Epidermolysis Bullosa Acquisita Antibodies Research Articles

The Cartilage Matrix Protein Subdomain of Type VII Collagen Is Pathogenic for Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is an acquired bullous disease of the skin characterized by IgG autoantibodies against type VII (anchoring fibril) collagen. We previously defined four immunodominant antigenic epitopes within the noncollagenous 1 (NC1) domain of type VII collagen. In this study, we produced an additional recombinant fusion protein from the NC1 domain corresponding to the N-terminal 227 amino acids (residues 1 to 227), which contains homology with cartilage matrix protein (CMP). Using enzyme-linked immunosorbent assay and immunoblot analysis, we tested sera from EBA patients (n = 32), bullous systemic lupus erythematosus patients (n = 3), bullous pemphigoid patients (n = 15), and normal humans (n = 12). Twenty-six of 32 EBA sera and two of three bullous systemic lupus erythematosus sera reacted with the CMP domain, whereas none of the control sera did. Affinity-purified anti-CMP EBA antibodies injected into hairless mice produced the clinical, histological, immunological, and ultrastructural features of EBA. F(ab')(2) fragments generated from anti-CMP EBA autoantibodies did not induce disease. Our studies provide the first evidence that EBA autoantibodies to the CMP subdomain of NC1 are pathogenic and induce blister formation. This is the first antigenic epitope on type VII collagen demonstrated to be a pathogenic target for EBA autoantibodies.

Case of concurrent epidermolysis bullosa acquisita and anti‐p200 pemphigoid – how to treat it?

Epidermolysis bullosa acquisita (EBA) is an uncommon, chronic, acquired, autoimmune, subepidermal blistering disease. The etiology of the disease is unknown. EBA antibodies bind to type VII collagen within anchoring fibrils at the dermo-epidermal junction. This results in a decreased number of anchoring fibrils, which therefore do not anchor the epidermis and its underlying basement membrane to the papillary dermis. To date, five clinical presentations of EBA have been described. 1 In general, the clinical features of classical EBA include increased skin fragility and skin lesions on the areas predisposed to trauma. EBA also affects the mucous membranes. The first two cases of EBA were reported and distinguished from dystrophic epidermolysis bullosa by Elliot in 1895. We present a patient with clinical, histological and immunological features of a mixture of EBA and anti-p200 pemphigoid.

A case of linear IgA buUous dermatosis with IgA anti-type VII collagen autoantibodies

In this study we present a patient with the sublamina densa type of linear IgA bullous dermatosis (LABD), with IgA autoantibodies reactive with the 290-kDa type VII collagen (the epidermolysis bullosa acquisita (EBA) antigen) and with immunoblotting of normal human dermal extracts. The clinical and histological features of the present case were compatible with those of LABD but quite different from those of EBA. Although EBA sera reacted with the bacterial fusion protein of the N-terminal globular (NC1) domain of type VII collagen, this patient's serum did not show reactivity. Furthermore, ultrastructural localization of target epitopes on the anchoring fibrils in this patient was considerably different from EBA. These results indicate that, whereas EBA antibodies react with the NC1 domain of type VII collagen, the epitope in this case is different from that of EBA (and is most likely on the central triple helical domain). This difference may be responsible for the clinical presentation in this patient being distinct from that of EBA.

Studies on Complement Deposits in Epidermolysis Bullosa Acquisita and Bullous Pemphigoid

Epidermolysis bullosa acquisita (EBA) is an inflammatory subepidermal blistering disease characterized by circulating and tissue-bound autoantibodies specific for type VII collagen of the basement membrane zone. The antibodies consist of both complement- and noncomplement-binding populations and belong to all four subclasses of IgG. We investigated the presence of the membrane attack complex C3b, C5, and S protein in EBA and compared C3b and C5 in EBA and bullous pemphigoid. In 10 patients with EBA, these components were detected at the basement membrane zone as follows: membrane attack complex, 90%; S protein, 90%; direct C5, 90%; C3b, 100%; and C5 binding, 90%. In the patients with bullous pemphigoid, the results were as follows: direct C5, 58%; C3b, 33%; and C5 binding, 19%. These results provide additional evidence for complement activation at the basement membrane zone in EBA, show that complement activation in EBA proceeds to activation of terminal complement components, and suggest that EBA antibodies are more potent activators of C5 than are bullous pemphigoid antibodies.

