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At least 19 recordsLinked to original sources
PubMed1985

Cicatricial pemphigoid, bullous pemphigoid, and epidermolysis bullosa acquisita antigens: differences in organ and species specificities and localization in chemically-separated human skin of three basement membrane antigens.

Bullous pemphigoid, cicatricial pemphigoid, and epidermolysis bullosa acquisita are three autoimmune diseases characterized by the presence of subepidermal blisters, in vivo-bound immunoreactants along the dermoepidermal junction, and variably detectable circulating anti-basement membrane autoantibodies. In order to better characterize the antigen(s) defined by cicatricial pemphigoid sera, indirect immunofluorescence was performed on a variety of human organs, skins of different animals, and on human skin chemically-split within the lamina lucida, comparing sera from cicatricial pemphigoid patients with sera from these two other blistering diseases. Sera from patients with each disease bound to the dermoepidermal junction of every laboratory animal species examined. In contrast, more mucosal tissues were bound by anti-basement membrane autoantibodies from patients with cicatricial pemphigoid and epidermolysis bullosa acquisita than from patients with bullous pemphigoid, consistent with the marked tendency for mucosal involvement in patients with the former two diseases. In addition, one of the cicatricial pemphigoid sera stained basal cell surfaces as well as dermoepidermal junction. Differences were also apparent in the staining of chemically-split human skin. The combined findings suggest that cicatricial pemphigoid and bullous pemphigoid antigens are distinct despite their common localization within the lamina lucida of the dermoepidermal junction. These data also suggest the presence of at least two different cicatricial pemphigoid antigens.

Adult↗
PubMed1985

Epidermolysis bullosa: variability of expression of cicatricial pemphigoid, bullous pemphigoid, and epidermolysis bullosa acquisita antigens in clinically uninvolved skin.

Indirect immunofluorescence was performed on skin from 13 patients with epidermolysis bullosa (EB) (simplex, 6; junctional, 2; dystrophic, 5) to compare the expression of 3 basement membrane components, bullous pemphigoid (BP) antigen, cicatricial pemphigoid (CP) antigen, and epidermolysis bullosa acquisita (EBA) antigen, in clinically uninvolved tissue. In addition, expression of laminin, type IV collagen, and KF-1 antigen was also evaluated. Whereas laminin, type IV collagen, and KF-1 antigen were each detectable in EB skin in a manner identical to that previously reported, marked variability was noted in the expression of BP, CP, and EBA antigens. However, no correlation was noted comparing lack of expression of any one of these latter antigens with either of the remaining two. Of these 3 antigens, BP antigen was the least often detectable, particularly in skin from patients with EB simplex. The lack of detectable BP antigen in EB simplex skin appeared to correlate with more extensive disease involvement and/or younger patient age. These findings may, therefore, limit the usefulness of BP serum in immunofluorescence mapping. Additionally, the disparity in expression of basement membrane antigens defined by BP and CP sera suggests that BP antigen and CP antigen are distinct entities.

Antigens↗
PubMed2001

Respective contribution of neutrophil elastase and matrix metalloproteinase 9 in the degradation of BP180 (type XVII collagen) in human bullous pemphigoid.

Bullous pemphigoid is a blistering disorder associated with autoantibodies directed against two components of hemidesmosomes, BP180 and BP230. Autoantibodies to the extracellular collagenous domain of BP180 are thought to play a key role in the pathogenesis of the disease. In a murine model of bullous pemphigoid, neutrophil elastase and 92 kDa gelatinase (matrix metalloproteinase 9) have been implicated in subepidermal blister formation via proteolytic degradation of BP180. In this study we sought to elucidate the contribution of these two enzymes to subepidermal blister formation by assessing the expression, localization, and activity of the two proteases in lesional skin, serum samples, and blister fluids obtained from 17 patients with bullous pemphigoid. The results indicate that (i) neutrophil elastase is found in skin biopsy specimens from bullous pemphigoid lesions and is recovered as active enzyme in blister fluids, and (ii) although proform of matrix metalloproteinase 9 is present in lesional skin, it is present only as proenzyme in blister fluids, which also contain high levels of tissue inhibitor of metalloproteinase-1. Next, the capacity of matrix metalloproteinase 9 and neutrophil elastase to degrade a recombinant protein corresponding to the extracellular collagenous domain of the BP180 was studied. Our data illustrate that (i) recombinant matrix metalloproteinase 9, neutrophil elastase, and blister fluid from bullous pemphigoid patients are all able to hydrolyze recombinant BP180; (ii) the pattern of recombinant BP180 proteolysis with blister fluid was similar to that obtained with neutrophil elastase; and (iii) recombinant BP180 degradation by blister fluid could be inhibited by chloromethylketone, a specific elastase inhibitor, but not by batimastat, a wide spectrum matrix metalloproteinase inhibitor. Our results confirm the importance of neutrophil elastase but not matrix metalloproteinase 9 in the direct cleavage of BP180 autoantigen and subepidermal blister formation in human bullous pemphigoid.

