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PubMed2002

Monitoring disease activity in pemphigus with enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3.

BACKGROUND: Pemphigus is an antidesmoglein (Dsg) autoimmune disease that is divided into two major subtypes: pemphigus foliaceus (PF) and pemphigus vulgaris (PV). We previously developed enzyme-linked immunosorbent assays (ELISAs) using recombinant Dsg1 and Dsg3 to detect IgG autoantibodies in patients with pemphigus. The protocol for the ELISAs was optimized for serological diagnosis, but under the conditions used, these assays were not particularly useful for monitoring disease activity in certain patients. That is, the sera from some patients with high-titre antibodies continued to show high index values in the ELISA after clinical improvement. OBJECTIVES: In the study reported here, we modified the ELISA protocol to obtain 'true' index values that exhibit a better correlation with disease activity. METHODS: We tested two cases of pemphigus foliaceus (PF) and four cases of pemphigus vulgaris (PV), each with ELISA index values greater than 150 for Dsg1 or Dsg3. We ran an ELISA with sera from these patients serially diluted from 1 : 100 to 1 : 12,800. We then performed ELISA with a series of PV No. 1 sera diluted to 1 : 800 and PV No. 2-4 and PF No. 1-2 sera diluted to 1 : 1600, after which we plotted the ELISA index values against the time course of disease activity. RESULTS: In each of these cases, there was no apparent decline, over the course of the disease activity, in the ELISA index values at a serum dilution of 1 : 100, probably because the antigen-antibody reaction was saturated at that dilution. After running an ELISA with sera serially diluted from 1 : 100 to 1 : 12,800 we found that a linear dose-dependency between the dilution value and the index value was only observed when sera were diluted to 1 : 800 or more in one case (PV No.1) and to 1 : 1600 or more in the other five cases (PV No. 2-4, PF No. 1-2). After performing ELISA with these series as outlined above we plotted the ELISA index values against the time course of disease activity and found that the index values obtained from these appropriately diluted sera fluctuated in parallel with disease activity, and declined with clinical improvement. CONCLUSIONS: These findings indicate that when appropriate dilutions are used in Dsg1 and Dsg3 ELISA, these assays can provide useful serological information for assessing disease activity in PF and PV.

Adult↗
PubMed1993

CD68 positive epidermal dendritic cells.

In a pilot study designed to investigate immunopathologic events in the evolution of cutaneous lesions in pemphigus foliaceus, we found that in this condition the epidermis is replete with CD68+ dendritic cells. The present study was designed to investigate the nature of this novel intraepidermal CD68+ cell population. For that purpose lesional skin of five patients with PF and, for comparison, of patients with another acantholytic autoimmune disease, pemphigus vulgaris, were examined using a panel of monoclonal antibodies in a three-step immunoperoxidase technique, in an immunofluorescence double-labeling technique, and by immunoelectron microscopy. We found epidermal CD1a+ Langerhans cells significantly decreased in pemphigus foliaceus compared to pemphigus vulgaris, but pemphigus foliaceus and not pemphigus vulgaris epidermis harbored large amounts of bone marrow-derived (CD45+) cells that expressed CD68, HLA-DR, and beta 2-integrin antigens, the most pronounced expression being observed for CD11c and CD18. These epidermal CD68+ cells were of dendritic shape, were CD1a-, and lacked Birbeck granules (BG); however, a small portion of CD68+ cells was also CD1a+ and exhibited BG as revealed by immunoelectron microscopy. These findings demonstrate that in certain conditions, i.e., in pemphigus foliaceus but not in pemphigus vulgaris, there is a shift from CD1a+/CD68- epidermal Langerhans cells towards CD1a-/CD68+ dendritic epidermal cells. The detection of a small number of CD1a+/CD68+/BG+ dendritic epidermal cells may identify these cells as a link between the CD1a+/CD68+/BG+ Langerhans cells and the CD1a-/CD68+/BG- cell population and suggests that these cells represent a transitional form of myelomonocytic cells during their phenotypic and morphologic transformation into resident epidermal Langerhans cells.

Adolescent↗
PubMed1985

Penicillamine-induced pemphigus foliaceus-like dermatosis. A case with unusual features, successfully treated by plasmapheresis.

A case of a severe, widespread bullous dermatosis clinically resembling pemphigus foliaceus occurred during treatment with penicillamine hydrochloride in a patient with rheumatoid arthritis. Histologically, the disease showed changes compatible with pemphigus vulgaris as well as with a bullous drug eruption. Treatment by plasmapheresis proved to be effective in controlling the disease.