The Subclass Distribution of IgG Autoantibodies in Cicatricial Pemphigoid and Epidermolysis Bullosa Acquisita

To study the subclass distribution of autoantibodies and their complement-fixing capacity in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA) we studied the sera from 23 patients by both indirect immunofluorescence (IIF) on 4-microns cryostat sections of normal human skin and immunoblotting of epidermal or dermal extracts. Monoclonal antibodies of strict specificity for human IgG subclasses were used. Sera from 20 patients with BP served as controls. In addition, total IgG subclass levels were determined by indirect competitive ELISA in all sera. Complement binding capacity was studied by IIF using antibodies to C3 after incubation of skin section with autoantibodies and source of fresh complement. CP autoantibodies reacting with the 230-240 kD and/or the 180-kD epidermal bands showed an IgG4/IgG1 subclass restriction, with a predominance of IgG4 in 10 cases, of IgG1 in four. In BP sera, IgG4 and IgG1 autoantibodies were detected with a similar frequency (100% and 83%, respectively). In EBA sera, autoantibodies reacting with the 290 kD and 145 kD dermal bands also showed an IgG1/IgG4 restriction. Concordant results were obtained by IIF. However, the IIF method had a lower sensitivity for the detection of IgG4 CP antibodies and IgG1 EBA antibodies than immunoblotting. Finally, when CP antibodies were analyzed for their complement-binding activity, it was found that sera containing IgG4 autoantibodies alone never fixed complement whereas all complement-fixing CP sera had IgG1 autoantibodies, suggesting that only this subclass of antibodies is capable of fixing complement.

Heavy and Light Chain Isotypes of Immunoglobulin in Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a chronic acquired blistering disease with characteristic clinical, pathologic, and immunopathologic features. The disease is characterized immunopathologically by circulating and tissue-bound IgG class autoantibodies (EBA antibodies) to the basement membrane zone of stratified squamous epithelium. Previous studies have shown that circulating and tissue-bound EBA antibodies are heterogenous in their ability to activate complement and have raised the possibility that functional heterogeneity might be related to IgG subclass restriction. In this study, we have characterized the IgG subclasses of the circulating and tissue-bound EBA antibodies by immunofluorescence and have examined the relationship between IgG subclass and complement binding. The results show that EBA antibodies belonging to all IgG subclasses are present in the skin of EBA patients. The results also show that EBA antibodies belonging to all IgG subclasses are present in the sera of most patients, including sera with and without complement binding EBA antibodies.

Epidermolysis bullosa acquisita antigen and the carboxy terminus of type VII collagen have a common immunolocalization to anchoring fibrils and lamina densa of basement membrane

In this study a variety of immunoelectron microscopic methods were used to define the precise ultrastructural binding site of epidermolysis bullosa acquisita antibodies (EBA-Ab). We used two EBA sera which immunoblotted with the same skin-extracted protein as that labelled by a monoclonal antibody (LH7.2) which is known to react with the carboxy terminus of type VII collagen. Gold-conjugated antibodies were used in two different immunoelectron microscopic procedures to compare the labelling characteristics of EBA-Ab and LH7.2 in normal human skin. Antibody incubations were performed using ultra-thin cryosections of unfixed skin and thin slices of fresh skin (en bloc technique) before conventional fixation and embedding in Epon. Both methods showed similar labelling features for both EBA-Ab and LH7.2. With ultra-thin cryosections there was labelling of the lamina densa and an undefined component of the sublamina densa region. With the en bloc technique, labelling of dermal ends of anchoring fibrils and of amorphous material recently defined as 'anchoring plaques' was evident. There was no labelling of the central banded portions of anchoring fibrils. We conclude that EBA-Ag is localized to the dermal ends of anchoring fibrils in addition to the lamina densa and possibly anchoring plaques, and thus has the same distribution as the carboxy terminus of type VII collagen.