Aged↗
PubMed1987

Bullous pemphigoid.

Bullous pemphigoid is an autoimmune blistering dermatologic disease characterized clinically by tense bullae that may develop on normal or erythematous skin. The major histologic feature is a subepidermal blister with variable degrees of dermal inflammation. Other immunologically mediated blistering skin diseases may mimic bullous pemphigoid, including herpes gestationis, cicatricial pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita. These diseases will be discussed. Most patients with bullous pemphigoid demonstrate circulating autoantibodies reactive with an antigen located in the lamina lucida region of the basement membrane zone. Complement activation by these autoantibodies initiates influx and activation of mast cells along with other inflammatory cells. Tissue injury with damage and eventual destruction of the basement membrane occurs as a result of the release of inflammatory mediators. The final result is subepidermal blister formation. The course of bullous pemphigoid tends to be self-limited, and successful treatment is usually effected with systemic glucocorticosteroids.

Animals↗
PubMed1993

Bullous pemphigoid.

Bullous pemphigoid is an acquired subepidermal blistering disease of the elderly characterized by tense blisters. Patients with bullous pemphigoid have circulating and tissue-bound antibodies that are directed against a normal component of the epidermal basement membrane. The course of bullous pemphigoid tends to be self-limited, and effective treatment is often affected with systemic glucocorticosteroids.

Diagnosis, Differential↗
PubMed1984

Deposition of the membrane attack complex of complement in bullous pemphigoid.

Bullous pemphigoid is associated with deposition of IgG and C3 at the dermal-epidermal junction. In order to see whether complement activation in bullous pemphigoid resulted in deposition of membrane attack complex (MAC) at the basement membrane zone, skin biopsies from patients with bullous pemphigoid were examined using a direct immunofluorescence technique. By employing a monoclonal antibody to a neoantigen of C9, the MAC was demonstrated in linear pattern at the basement membrane zone. These deposits were seen in both involved and uninvolved skin but the amount of MAC was greater in involved skin as judged by intensity of staining. Stippled deposits of MAC were also present in or around epidermal basal cells. The MAC could be generated in vitro by reaction of normal plasma with antibasement membrane antibody bound to sections of monkey esophagus. The IgG antibody activated complement and this complement activation proceeded all the way to the terminal step.

Basement Membrane↗
PubMed1994

Blistering on a squamous cell carcinoma graft site in a patient with bullous pemphigoid.

Bullous pemphigoid is a blistering disorder with blisters arising from normal, otherwise uninvolved tissue or from urticarial or erythematous plaques localized mainly on the trunk or upper extremities. Neoplasms, such as squamous cell carcinomas, have also been reported in patients with bullous pemphigoid. Large squamous cell carcinomas (greater than 8 cm in diameter) are best treated by surgical excision. We report a patient with bullous pemphigoid and squamous cell carcinoma who showed blisters on his graft site.

Blister↗
PubMed1988

[Use of the immunoblotting technic for the study of antibodies present in the serum of patients with bullous pemphigoid].

Bullous pemphigoid (BP) is an autoimmune disease characterized, at histology, by subepidermal bullous separations. Antibodies (Ab) and complement are present at the dermal-epidermal junction, and most patient with the disease have serum antibodies directed against a normal constituent of stratified epithelia (10, 25). During the past few years, the immunotransfer technique has been used to study autoimmune bullous diseases of the skin. The antigen (Ag) of bullous pemphigoid has been described by Stanley et al. (16, 17) as the polypeptidic doublet 220-240 KD. However, different results in favour of an heterogeneous antigen have been obtained by Labib et al. (11) who reported the presence of 5 separate polypeptides: 240, 200, 180, 97 and 77 KD. The purpose of the present study was to confirm on infirm these findings. We recorded the antigens recognized at immunotransfer by the circulating antibodies of BP patients, then extended this study to sera from BP patients in whom no antibody had been detected by indirect immunofluorescence (IIF). We report the results of our immunotransfer study in 9 seropositive and 9 seronegative BP patients and in 11 seronegative controls. The antigenic extract we used was prepared from suspensions of epidermal cells and represented the intracellular BP antigen. Epidermal cell suspensions were obtained by trypsinization of human abdominal skin. The cells were homogenized in a Tris-HCl 10 mM pH 7.8 buffer with SDS 2 p. 100 and B-mercaptoethanol 5 p. 100. The soluble proteins were analyzed in a polyacrylamide gel in the presence of SDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed2000

