A Case of Chronic Bullous Disease of Childhood That Was Reactive to the Antigen of 120 kDa (LAD-1)

Chronic bullous disease of childhood (CBDC) is an autoimmune blistering disease that is characterized by Immunoglobulin A (IgA) deposits at the basement membrane zone. IgA autoantibodies (aAbs) from the serum of patients with CBDC react with antigens of 97 kDa (LABD97) and 120 kDa (LAD-1), and both of which are fragments of the extracellular domain of bullous pemphigoid 180 (BP180, type XVII collagen). The CBDC sera reacts with the immunodominant NC16a domain of BP180, which is the major region recognized by IgG aAbs in patients with bullous pemphigoid. A five-year-old boy presented with multiple pruritic tense blisters on the umbilical and inguinal areas for six weeks. The direct immunofluorescence of the perilesional area demonstrated linear deposits of IgA at the basement membrane zone. Using immunoblotting and an enzyme linked immunosorbent assay (ELISA), we identified the IgA aAbs reactive to antigens with a molecular weight of 120 kDa (LAD-1), which is a fragment of the extracellular domain of BP180.     

Acquired bullous diseases of childhood: re-evaluation of diagnosis by indirect immunofluorescence examination on 1 M NaCl split skin and immunoblotting

Summary Acquired autoimmune bullous diseases of childhood are rare, and can be difficult to distinguish clinically. We have studied 12 children, with an initial diagnosis of bullous pemphigoid (BP) in eight patients, cicatricial pemphigoid (CP) in one, chronic bullous disease of childhood (CBDC) in one, and epidermolysis bullosa acquisita (EBA) in two.
All patients had positive indirect immunofluorescence (HF) of the BMZ with IgG. Using 1 M NaCl split skin, six patients showed epidermal binding of IgG, with additional IgA in three cases, and in five patients IgG antibodies bound a dermal protein. Immunoblotting studies revealed an antibody to type VII collagen (EBA antigen) in three patients who had a dermal pattern on IIF. Six sera reacted with an epidermal protein of 180 and/or 220 kDa, characteristic of BP and CP. One of the three IgA-positive sera detected 220-and 180-kDa epidermal proteins using anti-IgA antibody. Following these studies the diagnosis was changed in three of the children. The diagnosis of CBDC was changed to either BP or EBA because of the presence of circulating IgG autoantibodies. In two children with an initial diagnosis of BP the diagnosis was changed to EBA.
We conclude that the clinical picture in bullous disorders of childhood shows considerable overlap, and is often misleading. Additional circulating IgA autoantibodies seem to be more common in BP than has been recognized previously. Indirect immunofluorescence investigation on 1 M NaCl split skin may be helpful in differentiating between BP and EBA, but does not replace immunoblotting studies. EBA is apparently more common in children than in adults. No difference was found between the children with BP and EBA with regard to the duration of disease. The long-term outlook is good, although the course may be protracted.     

Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis

Linear IgA bullous dermatosis (LABD) is a rare autoimmune vesiculobullous disorder characterized by variable clinical presentations that may mimic bullous pemphigoid, dermatitis herpetiformis, cicatricial pemphigoid and erythema multiforme. A few cases of drug-induced LABD that clinically resembled toxic epidermal necrolysis (TEN) have been reported. A subset of patients with LABD have been found to be drug-induced; the most common drug being vancomycin. The diagnosis of LABD is confirmed by the presence of a linear band of IgA along the basement membrane zone on direct immunofluorescence microscopy. We report a case of a 77-year-old man who presented to us with vancomycin-induced LABD that presented clinically as TEN. He had a complete recovery over a 3-week period following discontinuation of the vancomycin and the addition of oral dapsone therapy. It is important to be aware that drug-induced LABD can mimic TEN.     

Drug-induced linear immunoglobulin A bullous dermatosis mimicking Stevens-Johnson syndrome: a case report

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare autoimmune disorder characterized by vesiculobullous mucocutaneous eruptions. LABD also has been reported as a drug-induced reaction. Idiopathic LABD and drug-induced LABD are clinically indistinguishable and can resemble bullous pemphigoid, dermatitis herpetiformis, or bullous erythema multiforme. LABD is diagnosed with direct immunofluorescence (DIF), and idiopathic LABD can be distinguished from drug-induced LABD with a careful medication history. We present the case of a 54-year-old man with drug-induced LABD after ingestion of rimantadine, zanamivir, and azithromycin for presumed influenza. The patient's bullous eruption resolved with discontinuation of the offending medications and treatment with prednisone and pentoxifylline.     

