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 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.     

Immunofluorescence of biopsy specimens: comparison of methods of transportation.

Immunofluorescence findings for IgG, IgA, IgM, and C4 on biopsy specimens quick frozen and transported frozen were compared with findings on portions of the same biopsy specimens placed in holding solution and transported at ambient temperatures. A total of 52 biopsy specimens were examined from normal individuals and patients with systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), pemphigus, pemphigoid, and dermatitis herpetiformis. Overall agreement of results was 90%: 88% in SLE; 50% to 66% in DLE, 96% in pemphigus; 92% in bullous pemphigoid; and 87% in dermatitis herpetiformis. Except for two of the 42 biopsy specimens, the combined IgG, IgA, IgM, and C4 findings were the same. In one DLE case, only the frozen biopsy specimen was positive. In one case of dermatitis herpetiformis, only the ambient temperature biopsy specimen was positive. Results indicate the holding solution at ambient temperature can be used in place of the frozen method.     

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.     

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.     

JUVENILE DERMATITIS HERPETIFORMIS IN THE LIGHT OF IMMUNOFLUORESCENCE STUDIES

Summary.— Eight cases of juvenile dermatitis herpetiformis (JDH) were investigated by direct and indirect IF methods with anti-IgG and anti-IgA conjugates.
In 3 cases the results were completely negative. In 3 cases there were in vivo fixed IgG in the basement membrane, and in 1 case also circulating antibodies as in bullous pemphigoid in adults. In 2 cases there were in vivo bound IgA deposits in the papillae of the apparently unchanged skin surrounding the lesions, as in dermatitis herpetiformis in adults.
The results of the IF studies suggest that JDH is not a nosological entity, and that cases occur with the immunological features of either bullous pemphigoid or dermatitis herpetiformis in adults. There remains the group of immunologically negative cases, the nature of which, moreover, requires further investigation.     

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.     

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.     

A subepidermal blistering dermatosis associated with coexistent IgG and IgA anti-dermal basement membrane zone antibodies; demonstration of IgG antibodies reactive against a 200-kDa dermal antigen

We report a 66-year-old woman presenting with an annular erythematous and bullous eruption. Her clinical and histological findings were similar to those of linear IgA bullous dermatosis or dermatitis herpetiformis. Direct immunofluorescence revealed linear deposition of IgA, IgG and C3 along the basement membrane zone (BMZ). Indirect immunofluorescence detected IgG and IgA antibodies against the BMZ. Salt-split skin technique demonstrated that IgG antibodies bound exclusively to the dermal side, while IgA antibodies bound not only to the dermal side, but also to the epidermal side with relatively weak intensity. On immunoblot analysis, the patient's IgG antibodies exclusively reacted with a band of 200-kDa, while the antigenic target of IgA antibodies was not identified. The present case is thought to be a unique bullous dermatosis mediated by both the IgG antibodies to a novel 200-kDa antigen and IgA antibodies against undetermined antigens.     

A dilemma: bullous-pemphigoid-like eruption in scabies or scabies-induced bullous pemphigoid

Several diseases may be confused with scabies. Atypical manifestations of scabies have previously been reported, including urticaria, contact dermatitis, and dermatitis herpetiformis. There are also reports of scabies mimicking bullous pemphigoid. Here we report a case of scabies in a patient with manifestation similar to bullous pemphigoid. Direct smear of the bullous lesions was performed and was positive for scabies mites. The skin biopsy specimens submitted for light microscopy and direct immunofluorescence study were considered to be compatible with bullous pemphigoid. The patient treated with single dose oral ivermectin and prednisolone. The pruritus subsided and the eruption improved dramatically in 2 weeks.     

Chronic bullous dermatosis of childhood.

The clinical features, laboratory studies, and therapeutic responses of two boys with chronic bullous dermatosis of childhood are described. Direct immunofluorescent preparations of sections from a lesion, skin adjacent to a lesion, and uninvolved skin demonstrated linear deposition of IgA at the dermoepidermal junction in all three biopsy specimens from one patient. Similar preparations from the second child were negative for staining. No circulating antibodies to skin components were detected in either child by means of multiple substrates. Neither child had clinical manifestations nor laboratory findings suggestive of an associated gastrointestinal lesion; therefore, small bowel biopsies were not performed. Immunologic studies failed to demonstrate any of the abnormalities frequently described in dermatitis herpetiformis. Both boys responded dramatically to sulfapyridine therapy.     

