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PubMed1995

Comparative study of autoantigens for various bullous skin diseases by immunoblotting using different dermo-epidermal separation techniques.

We investigated the reactivity of pemphigus vulgaris (PV), pemphigus vegetans, pemphigus foliaceus (Pf), Brazilian Pf, bullous pemphigoid (BP), and epidermolysis bullosa acquisita (EBA) sera with an immunoblot analysis using human epidermal and dermal extracts as a source of antigen. To obtain epidermal and dermal extracts three different dermo-epidermal separation methods were used: namely, ethylenediaminetetraacetic acid (EDTA) separation, heat separation, and dispase separation. All the 15 PV and the seven pemphigus vegetans sera demonstrated a 130-kDa PV antigen in epidermal extracts obtained by all the three methods. Furthermore, three PV sera also showed a 160-kDa Pf antigen, desmoglein. Ten of 14 Pf sera and six of 15 Brazilian Pf sera reacted with desmoglein in the same pattern in all the three epidermal extracts. Fifteen of the 22 BP sera showed reactivity with 230-kDa BP antigen in the same pattern in all the three epidermal extracts, whereas 14 BP sera detected the 180-kDa BP antigen in extracts of EDTA- and heat-separated epidermis but not in dispase-separated epidermal extract. Dermal extracts were obtained by EDTA- and heat-separated dermis, and all six EBA sera labelled a 290-kDa EBA antigen in both samples. These results suggest that heat-separated skin is as useful as EDTA-separated skin for detecting various autoantigens, but heat separation is preferable because the preparation time is shorter.

Autoantigens↗
PubMed1999

Autoimmunity against desmosomal cadherins in pemphigus.

Pemphigus is a unique and interesting autoimmune disease, in which autoantibodies play a major pathogenic role and cause blister formation. Several questions raised from clinical observation in pemphigus have been answered with logic at the molecular level owing to recent remarkable progress in research in the field of pemphigus. The clinical phenotype of classic pemphigus, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), is defined by anti-desmoglein autoantibody profile. Sera containing anti-Dsg3 IgG alone cause mucosal dominant PV with limited skin involvement. Sera containing both anti-Dsg3 and anti-Dsg1 cause mucocutaneous PV, which affects both the skin and mucous membrane. Sera containing only anti-Dsg1 cause PF, which shows cutaneous but no mucosal involvement. In herpetiform pemphigus (HP) most sera recognize Dsg1 and the rest of them recognize Dsg3, indicating that HP is a clinical variant of PF or PV. Patients with paraneoplastic pemphigus (PNP) have autoantibodies against multiple molecules. Now we know that they have autoantibodies against all members of the plakin family, which are cytoplasmic proteins and include desmoplakin, BPAG1, envoplakin, periplakin, and plectin. Cell surface target antigens of PNP, which blister-inducing pathogenic autoantibodies attack, were finally discovered to be Dsg3 and Dsg1. Therefore, PNP is characterized as an autoimmune disease against plakin molecules and desmogleins. Autoimmune targets of IgA pemphigus are likely more heterogeneous than originally thought. So far, desmocollin 1, Dsg3, and Dsg1 are known as their target antigens. Thus, pemphigus has become one of well-characterized tissue-specific autoimmune diseases. Pemphigus will be a good model disease in the next century to address the central issue of autoimmune disease and basic immunology; why and how do patients with autoimmune diseases start to recognize self as non-self?

Animals↗
PubMed1998

Pemphigus vulgaris associated with silicosis.

Pemphigus vulgaris has never before been associated with silicosis, although there are many reports of silicosis accompanied by several autoimmune diseases such as progressive systemic sclerosis, systemic lupus erythematosus, dermatomyositis or rheumatoid arthritis. We observed a patient with pemphigus vulgaris accompanied with silicosis. The patient was a 75-year-old man with a 2-month history of repeated oral erosions and blisters on the back, thighs and axillas. Histological examination showed suprabasal cleavage with acantholysis. Immunoblotting analysis demonstrated binding of the patient's serum to the 130-kD pemphigus vulgaris antigen (desmoglein 3) and the 160-kD pemphigus foliaceus antigen (desmoglein 1). The patient has radiographically been diagnosed as having silicosis. An elevated serum IgG, antinuclear antibody, anti-ssDNA, antimicrosomal antibodies and a biologically false-positive reaction to the Wassermann test were also detected. Although the clinical symptoms improved after treatment with systemic steroids, the patient died due to pneumonia. This is the first reported case in which the characteristics of both pemphigus vulgaris and silicosis could be detected.

