Autoimmune Blistering Skin Disease Research Articles

Autoimmune Bullous Diseases: Historical Perspectives

The first major finding that allowed us to progress in our understanding of autoimmune blistering skin diseases was that chronic blistering diseases of the skin could be differentiated. The initial major clinical differentiation was between pemphigus and pemphigoid and, still today, our major progress in understanding these diseases comes from patients with pemphigus and pemphigoid. Therefore, in this review of historical perspectives, we will focus on pemphigus and pemphigoid. The early history and the clinical and histological differentiation of pemphigus, pemphigoid, and related diseases is beautifully described in a classic monograph by a giant in the field, Walter Lever (1965). Although many contributed to the differentiation at the histological and clinical level, Walter Lever, informed by his own patients and their histology, was a major figure in synthesizing and distilling the essence of this information.

Bullous Pemphigoid with Esophageal Involvement Presenting as Exfoliative Esophagitis and Acute Upper Gastrointestinal Bleeding: Reports of Two Cases and Review of the Literature

Bullous pemphigoid is the most common autoimmune blistering skin disease usually occurs in the elderly. The characteristic skin lesions present large and tense blisters arising on normal, erythematous, or urticarial bases and most commonly involve lower abdomen, inner thighs and flexural areas. The mucous membrane lesions occur in about 10 to 35 percent of patients and are almost limited to the oral mucous membrane. Esophageal involvement is a rare condition which may be completely asymptomatic or complicates with dysphagia and even life-threatening massive upper gastrointestinal bleeding. We present two cases of elderly patients with newly onset extensive bullous pemphigoid confirmed by pathological and immunofluorescence studies. One patient developed severe dysphagia. Endoscopy revealed diffuse exfoliative esophagitis and upper gastrointestinal hemorrhage; the other patient developed poor feeding and hematemesis aspirated from nasogastric tube and endoscopy showed multiple ulcers occurred on mid and lower esophagus. Both patients showed much improvement after systemic corticosteroid use.

Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction

The autoimmune blistering skin disease pemphigus is caused by autoantibodies against keratinocyte surface Ags. In pemphigus vulgaris (PV), autoantibodies are primarily directed against desmosomal cadherins desmoglein (Dsg) 3 and Dsg 1, whereas pemphigus foliaceus (PF) patients only have Abs against Dsg 1. At present, it is unclear whether Dsg autoantibodies contribute to pemphigus pathogenesis by direct inhibition of Dsg transinteraction. Using atomic force microscopy, we provide evidence that PV-IgG directly interfere with homophilic Dsg 3 but, similar to PF-IgG, not with homophilic Dsg 1 transinteraction, indicating that the molecular mechanisms in PV and PF pathogenesis substantially differ. PV-IgG (containing Dsg 3 or Dsg 1 and Dsg 3 autoantibodies) as well as PV-IgG Fab reduced binding activity of Dsg 3 by approximately 60%, comparable to Ca(2+) depletion. Similarly, the mouse monoclonal PV Ab AK 23 targeting the N-terminal Dsg 3 domain and AK 23 Fab reduced Dsg 3 transinteraction. In contrast, neither PV-IgG nor PF-IgG blocked Dsg 1 transinteraction. In HaCaT monolayers, however, both PV- and PF-IgG caused keratinocyte dissociation as well as loss of Dsg 1 and Dsg 3 transinteraction as revealed by laser tweezer assay. These data demonstrate that PV-IgG and PF-IgG reduce Dsg transinteraction by cell-dependent mechanisms and suggest that in addition, Abs to Dsg 3 contribute to PV by direct inhibition of Dsg transinteraction.

Cutaneous pemphigus vulgaris with skin features similar to the classic mucocutaneous type: a case report and review of the literature

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease that specifically involves oral mucosa. It was recently shown that a very small number of patients with PV show no mucous membrane involvement although they have circulating autoantibodies directed against both desmoglein (Dsg)1 and Dsg3 that are associated with histopathological suprabasal acantholysis. These cases are classed as cutaneous-type PV. We report here a case of cutaneous-type PV that occurred in a 50-year-old man. Clinical examination revealed numerous tense and spreading blisters and erosions over the patient's entire body, similar to the classic mucocutaneous-type PV. Interestingly, none of the previously reported patients with cutaneous PV had shown skin features like those of mucocutaneous PV, whereas the present case clearly demonstrated very typical clinical features similar to those in mucocutaneous PV.