Dermatitis, Exfoliative↗
PubMed1997

Pemphigus IgG induces expression of urokinase plasminogen activator receptor on the cell surface of cultured keratinocytes.

We previously found that the binding of pemphigus IgG to desmogleins caused marked activation of phospholipase C, a transient increase in inositol 1,4,5-trisphosphate production, and a concomitant increase in the intracellular calcium concentration in DJM-1 cells, a squamous cell carcinoma line. The binding of pemphigus IgG to cell membranes increased the activity of urokinase plasminogen activator in culture medium and induced subsequent cell-cell detachment in DJM-1 cells. Because urokinase plasminogen activator activates the conversion of plasminogen to plasmin by binding to urokinase plasminogen activator receptor evading inhibitors in serum, it is likely that plasmin is generated only in microenvironments adjacent to urokinase plasminogen activator receptor on the cell surface. It is not known whether pemphigus IgG causes acantholysis by inducing urokinase plasminogen activator receptor expression on the cell surface and secreting urokinase plasminogen activator in inhibitor-rich environments. We examined the effects of pemphigus IgG on urokinase plasminogen activator receptor expression in DJM-1 cells and normal keratinocytes by immunoblot analysis and immunofluorescence microscopy using antibodies to urokinase plasminogen activator receptor. IgG were obtained from serum samples from eight patients with bullous pemphigoid, five patients with pemphigus vulgaris, seven patients with pemphigus foliaceus, and eight normal subjects. Pemphigus vulgaris and pemphigus foliaceus IgG significantly increased the urokinase plasminogen activator receptor expression on the surface of DJM-1 cells and normal keratinocytes after 3- and 7-d incubation compared with normal IgG. These results suggest that enhanced urokinase plasminogen activator activity and urokinase plasminogen activator receptor expression activates plasmin in the limited cell surface of pemphigus IgG-bound keratinocytes and may contribute to the pathogenesis of differential acantholysis in pemphigus vulgaris and pemphigus foliaceus.

Adult↗
PubMed2001

[The mosaic of pemphigus].

Pemphigus is an autoimmune blistering disease of skin and mucous membranes. The classic types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. In this review we summarize recent advancement in the etiology and the pathogenesis of pemphigus. Desmogleins--transmembrane glycoproteins involved in intracellular adhesion--were recognized as targets of pemphigus antibodies. It was found that the distribution and the expression of desmogleins can explain the difference in the localization of lesions in pemphigus vulgaris and pemphigus foliaceus. Pemphigus develops in a two-step process. The first step leads to the presence of a low titer of autoantibody, the second step results in a significant increase in the antibody titer which causes the clinical stage of the disease. Selective presentation of self peptides can explain the Major Histocompatibility Complex (MHC)--linked susceptibility to autoimmune diseases including pemphigus and rheumatoid arthritis. Peptides selective for the disease-associated molecules can be identified and used to search for microbiologic factors that can take part in the pathogenesis of pemphigus.

Autoimmune Diseases↗
PubMed2006

A truncated alternative spliced isoform of human desmoglein 1 contains a specific T cell epitope binding to the pemphigus foliaceus-associated HLA class II DRbeta1*0102 molecule.

Desmogleins (Dsg) are transmembrane glycoproteins of the desmosome that allow a cell-cell adhesion between keratinocytes and comprise four different isoforms (Dsg1 to Dsg4). Two Dsg are targeted by pathogenic autoantibodies produced in the course of autoimmune bullous skin diseases, Dsg1 in pemphigus foliaceus (PF), and Dsg3 and Dsg1 in pemphigus vulgaris. The genetic susceptibility to PF is associated with certain HLA class II alleles, which are thought to participate in disease pathogenesis through their capacity to accommodate autoantigen-derived peptides and present them to autoreactive T cells. So far, a unique isoform of Dsg1 has been described in humans, which includes several immunodominant T cell epitopes. In this study, we describe an alternative transcript of DSG1, which contains a 101-bp insertion corresponding to the 3' end of DSG1-intron 6 and introducing a stop codon in the nucleotide sequence. This alternative transcript leads to the synthesis of a truncated isoform of Dsg1 expressed in normal human epidermis. This isoform bears a specific peptide sequence that binds to the PF-associated HLA class II DRbeta1*0102 molecule as shown in a HLA-DR peptide-binding assay, and induces PF T cell proliferation. These data provide an illustration of an autoantigen encoded by alternative spliced transcript that may participate in the pathogenesis of the disease by bearing PF-associated HLA class II restricted-epitope.