Aged↗
PubMed1994

Comparative study of indirect immunofluorescence and immunoblotting for the diagnosis of autoimmune pemphigus.

The diagnosis of pemphigus relies on immunopathological criteria including the detection of circulating autoantibodies to desmosomal components. In the present work we compared the usefulness of immunoblotting (IB) and indirect immunofluorescence (IIF) in the diagnosis of pemphigus using monkey oesophagus (MO) and rabbit lip (RL) as epithelial substrates. Among 54 sera from patients with well-documented pemphigus (40 pemphigus vulgaris, PV, and 14 pemphigus foliaceus, PF), 46 (85%) proved positive by IIF (46 on MO and 41 on RL) as compared with 44 (81.5%) positive by IB. IIF and IB were equally sensitive (90%) for the diagnosis of PV whereas IIF (on RL) was more sensitive (71%) than IB (57%) for the detection of PF autoantibodies. However, when the two techniques were considered in combination, the sensitivity of the detection of pemphigus autoantibodies rose to 94.5%. An IB study would therefore be warranted in the presence of an (alleged) pemphigus serum that was IIF-negative since approximately 10% of these were found to be positive. Furthermore, the pattern of IB reactivity may assist in classification, since the 130- and the 160-kDa antigens seem specifically correlated with PV and PF, respectively.

Adult↗
PubMed1996

Abnormal desmoglein expression by squamous cell carcinoma cells.

Abnormal expression of cell adhesion molecules and related proteins has been observed in various carcinoma cells. We compared expression patterns of desmosomal cadherins, E-cadherin, and cytoplasmic plaque proteins of four different human squamous cell carcinoma cell lines and in vivo squamous cell carcinoma cells with those of normal human keratinocytes. Unlike normal human keratinocytes, the squamous cell carcinoma cells, both in culture and in vivo, exhibited diminished or unusual expression of desmoglein 3 and desmoglein 1, which bear pemphigus vulgaris and pemphigus foliaceus antigens, respectively. Abnormal expression of E-cadherin and cytoplasmic plaque proteins such as desmoplakin and plakoglobin was also observed. Western blotting study demonstrated that three squamous cell carcinoma cell lines expressed two desmogleins with a predominant 150 kDa molecule, and a minor 130 kDa one. Although these molecular sizes were similar to those of cultured normal human keratinocytes, the 130 kDa desmoglein, which usually carries pemphigus antigenic epitopes, was weakly or negatively reactive with pemphigus vulgaris serum. One squamous cell carcinoma cell line showed a doublet of 140 and 145 kDa bands in addition to the 130 kDa band. All the carcinoma cell lines constantly expressed desmoglein 2 and desmoglein 3 mRNA, whereas cultured normal human keratinocytes always expressed desmoglein 1 and desmoglein 3 mRNA, with or without desmoglein 2 mRNA. These findings indicate that the squamous cell carcinoma cells revealed abnormal expression of desmoglein isoforms, which may be related to tumor cell kinetics such as cell invasion and metastasis.

Antigens↗
PubMed1989

A procedure to obtain long-lasting fluorescence in formaldehyde fixed tissues.

The authors made a study of the small intestine by immunofluorescence in 5% phosphate-buffered formaldehyde fixed tissues, using the Nairn (1976) technique associated with Evans blue (Fry and Wilkinson 1963). The ability of the sections to fluoresce has been maintained after a storage time of more than 4 years. Similar very good results were obtained when skin biopsies from pemphigus foliaceus patients were fixed in formaldehyde for two h and afterwards washed in 30% sucrose solution for 12 to 18 h.

