Case of subepidermal autoimmune bullous disease with psoriasis vulgaris reacting to both BP180 C‐terminal domain and laminin gamma‐1

A number of cases of psoriasis vulgaris developing bullous skin lesions have been diagnosed as either bullous pemphigoid with antibodies to the 180‐kDa bullous pemphigoid antigen (BP180) non‐collagenous 16a (NC16a) domain or anti‐laminin‐γ1 (p200) pemphigoid. We report a case of subepidermal bullous disease with psoriasis vulgaris, showing antibodies to both BP180 C‐terminal domain and laminin‐γ1. A 64‐year‐old Japanese man with psoriasis vulgaris developed exudative erythemas and tense bullae on the whole body but he did not have mucosal involvement. The blistering lesion showed subepidermal blisters histopathologically. In indirect immunofluorescence of 1 mol/L NaCl‐split skin, immunoglobulin (Ig)G antibodies reacted with both the epidermal and dermal side. Immunoblotting showed positive IgG with recombinant protein of BP180 C‐terminal domain and 200‐kDa laminin‐γ1 in normal human dermal extract.     

Two cases of subepidermal blistering disease with anti-p200 or 180-kD bullous pemphigoid antigen associated with psoriasis

We describe two patients with psoriasis vulgaris who subsequently developed a subepidermal blistering disease which disclosed IgG and C3 at the basement membrane zone in direct immunofluorescence. The first case was a 75-year-old Japanese man with herpetiform lesions. Histopathology showed neutrophil infiltration. IgG antibodies bound to the dermal side of the salt-split skin. Immunoblot analysis identified a 200-kD antigen in dermal extracts. The second case was a 70-year-old Japanese man. Histopathology showed eosinophil infiltration. IgG antibodies bound to the epidermal side of salt-split skin. Immunoblot analysis identified a 180-kD bullous pemphigoid (BP) antigen in epidermal extracts. We review the clinical and pathological features of psoriatic patients who presented a subepidermal blistering disease in which antigens were detected by immunoblot analysis; i.e., anti-p200 pemphigoid (14 cases) or BP (12 cases). There were few distinct clinical differences between two diseases. However, neutrophils were predominant in anti-p200 pemphigoid, while eosinophils were predominant in BP. After blister formation, ciclosporin was used effectively in addition to systemic steroids in the treatment of anti-p200 pemphigoid. On the other hand, ciclosporin was not used in the treatment of BP with psoriasis.     

A bullous skin disease patient with autoantibodies against separate epitopes in 1 mol/L sodium chloride split skin.

BACKGROUND--We describe a patient with a subepidermal bullous skin disease associated with autoantibodies recognizing separate epitopes in 1 mol/L sodium chloride (NaCl) split skin. OBSERVATIONS--Direct immunofluorescence microscopy showed deposits of immunoglobulins and C3 in a continuous pattern in the patient's epidermal basement membrane zone. Direct immunoelectron microscopy demonstrated thick deposits of IgG overlying the lamina lucida and the lamina densa in a unique pattern. The patient had circulating IgG anti-basement membrane zone antibodies that bound both sides of 1 mol/L NaCl split skin, exhibited at least a fourfold-higher titer against the dermal side of this test substrate, and bound basal keratinocyte hemidesmosomes as well as focal sites along the superior portion of the lamina densa on indirect immunoelectron microscopy. Affinity purification of anti-basement membrane zone antibodies against epidermal or dermal strips of 1 mol/L NaCl split skin yielded IgG that only bound the side of split skin from which it was eluted. The patient's serum contained IgG that immunoprecipitated and immunoblotted the 230- and 170-kd bullous pemphigoid antigens. Affinity purification of patient antibody against bullous pemphigoid antigen immobilized on nitrocellulose paper yielded IgG that bound only the epidermal side of 1 mol/L NaCl split skin. The patient showed no evidence of reactivity against type VII collagen by direct immunoelectron microscopy, indirect immunoelectron microscopy, or immunoblot. CONCLUSIONS--This patient's bullous skin disease is associated with IgG anti-basement membrane zone antibodies with two specificities: one recognizing the bullous pemphigoid antigen in the epidermal side of 1 mol/L NaCl split skin, and another binding a distinct, yet presently unidentified, epitope in the superior aspect of the lamina densa.     