Linear IgA Bullous Dermatosis with Circulating IgG Autoantibodies to the 230 kD Epidermal Antigen

The patient was a 54-year-old woman with wide-spread bullous lesions on her trunk and oral mucosa. Histologic examination revealed a subepidermal blister with infiltration of neutrophils and eosinophils. Direct immunofluorescence showed an exclusively IgA deposition at the basement membrane zone (BMZ). Indirect immunofluorescence showed that the blister fluid, but not the serum, contained IgG antibodies against the BMZ antigen on the epidermal side of salt-split skin. Using immunoblot analysis with normal human epidermal extracts, both serum and blister fluid reacted with the 230 kD epidermal antigen. Using colloidal gold and direct immunoelectron microscopy, IgA deposition was detected in the lamina lucida. Clinically, the skin lesions responded well to dapsone. We diagnosed this case as linear IgA bullous dermatosis (LABD) with IgG class circulating autoantibodies against the epidermal 230 kD antigen. These antibodies were considered to be secondary to the damage to the epidermal basal keratinocyte in this case.     

Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood

Chronic bullous disease of childhood (CBDC) is the most common acquired autoimmune blistering disorder of childhood and is characterized by linear IgA staining of the basement membrane zone on direct immunofluorescence. This autoimmune attack on structural proteins, usually proteolytic fragments of collagen XVII, renders the dermal-epidermal junction prone to blistering. Diagnosis is confirmed by characteristic histology and direct immunofluorescence. Prognosis is generally favorable, with spontaneous remission usually occurring by puberty; however, cases with severe morbidity and cases persisting into adulthood have been reported. This article discusses the clinical features, diagnosis, and pathogenesis of CBDC in more detail.     

Piperacillin–tazobactam‐induced linear IgA bullous dermatosis presenting clinically as Stevens–Johnson syndrome/toxic epidermal necrolysis overlap

Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well‐described phenomenon. Most cases of LABD are idiopathic, but some cases are drug‐induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin–tazobactam‐induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin‐tazobactam and the development of LABD.     

The use of Michel's transport medium for immunofluorescence and immunoelectron microscopy in autoimmune bullous diseases

We report the use of Michel's solution, already a well established transport medium, in the combined use of direct immunofluorescence (IMF) and pre-embedding immunoelectron microscopy in 3 subepidermal bullous diseases - bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA) and dermal binding linear IgA disease (LABD). Our studies demonstrated that electron microscopy of normal skin maintained in Michel's medium for up to 28 clays showed remarkable preservation of all components of the basement membrane zone, including the ultrastructure of the basal keratinocytes, dermoepidermal junction and papillary dermis. However, epidermal cell cytolysis occurred after just 48 hours.
Immunoelectron microscopy using a gold probe has enabled us to localise the immunoreactants in bullous pemphigoid, epidermolysis bullosa acquisita and dermal-binding linear IgA bullous dermatoses. Our findings are comparable to and as equally reliable as those on immunoelectron microscopy of fresh skin biopsies with no loss of antigen deposition, and demonstrate an effective new use of a well established transport medium.     

The localization of the binding site of circulating IgA antibodies in linear IgA disease of adults, chronic bullous disease ofchildhood and childhood cicatricial pemphigoid

Biopsies from suction blisters raised in three normal volunteers were used as substrate in the indirect immunofluorescence technique to determine the binding site of circulating IgA antibodies in serum from three patients with adult linear IgA disease (LAD), nine with chronic bullous disease of childhood (CBDC), three with childhood cicatricial pemphigoid (CCP), and four with bullous pemphigoid (BP). Direct immunofluorescence was done using suction blisters raised in two patients with LAD and one with CCP. The circulating IgA antibodies in LAD and CBDC bound mainly to the roof of the blister but also to the base, and in CCP they bound only to the base of the blister. The circulating IgG antibodies in BP bound to the roof and base of the blister. These results demonstrate that the antigens in the various linear IgA dermatoses are heterogenous and are localized at different sites. The LAD and CBDC antigens are present in the lamina lucida, and the antigen in CCP is associated with the basal lamina.     

Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults

Disease-associated autoantibodies to basement membrane proteins have been used to characterize structural components of the epidermal basement membrane such as bullous pemphigoid (BP) antigen and epidermolysis bullosa acquisita (EBA) antigen (type VII collagen). The autoimmune bullous diseases characterized by IgA autoantibodies to the basement membrane zone (BMZ), i.e. linear IgA disease of adults (LAD) and chronic bullous disease of childhood (CBDC) may have circulating antibodies. Previous studies of tissue distribution and ultrastructural binding have suggested that the LAD and CBDC antigens are similar, if not identical, and differ from the target antigens of the other bullous diseases. We present the molecular characterization of the LAD/CBDC antigens by Western blotting of a large series of antisera. Seven of 33 sera (21%) were positive on immunoblotting and bound to the same antigen which has a molecular weight (MW) of 285 kDa. Using both defined polyclonal antisera to BP and LH 7.2 monoclonal antibody to type VII collagen (carboxy terminal) we have shown that the LAD and CBDC antisera both bind to an identical molecular weight protein which clearly differs from both the BP and EBA (type VII collagen) antigens. Although detectable in dermal tissue extracts like EBA, the MW of 285 kDa is heavier than type VII collagen (250 kDa, in our system, using non-collagenous standards). This study confirms the identity of LAD and CBDC antigens to be the same and to differ from previously described basement membrane proteins.     

Review of autoimmune blistering diseases: the Pemphigoid diseases

Autoimmune Blistering Diseases of the Pemphigoid type is characterised by sub‐epidermal blisters (SEB) with circulating autoantibodies against components of the basement membrane zone (BMZ). The main disorders to date include bullous pemphigoid (BP), pemphigoid gestationis, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), linear IgA disease (LABD), dermatitis herpetiformis (DH), lichen planus pemphigoides and bullous lupus. This is in contrast to pemphigus and related disorders, which demonstrate intraepidermal acantholysis and a positive Nikolsky sign. The classification and management is based on clinical, histological and direct and indirect immunofluorescence findings. There are, however, overlapping clinical and histological features between the conditions and clinical heterogeneity within each disease.     

IgA antibodies recognizing LABD97 are predominantly IgA1 subclass.

Linear IgA bullous dermatosis is a rare acquired subepidermal blistering disease of the skin. A recognized antigen in linear IgA bullous dermatosis is a 97-kDa basement membrane zone protein termed LABD97. Previous studies, using immunofluorescent techniques, have suggested that the IgA response is restricted to the IgA1 subclass. We studied the IgA antibody subclasses in the sera of 6 patients that contained circulating IgA antibodies reactive with LABD97. The methods used included direct and indirect immunofluorescence and Western immunoblot. All patients tested had IgA1 anti-LABD97 antibodies detected by all 3 methods. Two patients had IgA2 antibodies detected by direct immunofluorescence. Three patients had IgA2 antibodies on indirect immunofluorescence. Two of these also had anti-LABD97 IgA2 antibodies and 1 had secretory component containing anti-LABD IgA antibodies on Western immunoblot. We conclude that the predominant IgA antibody subclass reactive with LABD97 in LABD is IgA1, although the IgA2 subclass may be involved in some cases.     

A case of vancomycin‐associated linear IgA bullous dermatosis and IgA antibodies to the α3 subunit of laminin‐332

Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disease, which is defined by the histopathological finding of subepidermal vesicles with neutrophilic infiltration and linear IgA deposits in the basement membrane zone, revealed by immunofluorescence study. We present a case of LABD in which vancomycin (VCM) administration triggered LABD, and immunoblot analysis showed IgA antibodies reactive to the 145‐ and 165‐kDa α3 subunits of laminin‐332. This is the first report of VCM‐associated LABD in which the target antigen was laminin‐332. In the present case, we were compelled to continue administration of VCM along with systemic steroids, which eventually led to the attenuation of the symptoms, normalization of the serum IgA level, and negative results on both indirect immunofluorescence of 1 mol L^?1 NaCl‐split skin and immunoblot analysis.     