Biopsy↗
PubMed1999

HLA-DRB1 polymorphisms and autoimmune responses to desmogleins in Japanese patients with pemphigus.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are caused by autoantibodies against keratinocyte adhesion molecules desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. To determine possible major histocompatibility complex (MHC) class II associations with autoantibody responses to desmogleins, haplotype and allele distributions, along with molecular polymorphisms of HLA-DR and -DQ genes were analyzed based on the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) results in 85 Japanese patients with pemphigus. Each of 55 PV patients carried at least one allele of HLA-DRB1*04 and DRB1*14 subtypes, with significant increases of HLA-DRB1*0406/DQA1*0301/DQB1*0302, DRB1*14/DQA1*0104/DQB1*05 and DRB1*1406/DQA1*0503/ DQB1*0301 haplotypes compared to normal controls. The HLA-DRB1*04 and DRB*14 alleles carried by PV patients shared hydrophobic amino acid residues Phe26, Leu67 and Val86, as well as hydrophilic amino acid residues at positions 70 and 71 on the DRB1 beta chain. HLA-DR/DQ distributions did not differ among PV patients according to the presence or absence of anti-Dsg1 co-existing with anti-Dsg3. Thirty PF patients, all producing autoantibodies only to Dsg1, showed more diverse HLA-DR/DQ distributions, sharing hydrophobic amino acid residues at positions 26 and 67, as well as hydrophilic amino acid residues at positions 70 and 71, of the DRB1 chain. These findings suggest that autoantibody responses to desmogleins might be regulated by amino acid residues at positions 26, 67, 70, 71 and 86 at peptide binding sites of HLA-DRB1 molecules, and that autoimmune responses to Dsg3 might be more strictly regulated by specific amino acid residues at these positions on the HLA-DRB1 chain than responses to Dsg1.

Alleles↗
PubMed1994

Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus.

Pemphigus vulgaris (PV) is an autoimmune blistering disease, in which autoantibodies against PV antigen (PVA or Dsg3) play a pathogenic role in inducing blister formation. Bacterial fusion proteins of PVA failed to absorb pathogenic autoantibodies from PV patients' sera probably because they did not represent the proper conformation. Therefore, a chimeric protein, PVIg, consisting of the whole extracellular domain of PVA and the constant region of human IgG1, was produced in either in COS7 or in insect Sf9 eucaryotic cells. Both PVIg-COS7 and PVIg-Sf9 were recognized by all of the 35 PV sera tested, but not by any of 10 pemphigus foliaceus (PF), 16 Brazilian PF, 10 bullous pemphigoid, or five normal control sera. Incubation of PV patients' sera with PVIg-Sf9 removed heterogeneous autoantibodies and significantly reduced their immunofluorescence titers on normal human epidermis, although PVIg-Sf9 did not affect the titers of PF sera at all. Furthermore, PVIg-Sf9 absorbed pathogenic autoantibodies from patients' sera and prevented gross blister formation in a neonatal mouse model for pemphigus. These results indicate that this baculovirus product has the proper conformation of the authentic PVA and that its conformation is important in pathogenicity of pemphigus.

Animals↗
PubMed1994

[Paraneoplastic pemphigus. Induction of autoantibodies against structural proteins in the skin].

Paraneoplastic pemphigus (PP) is a newly reported autoimmune disease, which is always associated with an underlying neoplasia. It is characterized by painful mucosal erosions and ulcerations, and by polymorphous skin lesions reminiscent of erythema multiforme, pemphigus vulgaris and lichen planus pemphigoides. These patients have autoantibodies that bind to a distinct complex of epidermal proteins, including desmoplakin I (250 kD), major bullous pemphigoid antigen (230 kD), desmoplakin II (210 kD) and a 190-kD and a 170-kD protein, neither of which has yet been further characterized. Histological findings include acantholysis, epidermal cell necrosis, vacuolar interface changes and, sometimes, lichenoid infiltrates of the upper dermis. Direct immunofluorescence shows an intercellular deposition of immunoreactants in the epidermis and granular deposits at the dermal-epidermal junction. Indirect immunofluorescence with rodent bladder as substrate shows an intercellular pattern. This method is the most convenient and cost-effective method of screening for PP, since antigens of both pemphigus vulgaris and pemphigus foliaceus are not expressed in this tissue.

Adolescent↗
PubMed1993

An immunohistological study of desmosomal components in pemphigus.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune diseases in which there is loss of cohesion between keratinocytes (acantholysis) and blistering within the epidermis. PV is characterized by acantholysis predominantly between the epidermal basal cells and suprabasal layers, whereas in PF intraepidermal cleavage is higher in the epidermis. Adhesion between keratinocytes is dependent on the function of transmembrane glycoproteins of the cadherin family present in specialized adhesion junctions, the desmosomes. The pathogenesis of acantholysis in pemphigus is uncertain, but the pemphigus autoantibodies bind to epithelial cadherins. We have used monoclonal antibodies to desmosomal components to investigate their distribution in different forms of pemphigus. Our results show that the localization of desmosomal components is abnormal in intact perilesional epidermis, intact epidermis above the blisters in PV and intact epidermis below the blisters in PF. We suggest that autoantibody binding may have a direct effect on the function of specific epithelial cadherins, but will only cause cell separation where the antigen is the principal adhesion molecule.