A case of epidermolysis bullosa acquisita with autoantibody to anti-p200 pemphigoid antigen and exfoliative esophagitis

BACKGROUND: Some cases of a subepidermal blistering disease associated with autoantibodies to more than two antigens have been reported. OBSERVATION: A 52-year-old Japanese woman had pruritic blisters on almost the whole body as well as erosive lesions in the oral cavity and esophagus. A histological finding was subepidermal bullae. Direct immunofluorescence (IF) revealed a linear deposition of IgG, IgM and C3 at the epidermal basement membrane zone (BMZ). Indirect IF using human skin split by 1 M NaCl as a substrate showed IgG antibody reactive with the dermal side. By immunoblot analysis using normal human dermal extract, the 200-kDa and 290-kDa bands were detected. Indirect IF did not show any anti-BMZ antibody activity, when using the skin of the patient with recessive dystrophic epidermolysis bullosa as a substrate. CONCLUSION: We regarded our case as epidermolysis bullosa acquisita with autoantibody to anti-p200 pemphigoid antigen. This is the second case in the literature associated with autoantibodies to these two antigens.     

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.     

Childhood bullous pemphigoid successfully treated with diaminodiphenyl sulfone

Bullous pemphigoid (BP) is an acquired autoimmune blistering disease which predominantly affects the elderly. It is rare in children and infants. We reported a 14-year-old girl presenting with a month history of relapsing tense bullae on the face and extremities. Histopathological examination of the lesional skin revealed a subepidermal bulla with infiltration of eosinophils, neutrophils, and lymphocytes. Direct immunofluorescence showed linear deposits of IgM and C3 at the basement membrane zone. Indirect immunofluorescence using normal human skin sections as a substrate detected IgG anti-basement membrane zone antibodies in the patient's serum and that using 1M NaCl split skin sections showed that the patient's antibodies bound to the epidermal side of the split skin. Immunoblot analysis using normal human epidermal extracts demonstrated the presence of autoantibodies against the 230-kDa BP antigen. Furthermore, the patient's serum reacted with the recombinant protein of the NC16a domain of the 180-kDa BP antigen by immunoblot analysis and enzyme-linked immunosorbent assay. Our patient showed significant improvement of the skin lesions with systemic administration of diaminodiphenyl sulfone.     

Coexistence of psoriasis and an unusual IgG-mediated subepidermal bullous dermatosis: identification of a novel 200-kDa lower lamina lucida target antigen

Summary Bullous pemphigoid (BP) is characterized by autoantibodies against 230- and 180-kDa hemidesmosomal antigens located in the most superficial layers of the basement membrane zone (BMZ). Histologically. there is a predominance of eosinophils in the infiltrate. In a psoriatic patient, we identified an unusual autoimmune subepidermal bullous eruption which clinically resembled BP, but which was characterized by IgG autoantibodies against a novel 200-kDa lower lamina lucida component, Histologically there was a predominance of neutrophils in the infiltrate.
Direct immunofluorescence showed linear immunoglobulin (Ig)G and C3 deposition at the BMZ. The patient's IgG autoantibodies bound exclusively to the dermal side of salt-split normal human skin. Indirect immunogold electron microscopy showed a marked deposition of IgG at the lower lamina lucida and minimal deposition at the hemidesmosomes. Immunoblot analysis identified a unique 200-kDa autoantigen in dermal extracts and a faint band of the 230-kDa BP antigen in epidermal extracts. The patient responded dramatically well to cyclosporin A.
Although the patient's serum also reacted slightly with the 230-kDa BP antigen, there were significant findings different from the usual immunopathological changes of BP. These included finding a novel 200-kDa lower lamina lucida target antigen, the binding of IgG autoantibodies exclusively to the dermal side of the split skin and a predominance of neutrophils in blister infiltrate. The IgG autoantibodies against the 200-kDa lamina lucida target antigen seemed to play a major role in the pathogenesis of this unique autoimmune subepidermal dermatosis.     

A case of generalized pustular psoriasis followed by bullous disease: and atypical case of bullous pemphigoid or a novel bullous disease?