Case of shift from linear immunoglobulin A bullous dermatosis to pemphigus herpetiformis for a short period of time

Pemphigus herpetiformis (PH ) is a rare variant of pemphigus characterized by erythemas and vesicles, tending to present with annular‐shaped lesions. Immunologically, immunoglobulin (Ig)G deposition at the keratinocyte cell surfaces is observed. Linear IgA bullous dermatosis (LABD ) is a rare subepidermal blistering disease with linear IgA deposits at the epidermal basement membrane zone (BMZ ). The annular‐shaped skin lesions in PH mimic clinical manifestation of other autoimmune bullous diseases, including LABD , although PH and LABD have different immunological and histopathological features. Herein, we report the first case of a shift from LABD to PH . A 70‐year‐old Japanese man presented annular erythemas surrounded by vesicles on the trunk and extremities. Histopathological examination revealed subepidermal bullae and eosinophilic spongiosis. Direct immunofluorescence demonstrated linear IgA deposits at the epidermal BMZ . Immunoblot analyses of normal human epidermal and dermal extracts, supernatant of HaCaT cells, recombinant proteins of BP 180 NC 16a and C‐terminal domains, and purified laminin‐332 showed no reactivity for either IgG or IgA. IgG chemiluminescent enzyme immunoassays for desmogleins 1 and 3, and BP 180 were all negative. These findings led to the diagnosis of sole LABD . Although oral prednisolone temporarily improved the skin lesions, annular erythema without vesicles remained. A new skin biopsy revealed subcorneal pustules with eosinophils, but no subepidermal bullae. Direct immunofluorescence revealed IgG and C3 deposition at the keratinocyte cell surfaces. IgG enzyme‐linked immunosorbent assay for mammalian desmocollins 1–3 revealed desmocollin 1 reactivity. Based on these findings, we made a diagnosis of sole PH .     

成人线状IgA大疱性皮病5例临床分析

目的：了解5例成人线状IgA大疱性皮病的临床特点,以提高对该病的认识。方法：对5例成人线状IgA大疱性皮病的临床资料、组织病理、免疫荧光进行分析,并对相关文献进行复习。结果：5例患者中男3例,女2例,年龄在66—87岁之间,均表现为在红斑基础上的水疱,或外观正常的皮肤上出现的水疱,病理组织活检和免疫荧光确诊为成人线状IgA大疱性皮病。结论：成人线状IgA大疱性皮病好发年龄为〉60岁的老年人,皮疹表现类似大疱性类天疱疮、疱疹样皮炎,多数兼有两病的特点,容易误诊,直接免疫荧光检查发现沿基底膜带有均质型线状IgA沉积具有诊断价值。     

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 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.     

Drug-induced linear IgA bullous dermatosis

We report the case of a 69-year-old Japanese woman with multiple blistering lesions covering almost her whole body. Linear IgA and C3 depositions were seen at the basement membrane zone on direct immunofluorescence (IF). Linear IgA bullous dermatosis (LABD) is one of the autoimmune diseases resulting in subepidermal blisters. It is clinically similar to bullous pemphigoid and IF is required to distinguish the two diseases. In this case, the blistering lesions appeared after vancomycin treatment. This drug was strongly suspected as a cause of LABD in light of the clinical course of the patient even though a drug-lymphocyte stimulating test was negative. Among the various implicated causative drugs, vancomycin is the most commonly associated with LABD.     

Linear IgA bullous dermatosis: report of five cases in Chile

Background Linear IgA bullous dermatosis (LABD) is an acquired autoimmune sub‐epidermal vesiculobullous disease characterized by continuous linear IgA deposit on the basement membrane zone, as visualized on direct immunofluorescence microscopy. LABD can affect both adults and children. The disease is very uncommon, with a still unknown incidence in the South American population. Materials and methods All confirmed cases of LABD by histological and immunofluorescence in our hospital were studied. Results  The confirmed cases were three females and two males, aged from 8 to 87 years. Precipitant events associated with LABD were drug consumption (non‐steroid inflammatory agents in two cases) and ulcerative colitis (one case). Most of our patients were treated with dapsone, resulting in remission. Discussion Our series confirms the heterogeneous clinical features of this uncommon disease in concordance with a larger series of patients reported in the literature.     

Two Cases of Atypical Bullous Disease Showing Linear IgG and IgA Deposition in the Basement Membrane Zone

Patients showing coexistent linear IgG and IgA deposition along the basement membrane zone on direct immunofluorescence have been described as either bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, or cicatricial pemphigoid, depending on the clinical features and laboratory findings. In the present report, we describe two cases showing atypical clinical features distinct from those of other known bullous diseases. No circulating antibodies were detected by indirect immunofluorescence of normal human skin. Indirect immunofluorescence of 1 M NaCl split skin revealed IgG and/or IgA antibodies reactive with the dermal side of the split. Immunoblotting of normal human epidermal and dermal extracts showed no apparent reactivity with known autoantigens. The results suggest that there may be a unique and distinct bullous disease with linear IgG and IgA deposition at the basement membrane zone.