Acantholysis↗
PubMed1996

Tissue factor and thrombomodulin expression on keratinocytes as coagulation/anti-coagulation cofactor and differentiation marker.

Immunohistochemistry was used to investigate the expression of tissue factor (TF) as a coagulation factor and thrombomodulin (TM) as an anticoagulation cofactor in the epidermis. TM was expressed on Malpighian layer keratinocytes while TF was located on the supra-Malpighian layer. Epidermal shave extracts were biologically active for both factors. Keratinocytes cultured in high calcium, but not low calcium media, expressed both TF and TM. In pemphigus vulgaris pemphigus foliaceus and bullous pemphigoid, TF expression was increased on keratinocytes shielding the blister compared to the down-regulated TM expression by keratinocytes around the blister.

Biomarkers↗
PubMed1988

Disseminated superficial porokeratosis and immunosuppression.

We present a patient who developed skin lesions typical of disseminated superficial porokeratosis (DSP) while on immunosuppressive therapy for pemphigus foliaceus. Phototesting with artificial light sources did not have any effect on the DSP lesions. The literature describing occurrence of DSP on immunosuppression is reviewed and possible pathogenetic mechanisms are discussed.

Aged↗
PubMed1999

Mycophenolate mofetil in autoimmune and inflammatory skin disorders.

Mycophenolate mofetil (MMF) has been widely used as an immunosuppressant in organ transplantation. MMF has recently been added to therapeutic regimens for skin disorders. Expanding the use of MMF in dermatology, we describe additional patients with autoimmune and inflammatory skin diseases, including 4 cases of pemphigus vulgaris, 1 case of pemphigus foliaceus, 1 case of perineal and metastatic cutaneous Crohn's disease, 1 case of bullous pemphigoid and psoriasis, and 1 case of psoriasis. Most of these patients had refractory disease or had developed significant side effects to conventional therapy, including azathioprine, methotrexate, prednisone, cyclosporine, acitretin, PUVA, UVB, and tacrolimus. MMF was effective and well tolerated in all these patients. The dosages of MMF ranged from 500 mg twice daily (for psoriasis and Crohn's disease) to 1250mg twice daily (for 3 of 4 patients with pemphigus vulgaris). MMF is an effective and relatively safe immunosuppressant in autoimmune and inflammatory skin diseases.

Adult↗
PubMedDate not supplied

Pemphigus--paradigm of autoantibody-mediated autoimmunity.

Pemphigus encompasses a group of life-threatening autoimmune blistering diseases due to a loss of adhesion between keratinocytes, called acantholysis, which is caused by autoantibodies (AAb) against intercellular adhesion structures of epidermal keratinocytes. In pemphigus vulgaris (PV), the blisters are located in the suprabasal layer whereas in pemphigus foliaceus (PF), a clinically less severe disease, the blisters occur within the upper layers of the epidermis. In PV and PF, the AAb target the extracellular portions of desmoglein 3 (Dsg3) and Dsg1, respectively. AAb production in PV and PF is polyclonal and most AAb are of the IgG4 subclass in acute onset or active disease while patients in remission have mainly AAb of the IgG1 subtype. Evidence for the pathogenicity of these circulating AAb is provided by the observations that (1) the activity of pemphigus correlates with AAb titers, (2) newborns of mothers with active pemphigus temporarily exhibit blisters due to the transplacentar transfer of maternal AAb and (3) pemphigus-like lesions are induced in neonatal mice by transfer of IgG from PV patients. Clinically, pemphigus is characterized by extensive cutaneous blisters and erosions of the mucous membranes (PV). Patients with untreated pemphigus are prone to infections, loss of body fluids and proteins and to weight loss due to painful oral and esophageal erosions. The major therapeutic strategy in pemphigus is chronic immunosuppressive therapy with glucocorticosteroids in combination with immunosuppressive adjuvants.

Animals↗
PubMed2000

The use of chlorambucil with prednisone in the treatment of pemphigus.