A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood

Eighteen patients with benign chronic bullous dermatosis of childhood were studied and the findings compared with those of dermatitis herpetiformis (twenty-two cases) and bullous pemphigoid (five cases) beginning in childhood. The patients with benign chronic bullous dermatosis of childhood had a moderately pruritic bullous eruption with maximal involvement of the pelvic and perioral regions which tended to occur at an earlier age than either dermatitis herpetiformis or bullous pemphigoid. In contrast to dermatitis herpetiformis one-third of the cases with benign chronic bullous dermaiosis of childhood went into remission. Evidence of coeliac disease was only found in the dermatitis herpetiformis group. Surprisingly both diseases shared HLA-B8. A linear BMZ band of IgA was detected on direct immunofluorescence in all but one of the cases with benign chronic bullous dermatosis of childhood and circulating antibodies were detectable in two-thirds. Routine histopathology was of little value in distinguishing between benign chronic bullous dermaiosis of childhood and dermatitis herpetiformis or bullous pemphigoid. Several paradoxes have yet to be explained before it can be determined whether benign chronic bullous dermatosis of childhood is a variant of dermatitis herpetiformis or linear IgA disease.     

Renal involvement and circulating immune complexes in dermatitis herpetiformis

A fine-needle kidney biopsy was performed on eleven patients with dermatitis herpetiformis (DH) who had no previous signs or symptoms of renal disease. Of the eight patients whose biopsy specimens were representative, electron microscopic examination showed mesangial deposits in five. A subsequent conventional renal biopsy was obtained from one of these five, and immunofluorescence microscopy revealed IgA and complement deposits in the glomeruli. Renal involvement was not related either to the degree of jejunal villous atrophy or to the deposition of IgA and complement in the skin. Glomerular deposits, however, were associated with a high frequency of circulating IgA and IgG class immune complexes and IgA class antigliadin and antireticulin antibodies. These results suggest that, in DH, immune complexes or antibodies derived from the gut can be deposited in the kidney.     

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.     

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.     

Antiendomysial antibody — useful serological indicator of dermatitis herpetiformis

Summary Antiendomysial antibodies (EmA) of the IgA class are directed against reticulin components of the primate smooth muscle and are markers of gluten-sensitive enteropathy. These antibodies occur in essentially all active cases of celiac disease and in about 70% of dermatitis herpetiformis (DH) patients. IgA deposits in the dermal papillae of the skin are the hallmark of DH and are employed routinely in establishing its diagnosis. The incidence of IgA deposits in skin varies depending upon the site and type of biopsy specimen taken.We studied sera and skin biopsy specimens for EmA and for IgA deposits in the skin from 11 DH patients. EmA were detected in the sera of 10 of the 11 cases. Of these 11 patients, 9 were positive for IgA deposits in their skin, as revealed by direct immunofluorescence (IF). The immune deposits were detected in the normal, and not in the lesional skin. DH cases that were initially negative on biopsy and serum positive for EmA were found to be positive when a repeat biopsy of the normal skin was performed. Thus, serological studies in conjunction with direct IF studies of the normal skin are useful in making a diagnosis of DH.Presented at the Society for Investigative Dermatology Meeting, Washington, DC, May 2, 1986     

Failure to detect gliadin or gliadin binding sites in the skin of patients with dermatitis herpetiformis: immunofluorescence, organ culture and autoradiographic studies.

Recent investigations indicate an abnormal binding of gluten or gliadin to lymphocytes or intestinal mucosa cells in gluten sensitive enteropathy. Since dermatitis herpetiformis is closely associated to gluten sensitive enteropathy, similar receptors could also exist in the skin of patients with dermatitis herpetiformis. To prove this hypothesis, skin of normal volunteers and uninvolved skin of 3 patients with dermatitis herpetiformis was investigated for the presence of gliadin and gliadin binding sites. In vivo bound gliadin was not found by direct immunofluorescence using 3 different rabbit antigliadin antisera. In order to test skin for gliadin binding sites, normal sera and autologous dermatitis herpetiformis sera containing 25 mg% gliadin and tritium labeled gliadin, respectively, were used for incubation of normal and dermatitis herpetiformis skin cryocut sections and of normal and dermatitis herpetiformis skin specimens, grown under organ culture conditions. As checked by direct immunofluorescence and autoradiography, there was no specific in vitro binding of gliadin, indicating that gliadin does not fix to normal human or dermatitis herpetiformis skin. Thus, the role of gliadin in the fixation in vivo, of antibodies or immune complexes to skin in dermatitis herpetiformis, remains obscure.     

