Circulating IgA anti-basement membrane zone antibodies in dermatitis herpetiformis.

Criculating anti-basement membrane zone antibodies of the IgA class were detected in the sera of 2 or 6 dermatitis herpetiformis (DH) patients who had linear in-vivo-bound IgA deposits and in 1 of 42 DH patients who had granular vivo-bound IgA deposits. In the former 2 patients the circulating antibodies were localized ultrastructurally to the identical site where the in vivo-bound antibodies were localized and were bound by antigens in either the lamina lucida or the subbasal lamina anchoring fibril area of the basement membrane zone of normal human skin.     

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 (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.     

The ultrastructural localization of IgA deposits in chronic bullous disease of childhood (CBDC).

A case of bullous disease in a child with linear IgA immune deposits at the basement membrane zone and with some clinical, histological, and electron microscopic characteristics both of dermatitis herpetiformis and bullous pemphigoid, is described. The bulla formed between the basal lamina and basal cell membranes as in bullous pemphigoid, but at the same time there were numerous inflammatory cells in the dermis just below the partly destroyed basal lamina and also abundant fibrin deposits in very recent bulla and in the skin, all of which is rather characteristic of dermatitis herpetiformis. Ultrastructurally, the IgA deposits were located chiefly below the lamina basalis (the dermal type) but also, though less abundantly, in the lamina lucida, very much as we have seen them to be in adult cases with linear IgA immune deposits at the basement membrane zone. The investigations have supplied further evidence showing the chronic bullous disease of childhood to be actually a counterpart of the form in adults with the same linear localization of IgA deposits.     

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.     

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.     

Cutaneous IgA subclasses in dermatitis herpetiformis and linear IgA disease

The subclasses of the cutaneous IgA were studied in 8 patients with dermatitis herpetiformis and 4 with linear IgA disease. The cutaneous IgA in dermatitis herpetiformis consisted of both IgA1 and IgA2, although IgA1 predominated. This demonstrated that the IgA is polyclonal and may be both mucosal and blood derived. The IgA in linear IgA disease was exclusively IgA1, confirming previous work, and suggesting that mucosal IgA may not make a major contribution to the skin deposits.     

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.     

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.     

A clinicopathological study of mucosal involvement in linear IgA disease

Mucosal involvement in linear IgA disease was assessed clinically and immunologically using direct and indirect immunofluorescence (IF) techniques. There was clinical evidence of oral mucosal involvement in all 10 patients examined and conjunctival diseases in six. Direct IF findings correlated well with clinical oral disease, with all patients demonstrating linear IgA deposits in the basement membrane zone of oral mucosa. However, this was not true of conjunctiva where no linear IgA could be demonstrated. Conjunctiva did provide a good substrate for indirect immunofluorescence using patients' sera, and showed that five of the 10 patients had circulating anti-basement membrane zone IgA.     

Linear IgA disease and chronic active hepatitis--a coincidence or not?

Linear IgA disease (granular type) associated with chronic active hepatitis in a sixteen-year-old male patient is described. The diagnosis was established by clinical and histopathological findings supported by immunofluorescence studies. The immunofluorescence pattern (granular IgA deposits along the basement membrane, more pronounced at tips of papillae) showed much transition in dermatitis herpetiformis and also to a lesser extent in pemphigoid (linear IgG and IgM deposits along the basement membrane). Chronic active hepatitis as linear IgA disease are significantly correlated with HLA B8. This is the first report of the association of linear IgA disease and chronic active hepatitis.     

