Linear IgA bullous dermatosis associated with ulcerative colitis: A case report and literature review

We report the case of a 59-year-old Japanese woman who developed linear IgA bullous dermatosis during treatment for ulcerative colitis that manifested as pruritic vesicles with erythema on the trunk and scalp. Histopathological examination revealed subepidermal bulla with neutrophil and eosinophil infiltration in the upper dermis. Direct immunofluorescence revealed linear IgA deposits at the basement membrane zone, and indirect immunofluorescence using split skin revealed IgA reaction to the epidermal side (lamina lucida type). We reviewed 33 reported cases of linear IgA bullous dermatosis associated with ulcerative colitis and found that ulcerative colitis preceded the onset of linear IgA bullous dermatosis in 94% of the patients and that IgA-positive patients in split skin indirect immunofluorescence all showed the lamina lucida type, indicating that target antigens for serum IgA antibodies may reside in the lamina lucida. Regarding the pathogenetic association of ulcerative colitis and linear IgA bullous dermatosis, intestinal inflammation may induce the exposure and presentation of intestinal antigens that are cross-reactive to cutaneous antigens, stimulating autoimmune response to antigens of cutaneous basement membrane zones.     

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.     

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.     

Case of linear immunoglobulin A bullous dermatosis associated with acquired hemophilia

Linear immunoglobulin (Ig)A bullous dermatosis is a rare autoimmune subepidermal bullous dermatosis caused by circulating IgA autoantibodies directed against the antigens at the basement membrane zone. Most linear IgA bullous dermatosis cases are idiopathic, but some are associated with the use of certain drugs, infections, lymphoproliferative disorders, internal malignancies, autoimmune disorders, collagen diseases or, very rarely, other skin diseases, including autoimmune bullous diseases. Acquired hemophilia is also rare; it is a coagulation disease caused by anti-factor VIII IgG antibodies. Acquired hemophilia has been reported to be associated with malignant tumors, pregnancy or postpartum, drug reactions, collagen diseases such as rheumatoid arthritis, autoimmune disorders, and skin diseases such as psoriasis and pemphigus. We report a case of hemophilia acquired during the course of linear IgA bullous dermatosis and review reported cases of autoimmune bullous dermatoses associated with acquired hemophilia.     

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.     

The lesional skin of linear IgA bullous dermatosis expresses growth-regulated peptide (GRO)-alpha

The patient was a 62-year-old man with erythema with tense vesiculobullae and erosions on the bilateral elbows, right knee, and one buttock. A skin biopsy specimen revealed subepidermal blister formation with a predominant infiltration of neutrophils and papillary neutrophilic microabscesses. Direct immunofluorescence study showed linear deposition of IgA and weak deposition of IgG at the basement membrane zone of the lesional skin, and indirect immunofluorescence study showed linear deposition of IgA at the epidermal side of the 1M NaCl-separated normal skin. He was diagnosed with linear IgA bullous dermatosis. Immunohistochemical study revealed that the lesional and perilesional keratinocytes expressed growth-regulated peptide (GRO) -alpha, a potent chemoattractant for neutrophils. This suggests that GRO-alpha plays a role in the infiltration of neutrophils into the lesional skin and in bulla formation in linear IgA bullous dermatosis.     

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.     

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.     

Use of 1M NaCl split skin in the indirect immunofluorescence of the linear IgA bullous dermatoses

We compared 1M NaCl split skin with intact skin as substrates for detection of circulating IgA anti-basement membrane (BMZ) antibodies in linear IgA dermatosis (LAD). The sera of 63 patients with LAD including 27 adults and 36 with chronic bullous dermatosis of childhood (CBDC) were examined. 62% of patients overall had circulating IgA anti-BMZ antibodies detectable on intact skin. 73% of patients had circulating antibodies detectable on lM NaCl split skin as an additional 7 sera were positive. This was a statistically significant increase (p<0.01). The sera were mostly positive at a higher titre on the split skin when compared with intact skin. On routine indirect immunofluorescence (IIF) all positive sera produced linear fluorescence on the epidermal side of the split. Twenty serum samples were incubated with split skin overnight; 4 of these specimens exhibited linear fluorescence on the epidermal and dermal sides of the split after this prolonged incubation. These findings suggest that 1M NaCl split skin is a more sensitive substrate for detection of circulating IgA anti-BMZ antibodies in LAD, that these antibodies are heterogeneous and that the target antigen has an epidermal component.     

Detection of Autoantibody against 97-kD Antigen by Immunoblot,but not by Indirect Immunofluorescence,in a Patient with Linear IgA Bullous Dermatosis

A case of linear IgA bullous dermatosis in an 85-year-old man is reported. Direct immunofluorescence (IF) of the lesional skin showed linear deposition of IgA and weak deposition of IgG at the basement membrane zone. Although no circulating autoantibody was detected by indirect IF, immunoblotting analysis using NaCl-separated normal human epidermal extracts revealed a circulating IgA antibody which bound to the 97-kD antigen.     