Alternative Splicing↗
PubMed1988

Pemphigus foliaceus-like, immunologically negative dermatosis in a patient with T cell chronic lymphocytic leukemia.

A 56-year-old black man developed a pemphigus foliaceus-like bullous eruption as the initial presentation of chronic T cell lymphocytic leukemia. Histologic examination disclosed superficial acantholysis consistent with pemphigus foliaceus and an infiltrate of atypical lymphoid cells in the papillary dermis. Repeated direct and indirect immunofluorescence studies yielded negative results. Acantholysis could be reproduced in vitro by incubation of normal human skin with the patient's serum and plasma but not with blister fluid. In the following months, the course of the bullous eruption paralleled that of the leukemia.

Biopsy↗
PubMed1995

Pemphigus sera recognize conformationally sensitive epitopes in the amino-terminal region of desmoglein-1.

To identify regions of the Desmoglein-1 (Dsg1) extracellular domain that are targeted by pemphigus antisera, cDNA sequences encoding various regions of the Dsg1 extracellular domain were ligated to sequences encoding the E-cadherin extracellular anchor and transmembrane and cytoplasmic domains. These constructs were then expressed in mammalian cells, and pemphigus sera were tested for the ability to recognize the Dsg1 extracellular domains. When analyzed by immunoblot, very few pemphigus foliaceus sera recognized the Dsg1 domains. To determine whether pemphigus sera recognize non-denatured Dsg1 domains, constructs were expressed in cultured cells and tested for reactivity with pemphigus sera using live-cell immunofluorescence. The pemphigus foliaceus sera reacted strongly with the Dsg1 extracellular domain by live-cell immunofluorescence and recognized predominantly the amino-terminal region of the Dsg1 extracellular domain. In addition, sera from patients with pemphigus vulgaris also demonstrated strong reactivity with the Dsg1 extracellular domain when tested using live-cell immunofluorescence. In contrast, sera from normal human controls and sera from bullous pemphigoid patients did not react with the Dsg1 extracellular domain. These data indicate that both pemphigus foliaceus and pemphigus vulgaris sera react with conformationally sensitive epitopes in the amino-terminal region of Dsg1.

Base Sequence↗
PubMed2003

The men behind the eponym: Francis E. Senear, Barney Usher, and the Senear-Usher syndrome.

This historical review will summarize the report of Francis Senear and Barney Usher on a disease that they called pemphigus erythematodes and which later became pemphigus erythematosus (the Senear-Usher syndrome). It will then outline the lives of these two men. Finally, it will review the literature on that condition and relate the views of various authorities as to whether pemphigus erythematosus is merely pemphigus foliaceus, a variant of pemphigus foliaceus, a syndrome combining features of lupus erythematosus and pemphigus or whether pemphigus erythematosus (Senear-Usher syndrome) is a distinct and separate disease.

Dermatology↗
PubMed1999

The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic.

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.

Acantholysis↗
PubMed2003

Desmoglein as a target in autoimmunity and infection.

Clinical phenotypes of most diseases are complex. However, once the mechanism behind the scene is clarified, the nature shows amazing beauty. There is a simple logic behind a complex disease. The exact molecular mechanism of the blister formation in staphylococcal scalded skin syndrome (SSSS) remained to be elucidated for 3 decades since exfoliative toxin was discovered by Melish and Glasgow in 1970. A knowledge accumulated to understand the pathogenesis of pemphigus and cell-cell adhesion of keratinocytes led us to solve this question. Desmoglein 1, which is a cadherin type cell-cell adhesion molecule in desmosomes, is targeted in two different skin diseases, pemphigus foliaceus, and SSSS. In pemphigus foliaceus IgG autoantibodies are developed against desmoglein 1 and inhibit its adhesive function with resultant blister formation in the superficial epidermis. In SSSS, exfoliative toxin produced by Staphylococcus aureus specifically binds and cleaves desmoglein 1 with resultant blister formation at the identical site.

Animals↗
PubMed1996

[Cellular adhesion molecules and components of the extracellular matrix as target structures of autoimmunity].