BACKGROUND: Chlorambucil is an alkylating agent that preferentially affects B cells over T cells and has been shown to be effective in the treatment of bullous pemphigoid. OBJECTIVE: Our purpose was to determine whether chlorambucil is effective in the treatment of pemphigus. METHODS: We retrospectively reviewed the medical records of 9 patients with pemphigus (7 with pemphigus vulgaris and 2 with pemphigus foliaceus) in whom therapy with other immunosuppressive regimens failed and who were subsequently treated with chlorambucil and prednisone. RESULTS: There was clinical improvement in 6 of 9 patients and a decrease in indirect immunofluoresent antibody titers in 3 of the 5 patients who had titers drawn before and after treatment with chlorambucil. Three of the 9 patients failed treatment with chlorambucil, as evidenced by lack of improvement of lesions. CONCLUSION: Chlorambucil may be a potential adjuvant therapeutic approach with steroid-sparing effects in patients with pemphigus who have failed treatment with other immunosuppressive regimens.

Adult↗
PubMed2000

Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce pemphigus vulgaris-like lesions.

Pemphigus is an autoimmune disease of skin adhesion associated with autoantibodies against a number of keratinocyte antigens, such as the adhesion molecules desmoglein (Dsg) 1 and 3 and acetylcholine receptors. The notion that anti-Dsg antibodies alone are responsible for blisters in patients with pemphigus vulgaris (PV) stems from the ability of rDsg1 and rDsg3 to absorb antibodies that cause PV-like skin blisters in neonatal mice. Here, we demonstrate that PV IgGs eluted from rDsg1-Ig-His and rDsg3-Ig-His show similar antigenic profiles, including the 38-, 43-, 115-, and 190-kDa keratinocyte proteins and a non-Dsg 3 130-kDa polypeptide present in keratinocytes from Dsg 3 knockout mouse. We injected into Dsg 3-lacking mice the PV IgGs that did not cross-react with the 160-kDa Dsg 1 or its 45-kDa immunoreactive fragment and that showed no reactivity with recombinant Dsg 1. We used both the Dsg3(null) mice with a targeted mutation of the Dsg3 gene and the "balding" Dsg3(bal)/Dsg3(bal) mice that carry a spontaneous null mutation in Dsg3. These PV IgGs caused gross skin blisters with PV-like suprabasal acantholysis and stained perilesional epidermis in a fishnet-like pattern, indicating that the PV phenotype can be induced without anti-Dsg 3 antibody. The anti-Dsg 1 antibody also was not required, as its presence in PV IgG does not alter the PV-like phenotype in skin organ cultures and because pemphigus foliaceus IgGs produce a distinct phenotype in Dsg3(null) mice. Therefore, mucocutaneous lesions in PV patients could be caused by non-Dsg antibodies.

Acantholysis↗
PubMed1995

Adjuvant high-dose intravenous gammaglobulin in the treatment of pemphigus and bullous pemphigoid: experience in six patients.

At present, initial high-dose prednisone is the treatment of choice for patients with pemphigus and bullous pemphigoid. To reduce the risks associated with long-term corticosteroid treatment, other immunosuppressants are often given as steroid-sparing agents. Occasionally, the dose of steroids cannot be reduced. In this study, we report six patients with pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, in whom the daily corticosteroid dose could only be tapered to acceptable, effective, maintenance levels following treatment with high-dose intravenous gammaglobulin.

Adult↗
PubMed1999

Internalization of constitutive desmogleins with the subsequent induction of desmoglein 2 in pemphigus lesions.

Acantholytic blisters in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are caused by a dissociation of desmosomes mediated by autoantibodies against desmoglein (Dsg) 3 and Dsg 1, respectively. The blistering occurs at the suprabasilar level in PV and at the subcorneal level in PF, which corresponds to the distribution of target antigens in the epidermis: there is a more prominent expression of Dsg 1 in the upper layer, whereas Dsg 3 is more prominent in the lower layer. To elucidate the histogenesis of acantholysis, we studied the alterations of the desmosomal components and the expression pattern of Dsg isoforms in the lesional and perilesional epidermis of pemphigus patients. The results demonstrated an internalization of the desmosomes in the lower epidermis of PV, PF and pemphigus vegetans. A similar phenomenon was induced in monolayers of keratinocytes cultured with PV sera. However, little change was observed in E-cadherin expression until acantholysis became manifest. This internalization occurred prior to overt acantholysis, and was frequently associated with the induction of Dsg 2 expression in the basilar or lower layers of the epidermis. These findings indicate an alteration of Dsg isoform expression in subclinical pemphigus lesions, which might be related to the characteristic acantholytic patterns: the suprabasilar layer in PV and the upper epidermis in PF.

Cells, Cultured↗