A spontaneously arising porcine model of bullous pemphigoid.

Bullous pemphigoid (BP) is an IgG-mediated autoimmune blistering disease targeting the hemidesmosomal proteins bullous pemphigoid antigens 1 and 2. Currently, there is no active animal model in which to dissect the immunopathogenic mechanism. We noticed that cutaneous blistering arose spontaneously in 12 adult Yucatan minipigs. Skin lesions consisted of turgid, isolated or clustered vesicles that occasionally evolved from erythematous and pruritic patches. Histopathological examination revealed subepidermal vesicles rich in intact and degranulated eosinophils. Antigen mapping and transmission electron microscopy confirmed that dermoepidermal separation took place in the lamina lucida of the epidermal basement membrane zone. Direct immunofluorescence revealed the presence of IgG deposited linearly at the dermoepidermal junction in seven of nine skin specimens examined. Indirect immunofluorescence testing confirmed the presence, in the serum from eight of eight affected pigs, of circulating basement membrane-specific IgG autoantibodies (titers 1 : 50 to 1 : 250). Using uncleaved and salt-split lip substrates, the autoantibodies were shown to target antigens situated not only at the basal, but also at the lateral and apical aspects of stratum basale keratinocytes. Immunoelectron microscopy confirmed that circulating IgG autoantibodies recognized hemidesmosomal antigen(s). ELISA, immunoblotting and immunoadsorption demonstrated that five of eight serum samples exhibited high immunoreactivity against BPAG2-NC16A peptides. This novel porcine acquired blistering dermatosis could be proposed as a valuable model to conduct immunomechanistic studies on the natural progression of BP, correlation of autoreactive T cells or autoantibodies with disease activity, and the role of eosinophils in the blistering process, as these diseases cannot be modeled easily in human patients or in murine passive transfer models.

Amino Acid Sequence↗
PubMed2002

Cloning of hamster type XVII collagen cDNA, and pathogenesis of anti-type XVII collagen antibody and complement in hamster bullous pemphigoid.

Bullous pemphigoid is an inflammatory subepidermal blistering skin disease associated with an IgG autoimmune response to the type XVII collagen. The immunopathologic features of bullous pemphigoid can be reproduced in mice by the passive transfer of anti-type XVII collagen antibodies. In this model, it is thought that blister formation depends upon complement activation, neutrophil recruitment, and some proteolytic enzymes. In this study, we cloned hamster type XVII collagen cDNA, which contains a 4296 bp coding region and which is predicted to be a transmembrane protein with an extracellular collagenous domain, residing in type II orientation. Antipeptide antibodies (anti-1191 IgG) were obtained against a segment of hamster type XVII collagen homologous with the human type XVII collagen autoantibody-reactive site. The antipeptide antibodies were passively transferred to neonatal Syrian hamsters. The injected hamsters developed a microscopic subepidermal blister as seen previously in the mice. In order to test whether antigen-antibody complexes and complement initiate the subepidermal blister formation, we carried out experiments in vitro on condition that inflammatory cells were completely eliminated. Complement activation in sera was inhibited either by heating (at 56 degrees C for 30 min) or by preincubating with cobra venom factor. When the hamster skin was incubated with fresh anti-1191 antisera, separation of dermal-epidermal junction was observed. The anti-1191 IgG failed to induce C3 deposition and dermal-epidermal junction separation, however, if the anti-1191 IgG was added alone or complement activation in sera was inhibited. Under these conditions, IgG but not C3 was deposited on the basement membrane. These results strongly suggest that antigen-antibody complexes and complement initiate dermal-epidermal junction separation.

Amino Acid Sequence↗
PubMed2000

Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid.