Vancomycin-induced linear IgA disease manifesting as bullous erythema multiforme

BACKGROUND: Vancomycin-induced linear immunoglobulin A (IgA) disease, an autoimmune, blistering disease in response to vancomycin administration, is characterized by a subepidermal, vesiculobullous eruption and linear IgA deposition along the basement membrane zone on direct immunofluorescence. CASE REPORT: We report the case of an 81-year-old man treated with vancomycin who developed diffuse erythema multiforme and tense bullae involving the palmoplantar surfaces. Discontinuation of vancomycin therapy resulted in complete resolution of this patient's cutaneous eruption. RESULTS: Biopsy of a representative skin lesion demonstrated lichenoid interface dermatitis with focal subepidermal clefting, dyskeratosis, and prominent eosinophils. Direct immunofluorescence showed linear basement membrane staining with immunoreactants to IgA; indirect immunofluorescence demonstrated the presence of circulating IgG antibodies binding in an intercellular pattern. Immunoprecipitation studies using the patient's serum revealed 210, 130, and 83 kDa target antigens. CONCLUSIONS: Presenting with an initial clinical picture suggestive of bullous erythema multiforme, this patient's subsequent clinical course and direct immunofluorescence confirm the diagnosis of linear IgA bullous disease (LABD). His indirect immunofluorescence findings and immunoprecipitation results suggest that circulating non-IgA antibodies may represent a newly recognized immunopathologic feature of vancomycin-induced linear IgA disease, underscoring the variable and unpredictable manifestations of this drug-induced cutaneous disease.     

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.     

Linear IgA Dermatosis of Childhood: Case Report with an Immunoelectron Microscopic Study

A 7-year-old girl developed a cutaneous bullous eruption with genital and nasal mucous membrane involvement. Direct immunofluorescence revealed linear deposits of IgA and IgM at the basement membrane zone. No circulating antibasement membrane zone antibodies were detected. Small bowel biopsies showed a partial villous atrophy. The clinical, histologic, and immunopathologic findings were consistent with a diagnosis of linear IgA dermatosis of childhood. Immunoelectron microscopy revealed IgA deposits in the lamina lucida in association with hemidesmosomes, confirming results of two recent studies.     

Dermatitis herpetiformis and bullous pemphigoid. Intermediate and mixed forms.

Nine patients had clinical and histological features suggestive of both dermatitis herpetiformis (DH) and bullous pemphigold (BP). Five patients responded to treatment with sulfapyridine or sulfones: in two the response was inconsistent, and the disease was controlled by combined treatment with prednisone; in one patient, there was no response to sulfapyridine or sulfones. Immunofluorescence studies showed IgA deposits in a linear homogeneous pattern at the basement membrane zone in all patients, and IgG was present in five. No circulating anti-basement membrane antibodies were detected by repeated immunofluorescence examinations. The authors conclude that the occasional overlapping of BP and DH should not lead to dropping the distinction between the two entities. For overlap cases that cannot be classified as BP or DH, the term "intermediate or mixed form of DH and BP" seems to be most suitable.     

Subepidermal blasenbildende Autoimmundermatose mit linearen Ablagerungen von IgA und IgG

A 29-year-old female patient with an autoimmune subepidermal blistering disease had linear deposits of both IgA and IgG at the basement membrane zone. Clinically, the patient presented with tense blisters on the face, trunk, extremities and oral mucosa. Histologically, we found a subepidermal blister formation and a predominantly neutrophilic infiltrate. Direct immunofluorescence showed linear deposits of IgA along the basement membrane zone, as well as linear deposits of IgG and C3 as typically found in bullous pemphigoid. Indirect immunofluorescence demonstrated circulating IgA and IgG autoantibodies. This case extends previous reports on a subgroup of patients with subepidermal blistering diseases characterized by the presence of both IgA and IgG anti-basement membrane antibodies. These patients reveal clinical, histological and immunopathological features of linear IgA disease and bullous pemphigoid.     

Autoantibodies in a subgroup of patients with linear IgA disease react with the NC16A domain of BP1801

Linear IgA disease is an autoimmune subepidermal blistering disease characterized by IgA deposits at the cutaneous basement membrane zone. IgA antibodies from linear IgA disease sera react with antigens of 97 kDa (LABD97) and 120 kDa (LAD-1), both of which appear to be fragments of the extracellular domain of bullous pemphigoid 180 (type XVII collagen). The aim of this study was to determine whether linear IgA disease sera react with the immunodominant region of BP180 (NC16A domain), which is a major target of IgG autoantibodies produced by patients with bullous pemphigoid. Indeed, 11 of 50 linear IgA disease sera were found to contain IgA autoantibodies that recognized a recombinant form of NC16A by immunoblotting. The same sera also reacted with NC16A by enzyme-linked immunosorbent assay. An epitope mapping analysis uncovered four linear IgA disease-associated epitopes located within the 45 amino acid N-terminal stretch of NC16A, all of which were previously identified as antigenic sites targeted by bullous pemphigoid autoantibodies. Eight of the linear IgA disease sera that were reactive with NC16A also recognized LAD-1 secreted by the SCC-25 cell line, and five sera recognized BP180 extracted from keratinocytes. Linear IgA disease sera depleted of reactivity to NC16A by immunoadsorption continued to react with both the LAD-1 antigen and BP180 by immunoblotting and with the basement membrane zone by indirect immunofluorescence microscopy. Our results demonstrate that IgA autoantibodies from a subset of linear IgA disease patients react with the same sites on BP180 that are targeted by IgG autoantibodies in bullous pemphigoid.     