Dermatitis herpetiformis: close to unravelling a disease

Dermatitis herpetiformis is characterised by granular IgA precipitates in the papillary dermis. In contrast to other autoimmune blistering diseases, where tissue-deposited and circulating autoantibodies recognise the same target within the skin, in dermatitis herpetiformis a serum IgA reacting with a component of the healthy papillary dermis has not been detected. Recently, the antigenic specificity of pathognomic skin-bound IgA has been clarified: the immune precipitates contain epidermal transglutaminase, an enzyme not previously detected in the papillary region of normal skin. Furthermore, serum IgA in dermatitis herpetiformis has been found to bind epidermal transglutaminase. These findings may relate to the fact, that dermatitis herpetiformis is associated with gluten sensitive enteropathy, coeliac disease, which is characterised by IgA type autoantibodies to a closely related enzyme, tissue transglutaminase. The two transglutaminases are highly homologous, and therefore, cross reactivity of the two antibodies might explain why patients with gluten sensitive enteropathy, with or without skin disease, generally have serum autoantibodies to both enzymes. There is growing evidence that dermatitis herpetiformis should be considered as the skin manifestation of gluten sensitivity developing in those patients with mild coeliac disease, who produce epidermal transglutaminase autoantibodies of high avidity and affinity. Both the skin and the small bowel diseases are gluten dependent and are strongly associated with HLA DQ with no genetic differences to explain the two phenotypes. The question should be asked whether the rash in dermatitis herpetiformis is a classic autoimmune blistering disease or whether it has an immune complex basis, which is the most likely alternative.     

Drug-induced linear IgA bullous dermatosis

A 73-year-old man was admitted to the University of California Davis Medical Center for treatment of a pleural effusion and congestive heart failure. His hospital course was complicated by asymptomatic sustained ventricular tachycardia requiring placement of an implantable cardiac defibrillator. The patient was treated with vancomycin and cefazolin during the procedure. After 3 days he developed tense vesicles over the dorsal aspect of the hands. Perilesional skin biopsy showed subepidermal cleavage with a neutrophilic infiltrate. Direct immunofluorescence revealed granular IgA and C3 deposition along the dermal epidermal junction. A diagnosis of drug-induced linear IgA bullous dermatosis secondary to vancomycin was established. Linear IgA bullous dermatosis is a rare autoimmune blistering disorder with clinical features that can overlap with bullous pemphigoid and dermatitis herpetiformis. Drug-induced linear IgA bullous dermatosis is a less common variant that is correspondingly less well characterized. Although a variety of medications have been implicated, vancomycin is the most common associated drug.     

IgA autoimmune disorders: development of a passive transfer mouse model

IgA is present in the skin in several dermatoses, including dermatitis herpetiformis, linear IgA bullous dermatosis, and Henoch-Schoenlein purpura. The neutrophilic infiltration in the area of the IgA deposition suggests that IgA is responsible for the associated inflammatory events. The mechanism for this process is unproven, but is likely to involve IgA-mediated neutrophil chemotaxis with inhibition of chemotaxis by dapsone. Elucidation of the mechanism of IgA-mediated inflammation will require an animal model. We have established a model for linear IgA bullous dermatosis as a prototype disease to be studied. IgA mouse monoclonal antibodies against a linear IgA bullous dermatosis antigen have been passively transferred to SCID mice with human skin grafts. This has produced neutrophil infiltration and basement membrane vesiculation in 4 of 12 mice tested. We conclude that an animal model for the pathogenesis of IgA dermatoses with IgA deposition and inflammation can be produced by passive transfer of mouse IgA antibodies against a linear IgA antigen.