Bullous pemphigoid with a prolonged prodrome

Bullous pemphigoid is an autoimmune blistering skin disease of the elderly that may be preceded by a pruritic, urticarial or eczematous eruption. We report a case of bullous pemphigoid preceded by prodromal eczematous eruptions that lasted an unusually long time of 11 years. Elderly patients with persistent pruritic or eczematous eruption of unknown etiology should be carefully followed, as bullous pemphigoid may be a potential diagnosis.

Significado do epitope spreading na patogênese dos pênfigos vulgar e foliáceo

Os pênfigos são dermatoses bolhosas auto-imunes, em que há a produção de auto-anticorpos direcionados contra moléculas de adesão dos epitélios, levando à perda da coesão celular. A produção de auto-anticorpos ocorre quando os pacientes desenvolvem um desequilíbrio da resposta imune (quebra da tolerância imunológica), passando a reconhecer antígenos próprios. A resposta é geralmente direcionada contra um único epítopo alvo; entretanto, como conseqüência da resposta inflamatória do processo primário e do extenso dano tecidual ocasionado, pode haver exposição de componentes protéicos ocultos, levando à produção de diferentes auto-anticorpos. Assim, é possível que surja uma nova doença cutânea auto-imune, em decorrência do fenômeno intra ou intermolecular de epitope spreading. São revistos os principais conceitos desse fenômeno e sua ocorrência nas dermatoses bolhosas auto-imunes, com ênfase nos pênfigos, grupo de dermatoses bolhosas autoimunes mais prevalente no Brasil.

Transglutaminase Autoantibodies in Dermatitis Herpetiformis and Celiac Sprue

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with intestinal gluten sensitivity. Epidermal transglutaminase (TGe) and closely related tissue transglutaminase (tTG) are considered to be autoantigens in DH, because a majority of DH patients have IgA specific for TGe and for tTG. It is unknown where and how these autoantigen-specific IgAs are generated in DH. Results reported in this paper on nine DH patients on a gluten containing diet demonstrate that the levels of circulating anti-tTG IgA and anti-TGe IgA in DH are correlated with each other and that both appear to be correlated with the degree (extent) of enteropathy. An analysis of 15 untreated celiac sprue (CS) patients demonstrated that approximately 33% of CS patients had elevated levels of anti-TGe IgA. These results would indicate that intestinal damage is associated with the production of anti-tTG IgA and anti-TGe IgA in DH patients.

Neutrophils Contact to Plasma Membrane of Keratinocytes Including Desmosomal Structures in Canine Pemphigus Foliaceus

Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that affects certain mammals including dogs. In canine PF, neutrophils are infiltrated intensely into pustular lesions including acantholytic cells, although neutrophilic infiltration is not characterized in human PF. The roles of the neutrophils in the cutaneous lesions of canine PF have not yet been understood. The purpose of this study was to characterize the ultrastructural features underlying the acantholysis with pustule formation in canine PF. Four dogs diagnosed as PF on the basis of clinical signs, histopathological findings, and direct and indirect immunofluorescence examinations were performed. Electron microscopy revealed that the acantholytic cells were adjacent to multiple neutrophils in the pustules. At the contact points between neutrophils and acantholytic keratinocytes, half-desmosomes of acantholytic keratinocytes with intact attachment plaques were observed within invaginations of neutrophils. Furthermore, on the surface of acantholytic cells in the pustules, neutrophil granules seemed to be secreted to the surface of acantholytic cells and to degenerate the half-desmosome structures. Neutrophils were also observed within the epidermis adjacent to the pustule. At the intercellular gap between two dissociated keratinocytes, neutrophils inserted its pseudopodia into the gap between the two half-desmosomes of keratinocytes. These findings taken together suggested that, at least in the areas where we analyzed ultrastructurally, neutrophils contact desmosomal structures and seem to play some parts in separation of keratinocytes and degeneration of split-desmosomes in pustules of dogs with PF.

Paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a life-threatening autoimmune blistering skin disease. Clinically, it is characterized by severe mucosal erosions and various cutaneous lesions associated with lymphoproliferative neoplasmas. Suprabasal acantholysis and clefts with scattered necrotic keratinocytes are the unique histopathological features. PNP patient sera recognize multiple antigens, which have been identified as the plakin protein family that includes desmoplakin, bullous pemphigoid antigen I (BPAG1), envoplakin and periplakin, and desmogleins 1 and 3. Castleman's tumor, non-Hodgkin's lymphoma, thymoma, follicular dendritic cell sarcoma and chronic lymphocytic leukemia are the commonly associated neoplasmas in PNP. We have also demonstrated that the autoantibodies reacting to epidermal proteins are directly produced by the cells in the associated tumors. Bronchiolitis obliterans is frequently found in PNP and may cause respiratory failure and death. In our experience, the early detection and removal of the tumor and i.v. administration of immunoglobulin are critical for the treatment of PNP.

Plakoglobin‐dependent disruption of the desmosomal plaque in pemphigus vulgaris

We recently reported that the pathogenesis of pemphigus vulgaris (PV), an autoimmune blistering skin disorder, is driven by the accumulation of c-Myc secondary to abrogation of plakoglobin (PG)-mediated transcriptional c-Myc suppression. PG knock-out mouse keratinocytes express high levels of c-Myc and resemble PVIgG-treated wild-type keratinocytes in most respects. However, they fail to accumulate nuclear c-Myc and loose intercellular adhesion in response to PVIgG-treatment like wild-type keratinocytes. This suggested that PG is also required for propagation of the PVIgG-induced events between augmented c-Myc expression and acantholysis. Here, we addressed this possibility by comparing PVIgG-induced changes in the desmosomal organization between wild-type and PG knock-out keratinocytes. We found that either bivalent PVIgG or monovalent PV-Fab (known to trigger blister formation in vivo) disrupt the linear organization of all major desmosomal components along cell borders in wild-type keratinocytes, simultaneously with a reduction in intercellular adhesive strength. In contrast, PV-Fab failed to affect PG knock-out keratinocytes while PVIgG cross-linked their desmosomal cadherins without significantly affecting desmoplakin. These results identify PG as a principle effector of the PVIgG-induced signals downstream of c-Myc that disrupt the desmosomal plaque at the plasma membrane.

Anti-desmoglein autoantibody repertoire in pemphigus (B89)

Abstract Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune skin blistering diseases characterized by pathogenic autoantibodies against desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3), respectively. Fogo selvagem (FS) is the endemic form of PF. To study the etiology of PV and FS, hybridomas were generated from the B cells of 5 PV patients and 7 FS patients. The V genes of both H and L chain of the Dsg-specific autoantibodies from these hybridomas were sequenced and analyzed for the H and L chain pairing of the autoantibodies, the diversity of H and L chain V gene usage, and the extent of somatic mutation. The number of somatic mutations in the expressed genes ranged from zero to 42, and the replacement to silent mutation (R/S) ratio was much higher in CDRs than in FWRs of both IgM and IgG hybridomas from FS patients. The R/S ratio was also much higher in CDRs than in FWRs of IgG hybridomas from PV patients. In addition, clonally related sets of anti-Dsg1 or anti-Dsg3 hybridomas were identified from individual FS or PV patients based on VH-D-JH junctional sequence identity that reveals ongoing somatic mutation during clonal expansion. Thus, our evidence suggests that the anti-Dsg autoimmune response in both PV and FS is antigen selected.

Epidemiology of pemphigus in Macedonia: A 15‐year retrospective study (1990–2004)

Pemphigus is an autoimmune blistering skin disease mediated by auto-antibodies directed against desmoglein proteins. There are only a few epidemiological studies on pemphigus. Our objective was to determine the epidemiological features of pemphigus in Macedonia, and to compare the results with those reported elsewhere. Diagnosis in all cases was confirmed by histopathology and direct immunofluorescence. Binomial distribution testing and Fisher's exact-test at the 0.01 level of significance were used to determine if particular demographic groups were over-/ under-represented among the pemphigus patients. One hundred and thirty-three new pemphigus cases were diagnosed in Macedonia from 1990-2004. The average annual incidence was 0.44/100,000 inhabitants (SD = 0.17). The incidence doubled to 0.89 in 2001 during the local armed unrest. The disease did not affect either gender to a greater extent. The average annual incidence was 0.51 for ethnic Macedonians. Roma (Gypsies) had a statistically significantly higher incidence of pemphigus at 2.4 cases/100,000 individuals. Ethnic Albanians had statistically significantly lower incidence of 0.1 cases/100,000 individuals. The most common variant was pemphigus vulgaris (77.4%). The annual incidence for pemphigus in Macedonia is 0.44 cases/100,000 inhabitants. Most common form was pemphigus vulgaris. An epidemiological peak occurred in 2001 during the local armed conflict. Macedonian Roma had a sixfold higher incidence of pemphigus compared with the overall population; ethnic Albanians had a fourfold lower incidence.