IgA antiendomysial antibodies in dermatitis herpetiformis

Sera from 24 patients with dermatitis herpetiformis and 80 control subjects (patients with other bullous diseases, nonbullous dermatoses, and noncutaneous diseases) were studied to determine the usefulness of assay for IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of dermatitis herpetiformis. The overall sensitivity of IgA-EMA for the diagnosis of dermatitis herpetiformis was 79% and the specificity was 96%. When the three patients with dermatitis herpetiformis who were faithfully following gluten-free diets were excluded, the sensitivity was 90% and the specificity was 96%. No patient in the bullous disease control group (including patients with linear IgA bullous dermatosis) had circulating IgA-EMA. One patient, who did not have direct immunofluorescence evidence for dermatitis herpetiformis but had IgA nephropathy, had a positive IgA-EMA result, an interesting association in light of the rare reports of dermatitis herpetiformis in patients with IgA nephropathy and IgA antigliadin antibodies associated with IgA nephropathy. Although direct immunofluorescence testing of skin biopsy specimens remains the most definitive diagnostic test for dermatitis herpetiformis, indirect immunofluorescence assay of serum for IgA-EMA is a minimally invasive study with a high sensitivity and specificity for dermatitis herpetiformis.     

Circulating antibodies to gliadin subfractions in dermatitis herpetiformis and linear IgA dermatoses

Dermatitis herpetiformis (DH) and coeliac disease are associated and the rash of DH is gluten-dependent. The gliadin fraction responsible for the rash is unknown. In linear IgA dermatoses the role of gluten in the skin eruption remains controversial.
Anti-gliadin antibodies (AGA) were measured by an enzyme-linked immunosorbent assay in 10 normal controls; 35 patients with dermatitis herpetiformis (DH); 14 adults with linear IgA disease; and 13 patients with chronic bullous dermatosis of childhood. The presence of enteropathy was assessed by jejunal biopsy and intra-epithelial lymphocyte (IEL) counts.
DH with normal IEL counts on normal diet: IgG and IgA-AGA identical to controls. DH with raised IEL counts on gluten-free diet: slightly elevated IgG and IgA-AGA. DH with raised IEL counts on a normal diet: IgG and IgA were higher, with median IgG 1:2048 (control 1:512) median IgA 1:512 (control 1:128). DH patients with high IgG AGA had elevated titres to α, β, γ, and ω subfractions. The highest levels were for α and the lowest for ω.
For linear IgA disease IgG is normal but adults had raised IgA-AGA compared to controls ( P = 0.005).
In dermatitis herpetiformis the presence of anti-gliadin antibody was dependent on the degree of enteropathy, and, if present, was directed against all gliadin subfractions. The significance of the elevated IgA—AGA in the linear IgA disease is unknown.     

Chronic Bullous Disease of Childhood in a Patient with Acute Lymphoblastic Leukemia

Linear IgA disease is characterized by the presence of linear IgA deposits in the basement membrane zone of the skin, and circulating basement membrane zone antibodies are detected in 80% of cases. The disease occurs in both adults and children, and is designated adult linear IgA disease in the former and chronic bullous disease of childhood (CBDC) in the latter. We describe a 5-year-old boy with acute lymphoblastic leukemia in remission, in whom CBDC developed after treatment with trimethoprim/sulfamethoxazole (cotrimoxazole). To our knowledge, this is the first reported case of possible drug-induced CBDC.