Bullous pemphigoid (BP), an autoimmune skin disease of the elderly, is mediated by autoantibodies that bind to hemidesmosomes of epidermal basal cells. This study investigated BP-associated HLA-DR and -DQ genes among Japanese patients. We analyzed HLA-DR and -DQ genes among 23 Japanese BP patients based on the polymerase chain reaction-restriction fragment length polymorphism. Eighteen of these 23 patients (78%) carried at least one allele of HLA-DRB1*04 or DRB1*1101, with significant increases in HLA-DRB1*04 (*0403, *0406)/DQA1*0301/DQB1*0302 and DRB1*1101/DQA1*0505/DQB1*0302 haplotypes as well as the individual alleles DRB1*1101 and DQB1*0302 (corrected p < 0.05 for each comparison), when compared to control subjects. These data differ from the accepted DQB1*0301 (DQ7) association with the same disease among Caucasians. These findings indicate that different HLA class II haplotypes genetically influence susceptibility to BP among different ethnic groups. Our findings, together with previous reports on Caucasian patients with the pemphigoid group of bullous diseases, suggest that HLA-DRB1 molecules might participate in the regulation of autoimmune responses to BP antigens.

Aged↗
PubMed1998

Evaluation of clinical criteria for diagnosis of bullous pemphigoid. French Bullous Study Group.

OBJECTIVE: To check the potential usefulness of clinical criteria for the diagnosis of bullous pemphigoid when state-of-the-art techniques such as Western immunoblotting, immunoprecipitation, and indirect immunofluorescence on salt-split skin or direct immunoelectron microscopy are not available. DESIGN: Comparison of the clinical criteria between 2 groups (with and without bullous pemphigoid) as defined by immunoelectron microscopy used as standard criterion, in a prospective study. Multivariate logistic regression analysis was carried out by including all items that were statistically significant (at P < .05 level) in univariate analysis. SETTING: Five dermatology departments in teaching hospitals. PATIENTS: The 231 patients studied had subepidermal autoimmune bullous diseases with linear IgG or C3 deposits in the basement membrane zone (157 with bullous pemphigoid, 33 with cicatricial pemphigoid, 30 with epidermolysis bullous acquisita, 5 with lupus erythematosus, and 6 others). A second set of patients was used to calculate predictive values. RESULTS: The multivariate logistic stepwise analysis resulted in a final set of predictors that included only 4 items: absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and age greater than 70 years. No additional variables met the .05 significance level to enter into the model. If 3 of these 4 characteristics were present, a diagnosis of bullous pemphigoid could be made with a sensitivity of 90% and a specificity of 83%; these predictive values were calculated on a sample of 70 new cases. CONCLUSIONS: With and estimated incidence of bullous pemphigoid among subepidermal autoimmune bullous diseases of 80%, the presence of 3 of the 4 significant criteria allows the diagnosis of bullous pemphigoid, with a positive predictive value of 95%. Our set of clinical criteria thus allows the diagnosis of bullous pemphigoid with good validity for both clinical practice and therapeutic trials.

Aged↗
PubMed1993

In-situ preferential usage of V alpha 8 T-cell receptor gene segments in a patient with bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with the occurrence of autoantibodies directed to a limited series of antigens located at the basement membrane zone of the dermo-epidermal junction. Previous studies have demonstrated the presence of activated T cells in BP lesions although their actual contribution to the pathogenesis of the disease has remained unclear. One approach to better understanding the significance of these T-cell infiltrates is to study the diversity of the recognition receptors (TCRs) expressed at the lesion sites. We report here an extensive analysis, performed in one patient with typical BP, where 187 TCR in frame transcripts from a lesional area, from clinically normal skin or from peripheral blood lymphocytes have been sequenced and compared. The data show preferential usage of the V alpha 8 subfamily gene segments in the lesion. It is therefore suggested that T-cell infiltration in BP may not simply reflect a non-specific inflammatory process but include antigen-specific responses.

