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PubMed1989

Deposition of the membrane attack complex of complement in pemphigus vulgaris and pemphigus foliaceus skin.

The present study was performed to determine whether complement activation in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) results in the assembly of the terminal complement sequence or membrane attack complex (MAC) in skin lesions. Biopsy specimens of skin lesions from five patients with PV and three patients with PF contained C5, C7, C9, and the MAC related neoantigen (C5b-9 neoantigen) in intercellular substance areas (ICS), as well as IgG and the early complement components Clq, C4, and C3. The presence of these late complement components and the C5b-9 neoantigens in ICS sites of the skin lesions is indicative of complement activation by the pemphigus antibody, with subsequent assembly of the MAC. The binding of IgG and early complement components to ICS was observed in both non-lesional (normal appearing) skin and in skin lesions. However, no MAC could be detected in the normal appearing skin of our pemphigus patients. It was also noted that the MAC could be generated in vitro on cryostat sectioned normal human skin by pemphigus antibody in the presence of complement. Results of these studies suggest that complement activation may be related to membrane damage of epidermal cells in both PV and PF.

Complement Membrane Attack Complex↗
PubMed2005

Esophageal pemphigus vulgaris with carcinoma: postoperative steroid therapy based on pemphigus-related antibodies.

A 71-year-old man had been treated as an outpatient for pemphigus vulgaris. Endoscopic examination disclosed an ulcerated lesion in the middle of the esophagus. A biopsy specimen was diagnosed pathologically as squamous cell carcinoma. At surgery, the esophageal mucosa beyond the resection margin appeared edematous and blistered. We carried out anastomosis with sutures rather than staples at the site where the epithelium was least damaged, to minimize likelihood of anastomotic breakdown from poor blood flow. Histopathologic examination of the resected specimen additionally showed blisters and acantholytic cells throughout the esophageal mucosa, so esophageal pemphigus was diagnosed in addition to carcinoma. The patient's general condition deteriorated from worsening of pemphigus. We initiated steroid therapy, making adjustments according to changes in titers of anti-intercellular bridge antibody and antibodies to the cell adhesion molecules (desmoglein 1 and 3). Fever and extensive blistering subsided dramatically, and the patient was discharged in good condition on hospital day 103. When performing esophagectomy in the presence of esophageal pemphigus, the anastomosis must be fashioned cautiously because any mechanical stress can abrade the friable edematous esophageal mucosa. While steroid therapy is known to be effective for pemphigus vulgaris, our findings indicate that in patients with postoperative deterioration of their general condition, marked improvement can be obtained by using antibody titers to guide timing and dose in steroid administration.

Aged↗
PubMed1991

Coexistence of pemphigus foliaceus and bullous pemphigoid. Demonstration of autoantibodies that bind to both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen.

Pemphigus and bullous pemphigoid are autoimmune blistering diseases of the skin characterized by circulating autoantibodies directed against the keratinocyte cell surface and the epidermal basement membrane zone, respectively. The coexistence of pemphigus and bullous pemphigoid is very uncommon. We describe a patient with pemphigus foliaceus who later developed bullous pemphigoid and show, by means of immunoprecipitation studies utilizing both cultured keratinocytes and suction blister epidermis, that our patient had circulating autoantibodies directed against both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen. This report is the first to demonstrate the coexistence of pemphigus foliaceus and bullous pemphigoid at the molecular level.

Antigen-Antibody Complex↗
PubMed2006

Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgaris and Pemphigus foliaceous.

BACKGROUND: A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens. METHODS: Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences. RESULTS: Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous. The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK-RE sequence as a common motif with 75% residue identity. CONCLUSION: This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.

Journal Article↗
PubMed2000

HLA class II polymorphism contributes to specify desmoglein derived peptides in pemphigus vulgaris and pemphigus foliaceus.