Effect of influenza vaccination on serial MEI-images of MS patients : Scientific meeting of the Flemish Society of Neuro-Psychiatry, held in Kortrijk, 15th April 1989

Epidermolysis bullosa acquisita (EBA) is a chronic acquired blistering disease with characteristic clinical, pathologic, and immunopathologic features. The disease is characterized immunopathologically by circulating and tissue-bound IgG class autoantibodies (EBA antibodies) to the basement membrane zone of stratified squamous epithelium. Previous studies have shown that circulating and tissue-bound EBA antibodies are heterogenous in their ability to activate complement and have raised the possibility that functional heterogeneity might be related to IgG subclass restriction. In this study, we have characterized the IgG subclasses of the circulating and tissue-bound EBA antibodies by immunofluo- rescence and have examined the relationship between IgG subclass and complement binding. The results show that EBA antibodies belonging to all IgG subclasses are present in the skin of EBA patients. The results also show that EBA antibodies belonging to all IgG subclasses are present in the sera of most patients, including sera with and without complement binding EBA antibodies.

Neuropathology of Aids and the Aids-dementia complex : Scientific meeting of the Flemish Society of Neuro-Psychiatry, held in Kortrijk, 15th April 1989

Epidermolysis bullosa acquisita (EBA) is a chronic acquired blistering disease with characteristic clinical, pathologic, and immunopathologic features. The disease is characterized immunopathologically by circulating and tissue-bound IgG class autoantibodies (EBA antibodies) to the basement membrane zone of stratified squamous epithelium. Previous studies have shown that circulating and tissue-bound EBA antibodies are heterogenous in their ability to activate complement and have raised the possibility that functional heterogeneity might be related to IgG subclass restriction. In this study, we have characterized the IgG subclasses of the circulating and tissue-bound EBA antibodies by immunofluo- rescence and have examined the relationship between IgG subclass and complement binding. The results show that EBA antibodies belonging to all IgG subclasses are present in the skin of EBA patients. The results also show that EBA antibodies belonging to all IgG subclasses are present in the sera of most patients, including sera with and without complement binding EBA antibodies.

Organ-Specific, Phylogenetic, and Ontogenetic Distribution of the Epidermolysis Bullosa Acquisita Antigen

The organ-specific, phylogenetic, and ontogenetic distribution of the epidermolysis bullosa acquisita (EBA) antigen, a newly recognized basement membrane component, was determined using polyclonal sera from patients with EBA and a mouse monoclonal antibody, H3a. Both antibodies are distributed at the basement membrane zone of skin, oral, anal, and vaginal mucosae, and esophagus, but not in kidney, urinary bladder, lymph nodes, placenta, or blood vessels. Both polyclonal and monoclonal EBA antibodies react with a basement membrane antigen in primate and other mammalian skin, but not in avian, amphibian, or reptilian skin. The antigen is present initially in the 8-week-old human fetus, and increases in density until the adult linear pattern is reached at 15 weeks' gestational age.

Selected optic lobe extracts stimulating retinal neurite outgrowth : N.G. Carri ∗ and T. Ebendal, ∗IMBICE, CC 403, 1900 La Plata, Argentine Republic and Department of Zoology, Uppsala University, Box 561, Uppsala, Sweden

Epidermolysis bullosa acquisita (EBA) is a chronic acquired blistering disease with characteristic clinical, pathologic, and immunopathologic features. The disease is characterized immunopathologically by circulating and tissue-bound IgG class autoantibodies (EBA antibodies) to the basement membrane zone of stratified squamous epithelium. Previous studies have shown that circulating and tissue-bound EBA antibodies are heterogenous in their ability to activate complement and have raised the possibility that functional heterogeneity might be related to IgG subclass restriction. In this study, we have characterized the IgG subclasses of the circulating and tissue-bound EBA antibodies by immunofluo- rescence and have examined the relationship between IgG subclass and complement binding. The results show that EBA antibodies belonging to all IgG subclasses are present in the skin of EBA patients. The results also show that EBA antibodies belonging to all IgG subclasses are present in the sera of most patients, including sera with and without complement binding EBA antibodies.