Humanization of autoantigen

Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.

Frequency, function and CLA expression of CD4+CD25+FOXP3+ regulatory T cells in bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with autoantibodies to collagen XVII and tissue-separation along the dermo-epidermal junction. We addressed the question whether the loss of tolerance in BP patients is associated with a reduction and/or functional impairment of CD4+CD25+FOXP3+ regulatory T cells, which are essential for the active maintenance of self tolerance. The relative and absolute frequency of CD4+CD25+ and CD4+CD25(high) regulatory T cells in the peripheral blood of newly diagnosed, untreated patients was similar to that of healthy controls. Interestingly, more than 50% of circulating CD4+CD25(high) regulatory T cells from both patients as well as healthy controls expressed cutaneous lymphocyte-associated antigen. Considerable numbers of FOXP3+ cells were detected in lesional skin of patients. CD4+CD25+ regulatory T cells of patients were functionally intact as assessed by their ability to suppress allogeneic as well as antigen-specific T-cell proliferation. These data argue against a general defect of CD4+CD25+FOXP3+ regulatory T cells in patients with BP.

Prediction of desmoglein-3 peptides reveals multiple shared T-cell epitopes in HLA DR4- and DR6- associated Pemphigus vulgaris

BackgroundPemphigus vulgaris (PV) is a severe autoimmune blistering skin disorder that is strongly associated with major histocompatibility complex class II alleles DRB1*0402 and DQB1*0503. The target antigen of PV, desmoglein 3 (Dsg3), is crucial for initiating T-cell response in early disease. Although a number of T-cell specificities within Dsg3 have been reported, the number is limited and the role of T-cells in the pathogenesis of PV remains poorly understood. We report here a structure-based model for the prediction of peptide binding to DRB1*0402 and DQB1*0503. The scoring functions were rigorously trained, tested and validated using experimentally verified peptide sequences.ResultsHigh predictivity is obtained for both DRB1*0402 (r2 = 0.90, s = 1.20 kJ/mol, q2 = 0.82, spress = 1.61 kJ/mol) and DQB1*0503 (r2 = 0.95, s = 1.20 kJ/mol, q2 = 0.75, spress = 2.15 kJ/mol) models, compared to experimental data. We investigated the binding patterns of Dsg3 peptides and illustrate the existence of multiple immunodominant epitopes that may be responsible for both disease initiation and propagation in PV. Further analysis reveals that DRB1*0402 and DQB1*0503 may share similar specificities by binding peptides at different binding registers, thus providing a molecular mechanism for the dual HLA association observed in PV.ConclusionCollectively, the results of this study provide interesting new insights into the pathology of PV. This is the first report illustrating high-level of cross-reactivity between both PV-implicated alleles, DRB1*0402 and DQB1*0503, as well as the existence of a potentially large number of T-cell epitopes throughout the entire Dsg3 extracellular domain (ECD) and transmembrane region. Our results reveal that DR4 and DR6 PV may initiate in the ECD and transmembrane region respectively, with implications for immunotherapeutic strategies for the treatment of this autoimmune disease.

Inhibition of Rho A activity causes pemphigus skin blistering

The autoimmune blistering skin diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are mainly caused by autoantibodies against desmosomal cadherins. In this study, we provide evidence that PV–immunoglobulin G (IgG) and PF-IgG induce skin blistering by interference with Rho A signaling. In vitro, pemphigus IgG caused typical hallmarks of pemphigus pathogenesis such as epidermal blistering in human skin, cell dissociation, and loss of desmoglein 1 (Dsg 1)–mediated binding probed by laser tweezers. These changes were accompanied by interference with Rho A activation and reduction of Rho A activity. Pemphigus IgG–triggered keratinocyte dissociation and Rho A inactivation were p38 mitogen-activated protein kinase dependent. Specific activation of Rho A by cytotoxic necrotizing factor-y abolished all pemphigus-triggered effects, including keratin retraction and release of Dsg 3 from the cytoskeleton. These data demonstrate that Rho A is involved in the regulation of desmosomal adhesion, at least in part by maintaining the cytoskeletal anchorage of desmosomal proteins. This may open the possibility of pemphigus treatment with the epidermal application of Rho A agonists.

