subepidermal blistering diseases characterized by IgA deposits at the cutaneous epithelial basement membrane and in dermal papillae, respectively. Inflammation in both disorders localizes to sites of IgA deposition and is characterized by a predominance of neutrophils. From these observations we postulate that IgA deposits in both diseases may contribute to the recruitment and/or localization of neutrophils. In this study we examined the ability of in vitro and in vivo bound IgA anti-basement membrane autoantibodies from patients with linear IgA bullous dermatosis and in vivo bound IgA deposits in dermal papillae from patients with dermatitis herpetiformis to mediate adherence of neutrophils stimulated by granulocyte macrophage colony-stimulating factor. The study showed that stimulated neutrophils adhered to basement membranes and dermal papillae containing IgA deposits. Adherence was IgA anti-basement membrane antibody concentration dependent and correlated with the immunofluorescence staining intensity of IgA deposits in dermal papillae. Adherence to IgA deposits but not IgG deposits could be inhibited by purified exogenous secretory IgA but not IgG and adherence to IgG deposits could be inhibited by purified exogenous IgG but not secretory IgA. These results provide direct experimental evidence that cutaneous IgA deposits in linear IgA bullous dermatosis and dermatitis herpetiformis can function as ligands for neutrophil adherence and have a role in the localization of inflammation in these disorders.     

Polymorphic pemphigoid.

We describe 20 patients with a chronic polymorphic eruption; they shared clinical, histopathological, and therapeutic features of both dermatitis herpetiformis and bullous pemphigoid (BP). In 14 of these 20 cases, direct and indirect immunofluorescence studies corresponded to BP. The remaining six patients showed IgA deposits in a linear pattern at the basement membrane zone, and two of these six showed IgA pemphigoid antibodies in their sera as well. No significant clinical and histological differences were detected in the patients, in connection with the immunological findings. Furthermore, one patient's condition, which was studied by repeated immunofluorescence examinations, changed from a linear IgA pattern and a negative indirect test to a linear IgG pattern and a positive reaction for IgG pemphigoid antibodies. We concluded that these cases constitute a polymorphic variant of BP.     

A subepidermal blistering disease with histopathological features of dermatitis herpetiformis and immunofluorescence characteristcs of bullous pemphigoid: a novel subepidermal blistering disease or a variant of bullous pemphigoid?

A 64-year-old man presented with a bullous eruption which clinically and histopathologically resembled dermatitis herpetiformis. However, direct immunofluorescence analysis showed IgG deposits at the basement membrane zone, indicating a relationship with bullous pemphigoid or epidermolysis bullosa acquisita. Indirect immunofluorescence studies on salt-split skin showed binding of IgG mainly on the dermal side of the blister. Immunoblot analysis revealed a novel 200 kDa dermal antigen that could be associated with a major pathogen in this blistering a disease. The histopathological similarity to dermatitis herpetiformis and the immunofluorescence findings indicating bullous pemphigoid or epidermolysis bullosa acquisita seem typical of a distinct subepidermal blistering disease characterized by this 200 kDa antigen. However, the pathogenetic role of autoantibodies against this antigen should be further elucidated before confirming whether this case represents a novel subepidermal blistering disease or a special variant of bullous pemphigoid.     

Dermatitis herpetiformis with linear IgA deposition: ultrastructural localization of in vivo bound IgA

Ultrastructural localization of bound IgA in the skin of a patient suffering from dermatitis herpetiformis with linear IgA deposition at the dermo-epidermal junction was studied using the horseradish peroxidase labelled antibody method. The reaction products were observed as electron-dense materials, not only immediately below the cytomembrane of the basal cells but also in the uppermost dermis just below the basal lamina. The major portion of the lamina lucida was free of the reaction products. These findings suggest a diversity in the mode of IgA deposition and the possibility of the presence of different antigens in the basement membrane zone, to which IgA class antibodies may be bound respectively.     

Linear IgA Bullous Dermatosis

Linear IgA bullous dermatosis (LABD) can mimic bullous pemphigoid (BP) and/or dermatitis herpetiformis (DH) both clinically and histologically. LABD, however, can be distinguished from BP and DH by direct immunofluorescent (IF) demonstration of linear IgA deposits along the basement membrane zone. A retrospective study of 234 cases of BP, 27 cases of LABD, 60 cases of DH, and 20 cases of cicatricial pemphigoid (CP) revealed that BP patients are significantly older than LABD or DH patients and LABD patients are significantly older than DH patients. BP and CP occur more frequently in women (65-70%) than LABD or DH (44-48%). The frequencies of C3 deposits in the basement membrane zone (BMZ) are significantly higher in BP (85%) compared with LABD (18.5%) and DH (28.3%). LABD patients varied in their response to various therapeutic agents. Some responded to corticosteroids and some to sulfones alone, whereas others required a combination of corticosteroids and sulfones.