Amino Acid Sequence↗
PubMed1996

Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with autoantibodies directed against antigens associated with hemidesmosomes of basal keratinocytes. In addition to autoantibodies and activated complement, cellular mechanisms are crucial for blister formation in this disease. Mononuclear cells, which are the first cells infiltrating BP lesions, mainly belong to CD3, CD4+ T-helper (Th) cells. Elevated concentrations of IL-2, IFN gamma, TNF beta, and IL-5 have been recently demonstrated in BP blister fluid. In this study, we were interested in levels of other Th-type cytokines, including IL-3, IL-4, IL-6, IL-10, and GM-CSF in blister fluid of BP. Cytokines were determined by ELISA or bioassay. Levels in the blister fluid from ten BP patients were compared with those in serum samples taken at the time of blister puncture and with those in suction blister fluid of ten healthy volunteers. In blister fluid of BP, we found significantly elevated concentrations of IL-4, IL-6, and IL-10 relative to both concurrent serum samples and suction blister fluid from controls. No differences were detected for either IL-3 or GM-CSF. Our results suggest that IL-4, IL-6, and IL-10 are released at the site of blister formation in BP.

Adolescent↗
PubMed2000

[New aspects on the pathogenesis of bullous pemphigoid].

Bullous pemphigoid (BP) is a subepidermal blistering autoimmune disease of the elderly. Autoantibodies are directed against two hemidesmosomal proteins, designated BP180 and BP230. While BP230 localizes intracellularly and associates with the hemidesmosomal plaque, BP180 is a transmembrane glycoprotein with an extracellular domain consisting of approximately 1000 amino acids. The non-collagenous (NC) 16A domain, that encompasses 76 amino acids and localizes directly adjacent to the transmembrane region, has been identified as an immunodominant region of the BP180 ectodomain. In the majority of BP sera, circulating antibodies to BP180 NC16A are detected; their serum levels correlate with disease activity. Neonatal mice that are injected with rabbit anti-murine BP180 antibodies develop a BP-like subepidermal blistering disease demonstrating the biological importance of antibodies to BP180. The pathogenically relevant site on murine BP180 corresponds to a stretch of the NC16A domain on human BP180. In contrast to pemphigus, in BP, autoantibodies alone are not sufficient to induce blisters. In addition, complement activation, the infiltration of inflammatory cells and the release of proteases and various inflammatory mediators, including cytokines, are essential for lesion formation. In this review, we give an up-date on the pathogenesis of BP.

Animals↗
PubMed1996

Detection of IL-1 alpha, IL-1 beta and IL-1 receptor antagonist in blister fluid of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. In addition to autoantibodies, complement activation and inflammatory cells are necessary for lesion formation. In this study, we investigated the potential involvement of IL-1, secreted by various inflammatory and non-inflammatory cells, in BP lesions. We determined IL-1 alpha IL-1 beta and IL-1 receptor antagonist in both blister fluid and concurrent serum samples of 10 BP patients by ELISAs. For comparison, we assayed experimentally generated suction blisters from 10 healthy volunteers. IL-1 beta levels were significantly elevated in BP blisters, whereas levels of IL-1 alpha were decreased relative to those in controls. In concurrent serum samples, no IL-1 alpha or IL-1 beta were detected in patients or controls. Levels of IL-1 receptor antagonist were significantly higher in BP blisters in relation to both concurrent sera and suction blisters. Our data indicate the release of IL-1 beta, IL-1 receptor antagonist, and to a lesser extent, of IL-1 alpha, at the site of blister formation in BP and support the notion that cell-mediated immune mechanisms may contribute to blister formation in this disease.

Aged↗
PubMed2006

Decreased expression levels of CD22 and L-selectin on peripheral blood B lymphocytes from patients with bullous pemphigoid.

Bullous pemphigoid (BP), an autoimmune subepidermal-blistering disease of the elderly, is caused by antibodies against BP antigens at the epidermal basement membrane zone (BMZ). CD22 is a B lymphocyte specific response regulator, which is down-regulated after B-cell activation. Old CD22-deficient mice produce class-switched autoantibodies. To assess the role of CD22 in the pathogenesis of BP, we examined CD22 expression on B cells from BP patients and correlated its expression with clinical parameters. B cell expression of CD22 was 20% lower in BP patients when compared to healthy control subjects. In addition, B cells from BP patients showed decreased expression of L-selectin, which is an indicator of leukocyte activation, and CD22 expression levels were correlated with L-selectin expression. These results suggest that the decreased CD22 expression may be associated with the activation of B cells in BP. CD22 expression levels in BP patients did not correlate with the levels of anti-epidermal BMZ antibodies, and old CD22-deficient mice did not develop the anti-epidermal BMZ antibody. These results suggest that a decrease in CD22 expression may not be associated with BP-specific antibody production.

Adult↗