A review of autoimmune skin diseases in domestic animals: I – Superficial pemphigus

In humans, the pemphigus denomination encompasses a group of autoimmune blistering skin diseases with intraepidermal separation resulting from cell-cell detachment by acantholysis. Entities are classified based on the level of blistering in the epidermis, and both superficial (pemphigus foliaceus, IgA pemphigus) and deep (pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus) variants are recognized. In domestic animals, subsets of pemphigus have been recognized since the mid-1970s, and the disease classification resembles that used for human patients. This article reviews up-to-date knowledge on the epidemiology, clinical signs, histopathology, immunopathology and treatment outcome of superficial pemphigus in domestic animals. Detailed information on canine, feline, equine and caprine pemphigus foliaceus, canine and feline pemphigus erythematosus and canine panepidermal pustular pemphigus is provided.

Autoimmune subepidermal blistering diseases in Uganda: correlation of autoantibody class with age of patients

No data are available on the incidence and immunoreactivity of autoimmune subepidermal blistering skin diseases in East Africa. All patients with frank blisters/erosions on the skin and/or mucous membranes that attended the Department of Dermatology at Mbarara University, Uganda, from May 2000 to June 2002, were investigated. The diagnosis was based on the clinical presentation and on the presence of circulating autoantibodies detected by indirect immunofluorescence microscopy on 1 m NaCl-split human skin and by Western blotting of recombinant and cell-derived forms of BP180, BP230, and type VII collagen. Twenty-two patients with autoimmune subepidermal blistering skin disorders were identified, including nine with bullous pemphigoid (41%), four with linear immunoglobulin A (IgA) disease (18%), three with mucous membrane pemphigoid (14%), two with linear IgG/IgA bullous dermatosis (9%), and one each with cicatricial pemphigoid and epidermolysis bullosa acquisita (5%). In addition, two patients with immunoreactivity to both the epidermal and dermal side of salt-split skin by indirect immunofluorescence microscopy, who were unreactive to type VII collagen, were provisionally diagnosed as "mixed pemphigoid" (9%). In patients with subepidermal blistering diseases, IgG reactivity correlated significantly with old age, whereas younger patients preferentially developed IgA autoantibodies (P = 0.024). The age of patients with autoimmune subepidermal blistering diseases appears to influence the immunoglobulin class of autoantibodies. The high frequency of IgA autoantibodies in Ugandan patients may be explained by the age distribution of the Ugandan population.

Proteomic analysis of the autoantibody response following immunization with a single autoantigen

In most autoimmune diseases, the autoantibody response is directed against several antigens of the target organ whose identification is crucial for understanding the physiopathological process. Thus, technologies allowing a characterization of the whole autoantibody pattern of both human and experimental autoimmune diseases are required. Here we have used immunoproteomic analysis of human epidermal extracts to characterize the diversity of the anti-desmosome antibody response induced in normal mice immunized with desmoglein 1, the major autoantigen of pemphigus foliaceus, an autoimmune blistering skin disease. In particular, this analysis enables us to characterize the binding properties of anti-desmosome mAbs derived from these mice and to show that the autoantibody response induced upon immunization with a single autoantigen targets different epidermal autoantigens with a pattern similar to that observed in certain variety of human pemphigus.

P38MAPK inhibition prevents disease in pemphigus vulgaris mice

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease characterized by detachment of keratinocytes (acantholysis). It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis. Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27 after binding of PV antibodies to cultured keratinocytes. In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion. This study was undertaken to (i) determine whether p38MAPK and HSP25, the murine HSP27 homolog, were similarly phosphorylated in an in vivo model of PV and (ii) investigate the potential therapeutic use of p38MAPK inhibition to block blister formation in an animal model of PV. We now report that p38MAPK inhibitors prevented PV blistering disease in vivo. Targeting the end-organ by inhibiting keratinocyte desmosome signaling may be effective for treating desmosome autoimmune blistering disorders.