Linear IgA disease with IgA antibodies directed against 200- and 280-kDa epidermal antigens

We report an 80-year-old man with the lamina lucida type of linear IgA disease, with IgA autoantibodies reactive with 200-kDa and 280-kDa epidermal proteins. The patient presented with widespread bullous lesions on his trunk and extremities without mucosal involvement. Histopathology of lesional skin showed a subepidermal blister with papillary microabscesses of neutrophils and a few eosinophils. Direct immunofluorescence microscopy of perilesional skin showed linear deposits of IgA and C3 at the basement membrane zone. The patient's serum contained IgA autoantibodies that bound exclusively to the epidermal side of 1 mol L-1 NaCl split skin as determined by indirect immunofluorescence microscopy. Circulating IgA autoantibodies to 200- and 280-kDa antigens were detected in the patient's serum by immunoblot analysis using extracts from normal human epidermis and human epidermal keratinocytes. These two antibodies, eluted from individual nitrocellulose membranes, reacted with the epidermal side of 1 mol L-1 NaCl split skin on indirect immunofluorescence microscopy, and bound to hemidesmosomes as determined by immunoperoxidase electron microscopy. This observation suggests the presence of hitherto uncharacterized 200- and 280-kDa hemidesmosomal proteins distinct from BPAG1, BPAG2 and beta4 integrin as target antigens in linear IgA disease.     

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.     

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.     

C3d在大疱性类天疱疮患者皮损组织中的表达

目的 探讨C3d在石蜡包埋的大疱性类天疱疮患者皮损组织中的表达及临床意义。方法 免疫组化SP法在25例大疱性类天疱疮、10例大疱性表皮松解症及10例正常成人皮肤组织标本中进行C3d、IgG、IgA进行检测,并对其在大疱性类天疱疮皮损中阳性率进行比较。结果 大疱性类天疱疮皮损中C3d、IgG、IgA的阳性率分别为96%、72%、0%。C3d、IgG在BP组织中表达阳性率的差异有统计学意义（χ2 = 4.17,P < 0.05）,C3d、IgA在BP组织中表达阳性率的差异有统计学意义（χ2 = 22.04,P < 0.01）。C3d、IgG、IgA在10例EB及正常成人皮肤组织标本中表达均为阴性。结论 免疫组化方法检测C3d的表达可以协助在石蜡组织中进行大疱性类天疱疮的诊断。     

A case of linear IgA bullous dermatosis of childhood: immunoelectron microscopic and IgA subclass studies

A 2-year-old girl developed small tense bullae on the diaper area, face and extremities. Immunofluorescent studies revealed linear deposits of IgA, IgM and C3 at the basement membrane zone (BMZ). In addition, IgA2 deposits, as well as IgA1, were clearly demonstrated in the lesional skin. However, in circulation, only IgA1 anti-BMZ antibodies were found. Immunoelectron microscopic study showed IgA deposits just underneath the basilar surface of the basal cells, which seemed to be associated with hemidesmosomes. The survey of the literature suggests that the involvement of IgA2 is extremely rare in this disease.     

Acrodermatitis-enteropathica-ähnliche Hautveränderungen bei Morbus-Crohn-bedingtem Zinkmangel

We report a case of acrodermatitis enteropathica-like skin eruptions presenting with alopecia, perlèche, glossitis, and genital erosions as well as multifocal eczematoid, psoriasiform, and bullous skin lesions due to zinc deficiency in Crohn's disease.     

Association of vesiculobullous eruptions with mycosis fungoides

Mycosis fungoides (MF) is, on extremely rare occasions, associated with vesiculobullous eruptions. This report describes clinical, histological and immunohistochemical findings of a case of MF with vesiculobullous lesions. Characteristic features of our case included: bullous lesions evolving rapidly in 12-24 h with severe itch on erythematous and normal-appearing skin; a positive Nikolsky sign; an intraepidermal blister; direct and indirect immunofluorescence stainings were all negative with IgG, IgA, IgM and C3, and atypical lymphocytes in the infiltrates were of helper/inducer T cell type.     

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.     

Vesicular pemphigoid with circulating autoantibodies against 230-kDa and 180-kDa proteins, and additional autoantibodies against 97-kDa and 45-kDa proteins

The vesicular variant of bullous pemphigoid is a clinical entity in which the principal type of lesions are multiple small tense vesicles in a symmetric distribution, instead of the classical large, more randomly distributed large bullae. We describe a 62-year-old female who developed a vesicular variant of bullous pemphigoid, with intensely pruritic vesiculopapular eruptions and erythematous irregularly outlined patches confluent on the face, neck, trunk, extremities and oral mucosa. Direct immunofluorescence revealed a linear deposition of IgG and C3 at the basement membrane zone of the skin, and indirect immunofluorescence detected circulating IgG autoantibodies reacting with antigens located on the epidermal side of skin split with 1 M NaCl. Indirect immunogold electron microscopy revealed IgG deposition at the underneath membrane of the basal cells and in the lamina lucida. In addition to the 230-kDa and 180-kDa bullous pemphigoid antigen, immunoblot analysis also demonstrated the presence of IgG antibodies reactive with 97-kDa and 45-kDa protein. Treatment with systemic corticosteroid, minocycline and antihistamines plus topical steroid resulted in moderate improvement. A few vesicles, however, continued to appear intermittently during the past year of treatment.     