Cell-cell and cell-matrix adhesion molecules as well as extracellular matrix components are target structures of antibody-mediated autoimmunity that have recently been well characterized at the molecular biological level. Pathogenic autoantibodies against these molecules are causally related to disturbances of cell and tissue adhesion that become apparent as various (muco-)cutaneous blistering diseases. Desmosomal cadherins (desmogleins and desmocollins) mediate epidermal intercellular adhesion. Among these, desmoglein 1 and desmoglein 3 are the autoantigens of pemphigus foliaceus and pemphigus vulgaris, respectively, exhibiting intraepidermal blistering. The pathogenic relevance of autoantibodies against desmocollins. (IgA pemphigus) and desmoplakins (paraneoplastic pemphigus) still remains unclear. Hemidesmosomes contain the plaque protein BPAG1 and the partly collagen-like transmembrane protein BPAG2, representing the autoantigens of bullous pemphigoid and pemphigoid gestationis with subepidermal blistering. A certain subtype of cicatricial (benign mucous membrane) pemphigoid is characterized by autoantibodies against laminin 5 present in the subhemidesmosomal anchoring filaments, while epidermolysis bullosa acquisita and bullous SLE exhibit autoantibodies against collagen type VII constituting the anchoring fibrils. In addition, autoantibodies against a particular collagen type IV chain of the glomerular basement membrane are responsible for the manifestation of Goodpasture's syndrome. These recent molecular biological findings might be the basis for the development of novel therapeutic strategies.

Autoantibodies↗
PubMed1998

Epidermal adhesion molecules and basement membrane components as target structures of autoimmunity.

Intraepidermal and dermal-epidermal cohesion are of paramount importance for the integrity of the skin. Some constituent molecules of keratinocyte adhesion complexes and basement membrane-associated structures are the targets of antibody-mediated autoimmune reactions that give rise to various (muco-)cutaneous blistering diseases. The current state of our knowledge about these molecules--along with the main clinical, histological, and immunohistochemical features of the corresponding autoimmune diseases and their pathogenetic mechanisms--comprise the subjects surveyed in this review. Among the desmosomal cadherins (desmogleins and desmocollins) that mediate epidermal cell-cell adhesion, it has been demonstrated that desmoglein 1 and desmoglein 3 are the autoantigens of pemphigus foliaceus and pemphigus vulgaris, respectively, both diseases that result in intraepidermal blistering. Further, desmocollin autoantibodies may be involved in IgA pemphigus. Paraneoplastic pemphigus is associated with autoantibodies directed against the desmosomal plaque protein, desmoplakin. Of the constituents of hemidesmosomes, the plaque protein, BP230 (BPAG1), and the collagen-like transmembrane protein, BP180 (BPAG2), are the autoantigens of bullous pemphigoid and pemphigoid gestationis, the manifestations of both of which include subepidermal blistering. Several diseases arise from autoimmune reactions against certain proteins associated with the basement membrane located beneath hemidesmosomes, for example laminin 5 (cicatricial pemphigoid), ladinin (LAD-1; linear IgA disease), uncein, and collagen VII (epidermolysis bullosa acquisita), the last of which is the constituent protein of the anchoring fibrils. Such recent advances in the elucidation of the molecular nature of autoantigens may serve as the basis for the development of novel molecule-based therapeutic strategies.

Basement Membrane↗
PubMed1987

Localization of immunoglobulins and complement by the peroxidase antiperoxidase method in autoimmune and non-autoimmune canine dermatopathies.

Formalin-fixed, paraffin embedded skin biopsy specimens from 44 dogs with various dermatopathies were examined for the presence of immunoglobulins (IgG, IgM, IgA) and complement (C3) by the peroxidase antiperoxidase method (PAP). Final diagnoses of the skin diseases were determined by clinical findings, fungal and bacterial cultures, skin scrapings, serum endocrinologic tests, and histologic features of cutaneous biopsies. The dermatopathies included examples of pyoderma (folliculitis/furunculosis), demodecosis, sarcoptic mange, dermatophytosis, endocrine dermatopathy, and autoimmune skin disease (AISD). In the latter category, 7 cases of pemphigus foliaceus, 1 pemphigus vulgaris, 4 discoid lupus erythematosus (DLE) and 4 examples of indeterminate AISD were examined. Immunoglobulins, C3, or both, were localized in tissue sections from AISD (15/16), pyoderma (7/11), demodecosis (4/8) sarcoptic mange (3/3), and dermatomycosis (2/3). Endocrine dermatopathy biopsies were consistently negative for Ig and C3 (0/3). The pattern of localization was most often intercellular (31/44 positive biopsies) with basement membrane immunoreactivity in 4 cases of DLE, and 1 case of indeterminate AISD. There was no consistent correlation between histologic features of hematoxylin and eosin-stained biopsies and the presence of Ig and C3. Clinical outcome was similar in both Ig and C3 positive and negative cases of non-AISD dermatitis. The high percentage (95%) of positive results in AISD biopsies indicates the usefulness and sensitivity of the PAP method for the localization of Ig and C3. Because of the high percentage of Ig localization in pyoderma (73%), biopsy specimens with extensive inflammatory skin disease are not suitable for diagnosis of AISD. The PAP method is useful in the diagnosis of AISD in biopsy specimens with minimal inflammation. Caution is warranted in the interpretation of immunoreactivity independent of clinical and histologic information.