Summary We describe a 31-year-old Japanese woman with generalized pustular psoriasis treated with PUVA who subsequently developed a bullous disease. Throughout the disease coures, there was no phase of psoriasis vulgaris. Although several reports describe coexistence of psoriasis vulgaris and bullous disease such as bullous periphigoid, coexistence of generalized pustular psoriasis without any phase of psoriasis vulgaris and bullous disease is rare. As for the bullous disease, direct immunofluorescence study showed lgG and C3 deposition along the basement membrane zone. Indirect immunofluorescence disclosed lgG antibasement membrane zone antibodies. Indirect immunofluorescence on 1 mol/1 sodium chloride-split skin demonstrated linear lgG staining almost exclusively on the dermal side of the split. Western immunoblot analysis revealed that the antibody was directed to neither epidermolysis bullosa acquisita antigen nor bullous pemphigoid antigens. Considering the unusual clinical course, we suspect the possibility of a novel autoimmune blistering 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.     

Pemphigoid with antibodies to laminin γ1, BP180 and BP230, associated with psoriasis vulgaris: Successful disease control with cyclosporin

Both anti‐laminin γ1 pemphigoid and bullous pemphigoid are autoimmune subepidermal blistering diseases. The former is rare and characterized by autoantibodies to laminin γ1, a 200‐kDa dermal protein, while the latter is common among the elderly and characterized by autoantibodies to BP180 and BP230, both of which are hemidesmosomal proteins. We experienced a 69‐year‐old Japanese male patient with blister formation secondary to erythrodermic psoriasis, which was successfully treated with cyclosporin. The histopathology of erythema corresponded with psoriasis and that of a blistering lesion showed infiltration of neutrophils and eosinophils in and around the subepidermal blisters. Patient immunoglobulin G antibodies labeled both the epidermal and dermal sides of 1 mol/L NaCl‐split human skin by indirect immunofluorescent microscopy and recognized laminin γ1, BP180 and BP230 by immunoblotting. To the best of our knowledge, this is the first report of coexistence of psoriasis and atypical pemphigoid with these three autoantibodies.     

Anti-p200 pemphigoid: a novel autoimmune subepidermal blistering disease

Anti-p200 pemphigoid is a recently defined autoimmune subepidermal blistering disease characterized by circulating and tissue-bound autoantibodies to a 200-kDa protein (p200) of the dermal-epidermal junction (DEJ). This DEJ constituent is thought to be important for adhesion of basal keratinocytes to the underlying dermis. While the exact identity of p200 remains unknown, it has been demonstrated to be immunologically and biochemically distinct from all major autoantigens of the DEJ, including bullous pemphigoid antigens 180 and 230, laminin 1, 5 and 6, alpha6beta4 integrin, and type VII collagen. Clinically, most reported cases present with tense blisters as well as urticarial papules and plaques, closely resembling bullous pemphigoid. Histopathological examination of lesional skin biopsies shows subepidermal split formation and superficial inflammatory infiltrate typically dominated by neutrophils. Immunopathologically, linear deposits of immunoglobulin (Ig)G and C3 are detected along the DEJ by direct immunofluorescence microscopy of perilesional skin. Indirect immunofluorescence microscopy of patients' sera on NaCl-split human skin demonstrates circulating IgG autoantibodies labeling the dermal side of the split. By immunoblotting, these autoantibodies recognize a 200-kDa protein of human dermis. Biochemical characterization of the p200 molecule revealed a noncollagenous N-glycosylated acidic protein with an isoelectric point of approximately 5.5. We present an overview of the pathogenesis, clinical features, diagnosis and treatment of this new disease entity.     

Circulating IgA and IgE autoantibodies in antilaminin‐332 mucous membrane pemphigoid

Background Antilaminin‐332 mucous membrane pemphigoid (MMP) is a chronic autoimmune bullous disease that is often associated with internal malignancy. IgG autoantibodies against laminin‐332 in patients with MMP are well documented; however, IgA and IgE autoantibodies against laminin‐332 have not yet been described. Objectives To characterize IgA and IgE autoantibodies binding to laminin‐332 in sera from patients with antilaminin‐332 MMP. Methods Sera and skin samples from four patients who met the following criteria were used: (i) subepidermal blistering lesions present on the mucous membranes; (ii) in vivo deposition of IgG along the epidermal basement membrane zone of sampled skin; (iii) circulating IgG antibasement membrane zone antibodies that react with the dermal side of salt‐split normal human skin; and (iv) circulating IgG autoantibodies that do not show positivity against type VII collagen or 200‐kDa protein (p200 antigen) in immunoblot analysis using dermal extracts. Circulating IgG/IgA/IgE class autoantibodies against laminin‐332 were determined by immunoblotting. Results Circulating IgG autoantibodies against the γ2, α3/γ2, α3 and α3/β3/γ2 subunits of laminin‐332 were demonstrated in sera from four patients, respectively. Serum from one of the four patients showed IgA reactivity with the α3/β3/γ2 subunits of laminin‐332. Serum from one of the four patients showed IgE reactivity with the γ2 subunit of laminin‐332. The control sera failed to display IgG/IgA/IgE reactivity to laminin‐332. Conclusions In addition to IgG autoantibodies, circulating IgA and IgE autoantibodies against laminin‐332 are detectable in a subset of patients with antilaminin‐332 MMP.     