C3d immunohistochemistry on formalin‐fixed tissue is a valuable tool in the diagnosis of bullous pemphigoid of the skin

Background: Direct immunofluorescence (DIF) testing is an important procedure in the diagnosis of autoimmune bullous dermatoses. We investigated the expression of C3d in formalin‐fixed, paraffin‐embedded tissue of autoimmune bullous dermatoses. Methods: The immunohistochemical expression of C3d in bullous pemphigoid (BP) (n = 32), pemphigoid gestationis (PG) (n = 3), pemphigus (n = 14), dermatitis herpetiformis Duhring (DHD) (n = 10), linear immunoglobulin A (IgA) dermatosis (n = 4), mixed forms of BP and linear IgA dermatosis (n = 2), and 44 controls was analyzed on formalin‐fixed tissue. Results: Thirty‐one of 32 cases (97%) of BP and 3 out of 3 cases (100%) of PG showed a linear positivity of C3d along the basement membrane. Only 3 out of 14 (21%) cases of pemphigus showed an intraepidermal intercellular expression of C3d. The two mixed forms of linear IgA dermatosis and BP showed a linear positivity of C3d along the basement membrane. All cases of DHD, linear IgA dermatosis and all of the controls were negative for C3d. Conclusions: C3d immunohistochemistry is a valuable tool in the diagnosis of BP and PG of the skin with a sensitivity of at least 97%. Mixed forms of linear IgA dermatosis, and BP, DHD and linear IgA dermatosis can only be identified by DIF. A positive result may prompt serologic confirmation of BP without further need for DIF. Pfaltz K, Mertz K, Rose C, Scheidegger P, Pfaltz M, Kempf W. C3d immunohistochemistry on formalin‐fixed tissue is a valuable tool in the diagnosis of bullous pemphigoid of the skin.     

False-negative results in immunoblot assay of serum IgA antibodies reactive with the 180-kDa bullous pemphigoid antigen: the importance of primary incubation temperature

BACKGROUND: Different subepidermal autoimmune blistering skin disorders are characterized by linear deposition of IgA, sometimes accompanied by linear IgG, along the epidermal basement membrane zone. Identification of the targeted autoantigen is usually attempted by immunoblotting. Although immunoblotting works well for human IgG, the method is less successful for IgA and often no or only faint signals are obtained. OBJECTIVES: To improve the method of immunoblotting for diagnosis of IgA-mediated bullous dermatoses. METHODS: Eleven sera, selected from patients with linear deposition of IgA along the epidermal basement membrane zone in vivo, were tested by immunoblotting for antigen specificity using different primary incubation temperatures. RESULTS: No reliable information regarding IgA antigen specificity was obtained when the primary incubation was undertaken at room temperature. In 10 of 11 sera, IgA bound to the 180-kDa bullous pemphigoid antigen (BP180) when the primary incubation temperature was increased to 37 degrees C. CONCLUSIONS: Primary incubation at room temperature may result in false-negative results in the IgA-BP180 immunoblot assay.     

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.     

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 chronic renal failure: response to intravenous immunoglobulin therapy

Linear IgA bullous dermatosis is a blistering disease with a heterogeneous clinical manifestation, characterized by deposition of IgA along the basement membrane zone of perilesional skin on direct immunofluorescence. We describe a patient with chronic renal failure who experienced linear IgA bullous dermatosis. Long-term administration of intravenous immunoglobulin therapy was associated with clinical remission lasting more than 12 months.     

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.     

Treatment of dermatitis herpetiformis and linear IgA bullous dermatosis

Dermatitis herpetiformis (DH) and linear IgA bullous dermatosis (LABD) are IgA-mediated autoimmune bullous diseases. They share an identical histopathology, but are differentiated on the basis of the pattern of IgA deposition on direct immunofluorescence. While DH responds to a gluten-free diet, LABD rarely responds to gluten restriction. In the management of DH, adhering to a gluten-free diet promotes healing of small intestine villus atrophy, resolution of cutaneous disease, and lowers the risk of lymphoma. Dapsone is palliative but not curative in the treatment of DH and LABD. Patients taking systemic dapsone or sulfa-based medication for the treatment of DH or LABD should have a reasonable knowledge of the inherent side effects.     

Bullöse Autoimmunkrankheiten bei Kindern

We review the pathogenesis, clinical features, diagnosis, differential diagnosis, and therapy of autoimmune bullous skin diseases of childhood, especially of the most common linear IgA dermatosis. In autoimmune bullous diseases, autoantibodies are formed against different adhesion molecules of the skin. These are not only pathophysiologically relevant, but also serve as basis for diagnosis and follow-up of these diseases. In case an autoimmune bullous disease is suspected, histopathology and immunohistopathology (direct immunofluorescence microscopy) as well as serological tests (indirect immunofluorescence microscopy, ELISA, immunoblot) should be performed. Therapy depends on the diagnosis. In IgA-mediated pathogenesis, dapsone can be successfully used. In IgG-mediated diseases, immunosuppression with corticosteroids and steroid-sparing agents should be initiated, although only local therapy is sufficient to control a self-limiting pemphigus neonatorum. In dermatitis herpetiformis, a life-long gluten-free diet is recommended.     

Linear IgA bullous dermatosis of adults and children: an immunoelectron microscopic study

The ultrastructural localization of the IgA deposits in the skin of 15 patients with linear IgA bullous dermatosis of adults (LAD), 13 with chronic bullous dermatosis of childhood (CBDC) and three with childhood cicatricial pemphigoid (CCP) were studied. The site of the antigen was determined using sera from two LAD, 13 CBDC and two CCP patients. In all 31 patients the IgA was located predominantly below the lamina lucida (sublamina densa). Similarly, the indirect immunoelectron microscopic studies demonstrated the antigen to be present at the same site, below the lamina densa. This suggests that in linear IgA bullous dermatosis the antibody reacts with the antigen in the sublamina densa region of the basement membrane zone.     

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.