Animals↗
PubMed1990

The relationship of pemphigus to neoplasia.

A statistically increased incidence of malignancy has been observed in patients with pemphigus. A review of the literature reveals 42 cases of nonthymic malignancies and 18 cases of thymic malignancies. A significant predominance of men, with mean age at onset of 50 years, was observed. Pemphigus vulgaris is more common in patients with nonthymic neoplasms, whereas pemphigus foliaceus or pemphigus erythematosus and pemphigus vulgaris are equally common in patients with thymic neoplasms. Lymphoreticular malignancies, especially Kaposi's sarcoma, are most frequently observed. The majority of patients with nonthymic neoplasms have pemphigus before the detection of the malignancy and have a favorable 5-year survival rate after tumor resection. The majority of the patients with thymic neoplasms have a thymoma before the development of pemphigus. In some patients pemphigus develops after thymectomy and myasthenia gravis is often associated. Overall, 37 of the 60 patients, or 61%, had a neoplasm of the immune system.

Adult↗
PubMed1985

Clinical correlations of antibodies in pemphigus studied by radioimmunoassay.

Pemphigus antibodies of class G immunoglobulins (IgG) were studied with the use of a solid-phase radioimmunoassay (RIA) that utilizes COLO-16, a squamous cell tumor line, as the substrate. Sera from patients with pemphigus vulgaris and pemphigus vegetans showed greater average binding than did sera from patients with pemphigus foliaceus and pemphigus erythematosus. The patients were subgrouped according to their clinical presentations and were divided into patients with skin lesions only, those with mucous membrane lesions only, and those with both skin and mucous membrane lesions. No significant differences were observed between these groups. There was good correlation between IgG binding in the RIA and both the disease activity and the response to therapy. Blood group antigen absorbable "false positive" anti-intercellular substance antibodies were not detected in the RIA.

Animals↗
PubMed2002

Pemphigus is not associated with allotypic markers of immunoglobulin kappa.

The kappa light chain constant region of immunoglobulins bears polymorphic markers involved in susceptibility to various autoimmune diseases. To determine whether it also contributes to the occurrence of pemphigus, a group of autoimmune blistering skin diseases owing to pathogenic autoantibodies, the genotypic frequencies of Km allotypes were evaluated in patients with pemphigus foliaceus or pemphigus vulgaris and ethnically-matched healthy controls in both Tunisia and France. No difference in the distribution of Km genotype or allele frequencies was observed between patients and controls in either countries. Therefore, Km allotypes do not appear to constitute a genetic factor contributing to pemphigus.

Adult↗
PubMed2000

An extract of cultured A431 cells contains major tissue antigens of autoimmune bullous diseases.

BACKGROUND: Autoantibodies that are characteristic of autoimmune bullous diseases (AIBDs) can be detected by immunoblot assay using epidermal or dermal extracts. However, none of the substrates obtained by ordinary methods seems to contain a sufficient amount of all of the autoantigens involved in AIBDs, and diagnosis may require the use of several different substrates. OBJECTIVES: To examine the potential of A431 cell extracts as a substrate for immunoblotting. METHODS: Fourteen sera obtained from patients with major AIBDs (pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid and epidermolysis bullosa acquisita) were tested using this substrate. RESULTS: Bands corresponding to desmoglein 1 and 3, desmoplakin 1 and 2, periplakin, BPAG1, BPAG2 and type VII collagen were identified distinctly with these sera. CONCLUSIONS: This finding suggests that culture extracts of A431 cells provide an effective substrate for the diagnosis and differential diagnosis of major AIBDs.

Adult↗