Anti-p200 pemphigoid responding to dapsone

Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Clinical presentation is similar to standard bullous pemphigoid (BP) but mucous membranes and cephalic lesions are more frequent. Histology and direct immunofluorescence (IF) are identical to BP but indirect IF discloses linear deposits of immunoglobulin G (IgG) on the dermal side of artificial salt-split skin. Specific diagnosis is based on western immunoblotting that shows circulating IgG recognizing a 200-kDa protein localized on the dermal extract. The 200-kDa antigen was recently identified as laminin γ1. Anti-p200 pemphigoid should be considered before all atypical or topical steroid-resistant bullous disease, as well as mucous membranes pemphigoid or epidermolysis bullosa acquisita. Dapsone appears to be the most effective treatment and should be used as the first option in combination with topical steroids. In this report, we describe the case of a patient with a typical clinical and immunopathological anti-p200 pemphigoid, responding to a combination of topical steroids and dapsone.     

Psoriasis bullosa acquisita

We report a 51-year-old man with a 20-year history of chronic plaque psoriasis who developed an autoimmune subepidermal blistering eruption that had clinical features of bullous pemphigoid, erythema multiforme and epidermolysis bullosa acquisita. Investigations revealed a 1 : 400 titre circulating and in vivo bound IgG autoantibody that mapped to the dermal side of 1 m NaCl-split skin and localized to the lower lamina lucida/upper lamina densa on immunogold electron microscopy. Immunoblotting, using dermal extracts, showed serum binding to antigens of approximately 200- and approximately 260 kDa. Indirect immunofluorescence microscopy, using the patient's serum on archival skin sections taken from selected individuals with different forms of inherited epidermolysis bullosa as substrate, showed normal basement membrane labelling on all samples apart from recessive dystrophic epidermolysis bullosa skin (with inherent mutations in the type VII collagen gene): in these cases there was a complete absence of immunostaining. Clinically, the patient responded rapidly to combination treatment with intravenous immunoglobulin and oral corticosteroids, dapsone and mycophenolate mofetil. Autoimmune subepidermal blistering has been reported in other patients with psoriasis, although no specific target antigen has ever been determined. Our study provides preliminary evidence that, for this patient at least, the autoantibody may be targeted against a skin component closely associated with type VII collagen (the epidermolysis bullosa acquisita antigen). Therefore, we propose the term 'psoriasis bullosa acquisita' for this and possibly other patients with similar skin eruptions.     

Anti‐p200‐Pemphigoid – Eine neue blasenbildende Autoimmundermatose

Anti‐p200 pemphigoid is an autoimmune skin disease characterized by tense blisters, subepidermal split formation, and mainly neutrophilic inflammatory infiltration of the dermal‐epidermal junction (DEJ). Direct immunofluorescence microscopy of perilesional skin biopsies demonstrates linear deposits of IgG and C3 along the DEJ, while by indirect immunofluorescence microscopy on NaCl‐split human skin, patients' IgG labels the dermal side. The antigenic target of the autoantibodies is a 200 kD protein (p200) of the lower lamina lucida that can be detected in human dermal extracts by immunoblotting. While p200 is thought to be important for cell‐matrix adhesion, its exact identity is unknown. To date, the p200 autoantigen has been demonstrated to be distinct from bullous pemphigoid antigens 180 und 230, laminin 1, 5, and 6, α6β4 integrin, and type VII collagen. Biochemical characterization of the p200 molecule revealed a noncollagenous N‐glycosylated acidic protein with an isoelectric point of approximately 5.5. We provide an overview on pathogenesis, clinical features, diagnosis, and treatment of this unique autoimmune dermatosis.     