Evidence That Anti-Basement Membrane Zone Antibodies in Bullous Eruption of Systemic Lupus Erythematosus Recognize Epidermolysis Bullosa Acquisita Autoantigen

Circulating and tissue-deposited IgG antibodies to the cutaneous basement membrane zone (BMZ) were detected in 3 patients with the clinical, pathologic, and immunologic features of bullous eruption of systemic lupus erythematosus (SLE). The antibodies were present in sera and IgG fractions in all cases and in eluates of cutaneous immune deposits from one of the cases. The antibodies were easily detected in sera by indirect immunofluorescence on adult human thigh skin separated through the lamina lucida by incubation in 1.0 M NaCl but were less easily detected on intact neonatal foreskin. The antibodies had features of epidermolysis bullosa acquisita (EBA) anti-BMZ antibodies including binding to the dermal side of the BMZ in separated skin, binding to the cutaneous but not vascular or glomerular basement membranes, binding to and just below the lamina densa, and binding to 290 or 290 and 145 kD dermal proteins previously identified as components of the EBA autoantigen. The antibodies were relatively specific for SLE patients with features of bullous eruption of SLE since they were detected in 3 of 4 of those cases and in only 1 of 20 SLE patients without blisters. These results show anti-BMZ antibodies with features of EBA antibodies are present in patients with bullous eruption of SLE and suggest there may be a close relationship between that disease and EBA. The results also suggest that EBA antibodies may be part of the autoantibody spectrum of SLE and that separated skin is more sensitive than intact skin for their detection.

Epidermolysis bullosa acquisita—a pemphigoid-like disease

Epidermolysis bullosa acquisita (EBA) is an immunologically distinctive disease with characteristic clinical features. These include extreme skin fragility, trauma-induced blisters and erosions, and healing with scars and milia. These clinical features are currently the major means of routinely distinguishing EBA from bullous pemphigoid (BP) and cicatricial pemphigoid (CP). In this study we describe five patients with EBA who presented with or developed clinical as well as histologic and immunohistologic features indistinguishable from those characteristic of BP or CP. At different times during the course of their disease, it closely resembled classic BP or CP and cases of BP or CP with atypical features or evolving features of EBA. To determine how often EBA might present and be misdiagnosed as BP, we reviewed our experience with bullous diseases and screened eighty-five "BP" sera for EBA antibodies. The results of this study show EBA can mimic the clinical, histologic, and immunohistologic features of BP and CP, suggest that a BP-like clinical presentation occurs in as many as 50% of EBA patients, and suggest that 10% of patients referred to medical centers and diagnosed as BP have EBA.

Differences in Complement-Dependent Chemotactic Activity Generated by Bullous Pemphigoid and Epidermolysis Bullosa Acquisita Immune Complexes: Demonstration by Leukocytic Attachment and Organ Culture Methods

Bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA) are chronic blistering diseases associated with circulating complement (C)-binding anti-basement membrane zone (BMZ) antibodies and tissue-deposited immune complexes at the BMZ. Experimental evidence supporting a role for C-activating immune complexes in the pathogenesis of dermal inflammation and blisters has been reported in BP but not in EBA. In this study tissue-deposited immune complexes composed of EBA or BP antibodies were tested for generation of C-dependent chemotactic activity and the capacity to cause dermal leukocyte infiltration and dermal-epidermal separation (DES). Chemotactic activity was measured by the leukocyte attachment (LA) method. The capacity of complexes to mediate leukocyte infiltration and DES was examined in vitro using a newly described organ culture method. The results of LA showed immune complexes formed in vivo in EBA skin or in vitro by treating normal human skin with EBA antibodies were significantly more active in mediating C-dependent chemotaxis than complexes in BP skin or those formed with BP antibodies of equivalent or higher C-binding titers. Furthermore EBA antibodies and C caused leukocyte infiltration and DES in organ culture while BP antibodies did not. These results support a role for C-binding anti-BMZ antibodies in the pathogenesis of EBA lesions and demonstrate differences in the capacity of BP and EBA immune complexes to generate C-dependent chemotactic activity. These results suggest factors in addition to C-binding titers are important in the activation of C by BP and EBA immune complexes and suggest chemotactic factors other than those derived from C activation may be important in the recruitment of leukocytes in BP.