Intravenous Immunoglobulin-Induced, Non-Eczematous, Vesiculobullous Eruptions in Stevens-Johnson Syndrome

Intravenous immunoglobulin (IVIG) has emerged as a promising treatment that interrupts the progression of Stevens-Johnson syndrome (SJS). Our patient experienced an uncommon adverse effect, noneczematous, vesiculobullous eruptions, after treatment with IVIG. These new lesions developed rapidly on the palms while most previous SJS bullous lesions subsided. A skin biopsy of these new lesions showed an intracorneal vesicle, without epidermal necrosis, with inflammatory cell infiltration. IVIG-induced, vesiculobullous eruptions are discussed, along with their possible pathogenesis. With the increasing use of IVIG for treatment of bullous dermatoses, recognition of this rare adverse effect is important for prompt differential diagnosis.     

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

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

Immunoelectronmicroscopic differentiation of linear IgA bullous dermatosis of adults with coexistence of IgA and IgG deposition from bullous pemphigoid.

BACKGROUND: The differentiation between linear IgA bullous dermatosis (LABD) and bullous pemphigoid (BP) is sometimes difficult in patients who have both IgA and IgG deposition in a linear pattern at the basement membrane zone. OBJECTIVE: We address whether two cases of acquired subepidermal blistering disease with coexistence of IgA and IgG deposition in a linear pattern at the basement membrane zone are LABD or BP. METHODS: The two cases were investigated by immunoelectron microscopy and compared with two typical cases of LABD. RESULTS: In both cases, the deposition of IgA and IgG was ultrastructurally localized below the lamina densa in close association with anchoring fibrils, as was seen in two cases of typical LABD. CONCLUSION: These findings indicate that our two cases of acquired blistering disease with co-existence of IgA and IgG deposition are LABD, rather than BP.     

Ultrastructural immunogold studies in two cases of linear IgA dermatosis. Are there two distinct types of this disease?

It has been suggested that patients with homogeneous linear IgA deposits at the basement membrane zone constitute a distinct bullous disorder called linear IgA dermatosis (LAD) of adults or children. The results of the present ultrastructural immunogold study in two patients with LAD suggest that LAD is not a single disease entity. LAD in a 10-year-old girl was found to be ultrastructurally similar to an IgA-type pemphigoid. IgA was detected in the uppermost lamina lucida underlying the basal cell plasma membrane. In a second patient, an 86-year-old man, IgA deposits were present within the lamina densa and the anchoring plaques. The distribution of IgA in this patient was ultrastructurally identical with that of IgG in epidermolysis bullosa acquisita skin and with that of the non-collagenous globular terminus of collagen VII within the basement membrane zone of normal skin. By using the immunogold technique, we could distinguish two distinct types of LAD according to the IgA binding sites in the diseased skin. We suggest that different labelling patterns may correspond to different clinical pictures.     

Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis

Linear immunoglobulin (Ig)A/G bullous dermatosis (LAGBD) is an autoimmune bullous disease characterized by formation of subepidermal blisters and linear deposition of IgA and IgG antibodies along the basement membrane zone (BMZ). The association between linear IgA bullous dermatosis and ulcerative colitis (UC) is well recognized, but reports of UC‐associated LAGBD are lacking. We have reported a 24‐year‐old man suffering from LAGBD associated with UC, which occurred before exacerbations of skin rash. A skin biopsy indicated a subepidermal blister with an infiltration of primarily neutrophils and eosinophils in the dermis. Direct immunofluorescence (IF) studies showed a linear deposition of IgA, IgG and C3c. Indirect IF of human skin revealed IgA and IgG anti‐BMZ autoantibodies. Indirect IF of 1 M NaCl‐split human skin demonstrated reactivity of IgA and IgG antibodies at the epidermal side. Immunoblotting showed that IgG antibodies reacted to the BP180 NC16a domain and 120‐kDa linear IgA dermatosis‐1, and enzyme‐linked immunoassay detected IgG anti‐BP230 antibodies. Administration of prednisolone and diaminodiphenyl sulfone (DDS) via the p.o. route improved skin lesions and bowel conditions. These results suggest that the bowel inflammation observed in UC may have a causative effect of initiation of the immune response to the skin and development of the bullous skin lesions in LAGBD. A combination of DDS and corticosteroid could be a recommended therapeutic option for patients with LAGBD with UC.     