Psoriasis vulgaris coexistent with epidermolysis bullosa acquisita

Summary Autoimmune bullous diseases, such as bullous pemphigoid or pemphigus vulgaris. occasionally develop in psoriatic patients. In addition, a novel subepidermal bullous disease with autoantibodies against a lower lamina lucida antigen of 200kDa has recently been reported in association with psoriasis. We describe here a patient with psoriasis vulgaris who developed epidermolysis bullosa acquisita (EBA). Direct immunofluorescence revealed linear deposition of IgCl and C3 at the basement membrane zone. The patient's serum bound to the dermal side of salt-split normal human skin. However, immnumohlol analysis demonstrated that the patient's serum reacted with an EBA antigen of 290 kDa. EBA should be included in the list of autoimmune diseases associated with psoriasis vulgaris.     

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.     

Concomitant Occurrence of Circulating IgA Anti-intercellular and Anti-basement Membrane Zone Antibodies in Autoimmune Blistering Diseases: Immunofluorescence and Immunoblot Studies

Recently, cases with circulating IgA anti-intercellular antibodies have been described. The objective of this study was to present immunofluorescence and immunoblot findings in three cases of bullous diseases with concomitant circulating IgA anti-intercellular and anti-basement membrane zone antibodies. Direct immunofluorescence, indirect immunofluorescence on intact and 1M NaCl-split skin, immunoblotting of epidermal extracts from dispase- and EDTA-separated (two different procedures) human skin, and immunoblotting of the bovine desmosome preparation were performed. All three cases had IgA anti-intercellular and anti-basement membrane zone antibodies. However, immunoblot results were divergent. Case 1 had antibodies against the 150 kD pemphigus foliaceus antigen (IgG), the 170 kD protein (IgG and IgA), and the 97 kD antigen (IgG and IgA). Case 2 had IgG antibodies reactive with the 230 kD and the 170 kD bullous pemphigoid antigens, while case 3 had IgA antibodies against the 97 kD antigen only. The results of immunofluorescence and immunoblot studies in our patients widen the spectrum of laboratory features in blistering skin diseases mediated, at least in part, by antibodies of the IgA class.     

Case of epidermolysis bullosa acquisita with concomitant anti‐laminin‐332 antibodies

Subepidermal autoimmune blistering disease including bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, anti‐laminin‐γ1 pemphigoid, linear immunoglobulin A bullous disease and epidermolysis bullosa acquisita (EBA), are all characterized by direct immunofluorescence microscopy or immunoglobulin deposition on the basement membrane zone. Among them, EBA is a rare acquired subepidermal autoimmune blistering disease of the skin and mucous membranes reactive with type VII collagen, a major component of the epidermal basement membrane zone. Anti‐laminin‐332‐type mucous membrane pemphigoid has pathogenic autoantibodies against laminin‐332, which is a basement membrane heterotrimeric protein composed of α3, β3 and γ2 laminin chains. We describe a 73‐year‐old Japanese man presenting with multiple, annular, tense blisters on the lower legs and oral lesions. Despite the severe clinical manifestations, the disease was successfully controlled by combination therapy of oral prednisolone and mizoribine. This case was confirmed to have autoantibodies to both type VII collagen and laminin‐332 α3 chain by indirect immunofluorescence of 1 mol NaCl‐split normal human skin, various immunoblot analyses and enzyme‐linked immunosorbent assays. This case was a rare case of EBA with concomitant anti‐laminin‐332 antibodies.     

A case of mixed bullous disease of epidermolysis bullosa acquisita and linear IgA bullous dermatosis

A 75-year-old Japanese male visited us with bullous eruptions on the extremities. Physical examination revealed large bullae on the hands, lower legs and feet. The oral mucosa was also involved. Histology disclosed subepidermal blister with inflammatory cell infiltrates in the dermis. Direct immunofluorescence showed deposits of IgG and IgA at the cutaneous basement membrane zone. Indirect immunofluorescence on 1 M NaCl-split human skin sections demonstrated that the patient's IgG antibodies reacted with the dermal side of the split, while IgA antibodies reacted with the epidermal side. Immunoblotting showed that the patient's serum reacted with the NC1 domain of type VII collagen (290-kDa epidermolysis bullosa acquisita antigen) as well as the 120-kDa linear IgA bullous dermatosis antigen, LAD-1. Systemic prednisolone resulted in a favorable response. From the clinicopathological findings, the present case is not consistent with either epidermolysis bullosa acquisita or IgA bullous dermatosis. Therefore, we regarded the case as mixed bullous disease of epidermolysis bullosa acquisita and linear IgA bullous dermatosis. Such a case has not been previously reported.