Susceptibility to Pemphigus, an autoimmune disease of the skin, has been previously linked to DRB1*0402, 1401/04 and DQB1*0503 in pemphigus vulgaris (PV), to DRB1*0102, 0404, 1402/06 in endemic pemphigus foliaceus in Brazil and to DRB1*04 in Italian patients suffering from pemphigus foliaceus (PF). The disease is caused by autoantibodies against desmoglein (Dsg1 in PF, Dsg3 in PV). Molecular typing of 57 French patients suffering from PV (37) and from PF (20) confirmed previous results concerning PV and showed that DRB1*0102 and 0404 are susceptible molecules to PF in France. We have analysed the characteristics of the 'pockets' of the susceptibility-associated molecules to PV and PF and we showed that (i) in PV, two kinds of Dsg3 derived peptides may be presented by HLA-DR according to HLA polymorphism (DRB1*0402 or DRB1*14/0406), (ii) the same Dsg1 peptides may be presented by DRB1*0102, DQB1*0404 or DRB1*14 in PF, (iii) the DRB1*14/0406 PV-related molecules may be able to present Dsg1 and Dsg3 peptides thereby providing an explanation for the cases of PV with combined responses to Dsg1 and to Dsg3 which are typified by a muco-cutaneous clinical phenotype.

Alleles↗
PubMed1981

Penicillamine-associated pemphigus: is it really pemphigus?

Penicillamine-associated bullous eruptions share with spontaneously occurring pemphigus intraepidermal acantholysis, epidermal intercellular deposition of immunoglobulin, and circulating serum antibody against the intercellular regions of the epidermis. We report the case of a penicillamine-associated bullous eruption in which there were some of the histologic features of pemphigus, but none of the immunofluorescent features. Instead, the immunofluorescent findings of bullous pemphigoid were demonstrated. Review of the literature reveals that clinical and histologic features of penicillamine-associated bullous eruptions differ in important respects from those of spontaneously occurring pemphigus. Our report adds immunologic data to evidence that the penicillamine-associated bullous eruptions may not be the same disease as spontaneously occurring pemphigus.

Arthritis, Rheumatoid↗
PubMed1998

Novel non-radioisotope immunoprecipitation studies indicate involvement of pemphigus vulgaris antigen in paraneoplastic pemphigus.

We have developed two different novel immunoprecipitation assays in which radioisotopes are not used, and have examined antigens for four cases of paraneoplastic pemphigus (PNP) including three new patients. The PNP sera showed a clear reactivity with transitional epithelia of rat urinary bladder by immunofluorescence, and reacted with a characteristic doublet of the 210 and 190 kD proteins by immunoblotting of normal human epidermal extract, confirming the diagnosis of PNP. In addition, by immunoprecipitation using silver-stain to detect immunoprecipitated proteins, the PNP sera detected the 250, 210 and 190 kD proteins, while control bullous pemphigoid sera detected only the 230 kD bullous pemphigoid antigen. Furthermore, with another immunoprecipitation using cell surface biotinylation, three of the four PNP sera specifically reacted with the 130 kD pemphigus vulgaris antigen (Dsg3), indicating that pemphigus vulgaris antigen may be involved in PNP. This reactivity was further suggested by the immunoblot analysis using recombinant pemphigus vulgaris antigen. In future, these non-radioisotope immunoprecipitation assays should become a useful tool not only to unravel the complex situation for the PNP antigens, but also to study antigens in other autoimmune bullous skin diseases.

Animals↗
PubMed2000

The distribution of pemphigus vulgaris-IgG subclasses and their reactivity with desmoglein 3 and 1 in pemphigus patients and their first-degree relatives.