History of pemphigus

The modern concept of pemphigus divides it into variants: pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus (Senear-Usher syndrome), and pemphigus herpetiformis. These conditions are all related by the fact that they are all bullous diseases at some time during their clinical course and are histologically characterized by acantholysis. In pemphigus vulgaris and pemphigus vegetans, acantholysis is generally above the basilar cell layer (suprabasilar) or in the lower half of stratum spinosum. In pemphigus foliaceus, pemphigus herpetiformis and pemphigus erythematosus, acantholysis occurs in the granular cell layer or upper stratum spinosum. Autoantibodies to the intercellular cement substance of the epidermis are present in all the variants.

The changes in the concept of pemphigus over time has been reviewed.^1,2 The term “pemphigus,” itself, was first proposed by Boissier de Sauvages in his classification of skin diseases.³ He described pemphigus maior as an acute, febrile, blistering disease lasting only two weeks. Today, the diagnosis would probably be erythema multiforme.

Wichmann^4,5 was the first to describe pemphigus as a chronic bullous disease; he used the term, febris bullosa, to describe bullous eruptions of short duration. Unfortunately, few authors agreed with Wichmann's more restricted concept, and continental dermatologists continued to use the term pemphigus for a wide range of vesicular or bullous diseases. For example, Gilibert,⁶ in his monograph on pemphigus, included almost every disease with bullae in his classification. His “chronic pemphigus” most closely corresponds to the modern concept of pemphigus. Von Martius⁷ had an equally liberal definition of pemphigus, dividing it into 97 types.

Willan had a much more restricted view of the disease. In his classification of skin diseases, pemphigus vulgaris was a febrile, bullous eruption of short duration.⁸ He applied the term “pompholyx duitinus” to a chronic, bullous eruption, without inflammation and fever, similar to the modern concept of pemphigus vulgaris.     

Childhood cicatricial pemphigoid with linear IgA deposits: a case report

A 16-year-old boy with a bullous eruption from the age of thirteen, also presented symptoms of scarring conjunctivitis and involvement of oral mucosal membranes. Linear IgA deposits were demonstrated in the basement membrane zone in skin and conjunctiva. The eruptions improved during therapy with aldesulfonsodium, but complete remission was not obtained. Gluten-free diet did not significantly influence the activity of the disease. The described patient seems to fit in a recently described entity of chronic bullous diseases.     

Linear IgA Bullous Dermatosis in a Neonate

Abstract: A newborn black boy had two facial blisters at birth that progressed to bullous lesions over the trunk, genitals, extremities, and oral and tracheal mucosa. A biopsy specimen demonstrated a subepidermal bulla with mixed eosinophilic and neutrophille, inflammatory infiltrate. Direct immunofluorescence showed linear IgA, IgG, and C3 depositions along the basement membrane zone, consistent with a diagnosis of childhood linear IgA bullous dermatosis (chronic bullous dermatosis of childhood). The skin disease was controlled with combined prednisone and dipsone. This is the youngest reported patient with the disease. Linear IgA bullous dermatosis should be considered in the differential diagnosis of blistering diseases of the newborn, and immunofluorescence should be performed on a skin biopsy specimen.     

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。     

Linear IgA bullous dermatosis in a patient with acute lymphocytic leukemia: possible involvement of granulocyte colony-stimulating factor

We describe a case of linear IgA bullous dermatosis (LABD) in a patient with acute lymphocytic leukemia during treatment with granulocyte colony-stimulating factor (G-CSF). After a drug eruption due to imipenem cilastatin sodium had disappeared, bullous lesions appeared on the trunk. Results of histopathological studies and direct immunofluorescence studies of the lesion were consistent with LABD. Reinstitution of G-CSF after the resolution, however, did not reproduce the bullous eruptions. This suggests that in addition to G-CSF, the presence of precipitating factors that can synergistically enhance or accelerate the outbreak of the disease is required for the development of bullous lesions. Various cytokines, such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), endogenously produced from activated lymphocytes during the drug eruption might have provided a favorable milieu for the onset of G-CSF-induced LABD. We suggest that patients with LABD will need special attention with respect to the type of cytokines or combination of cytokines given as therapeutic modalities.     

Subacute cutaneous lupus erythematosus with bullae associated with porphyria cutanea tarda

A 58‐year‐old patient presented with both annular and polycyclic as well as vesicular lesions. Histology revealed an interface dermatitis with focal hyperkeratosis and subepidermal blistering. Antinuclear antibodies were elevated (1 : 1280) and autoantibodies against Ro‐SS‐A were found. Based on these findings we made a diagnosis of subacute cutaneous lupus erythematosus (SCLE) with blister formation. Additionally, we diagnosed porphyria cutanea tarda (PCT) triggered by alcohol abuse. Treatment with systemic corti‐costeroids and low‐dose hydroxy‐chloroquine led to rapid resolution of the skin changes. SCLE with blister formation is a rare cause of bullous skin eruptions and has to be distinguished from bullous autoimmune diseases as well as from bullous SLE. Recognition of concomitant PCT, which may be associated with all forms of LE, is especially important because of the therapeutic implications, since a reduced dosage of antimalarials is required.