BACKGROUND: Pemphigus vulgaris (PV) autoantibodies (PV-IgG) have been found in 40-70% of sera of first-degree relatives of pemphigus patients. OBJECTIVES: To determine the possible role of PV-IgG subclasses in the pathogenesis of the disease. PATIENTS AND METHODS: Study groups comprised 25 PV patients, 55 unaffected family members and 56 sera of healthy individuals. Indirect immunofluorescence (IIF) staining and Western immunoblotting (WB) techniques were used to determine total PV-IgG and PV-IgG subclasses and their reactivity to desmoglein (Dsg) 1 and 3. RESULTS: By IIF staining, circulating PV-IgG were found in 64% of the patients, in 15% of the relatives and in none of the controls (P < or = 0.001); by WB the results were 91%, 49% and 12%, respectively (P < or = 0.001). The distribution of PV-IgG subclasses 1-3 was similar among patients and their relatives. PV-IgG4 was found in 62% of the patients but in only one relative and was absent in the controls (P < or = 0.001). PV-IgG1, 2 and 4 were found to react mainly with Dsg3 and PV-IgG3 mainly with Dsg1 and 3. CONCLUSIONS: These results support the concept of a genetic predisposition in pemphigus. The non-complement-fixing PV-IgG4 and at least one complement-fixing PV-IgG subclass appear to be involved in the pathogenesis of the disease. The absence of PV-IgG4 among relatives who were PV-IgG carriers seems to be linked to the fact that they do not develop pemphigus. The exact nature of this linkage is still unclear.

Adult↗
PubMed2002

A nonfatal case and 2 fatal cases of paraneoplastic pemphigus: can a complement indirect immunofluorescent test help to identify fatal "group A" paraneoplastic pemphigus cases?

We studied 3 recent cases of paraneoplastic pemphigus (PNP) in detail. Two patients died despite concerted management efforts. One patient received no treatment after the appearance of PNP and recovered completely from both PNP and lymphoma. Multiple serum studies of these 3 patients plus 9 other proven PNP cases revealed that 8 of 9 fatal PNP cases (referred to here as "group A") had distinctive cell surface antibodies detected by complement indirect immunofluorescent (CIIF) tests on monkey esophagus sections. By contrast, none of the sera from 3 patients with PNP who experienced long-term survival (referred to here as "group B") and none of 20 pemphigus vulgaris or 10 pemphigus foliaceus control sera revealed similar beaded cell surface CIIF reaction patterns, a difference that is statistically significant (P <.0001). Cell surface CIIF reaction patterns of group A PNP antibodies resemble the pattern of pemphigus antibody reactions in indirect immunofluorescent tests on the same substrate; however, the latter tend to be thinner and more linear, whereas the cell surface CIIF pattern tends to be more beaded, suggesting possible desmosomal reactions. We believe this test is useful in identifying an aggressive group A form of PNP.

Antibodies, Antinuclear↗
PubMed1989

Proteinase inhibitors block formation of pemphigus acantholysis in experimental models of neonatal mice and skin explants: effects of synthetic and plasma proteinase inhibitors on pemphigus acantholysis.

In organ culture experiments, the induction of pemphigus acantholysis is known to be blocked by the addition of serine proteinase inhibitors. Recently, nontoxic synthesized low molecular weight proteinase inhibitors have been clinically available for the treatment of disseminated intravascular coagulation and pancreatitis. To determine if these drugs are useful aids to treat patients with pemphigus, we examined the effect of omega-guanidino ester analogues, i.e., 1) gabexate mesilate, 2) camostat mesilate, and 3) nafamostat mesilate, on experimental pemphigus acantholysis in both organ culture and neonatal BALB/c mice. Furthermore, the effect of plasma natural proteinase inhibitors (alpha-1-proteinase inhibitor) isolated from human plasma was similarly examined. Results revealed that synthesized low molecular weight inhibitors (drugs) were able to inhibit the induction of acantholysis in organ culture system, but had little or no effect on lesion formation in the neonatal mouse system. By contrast, alpha-1-proteinase inhibitor could completely inhibit acantholysis formation in mice. These findings implied a possible new therapeutic approach using proteinase inhibitors for patients with pemphigus.

Acantholysis↗
PubMed1994

Immunohistopathological study of autoimmune pemphigus. Lack of strictly specific histological and indirect immunofluorescence criteria for paraneoplastic pemphigus.

Paraneoplastic pemphigus (PNP) is a form of pemphigus considered to bear characteristic immunohistopathological features (vacuolar-interface dermatitis, keratinocyte dyskeratosis and reactivity of patients' sera with transitional epithelia). The present study was undertaken in order to investigate whether these criteria are specific enough so as to allow the diagnosis of PNP in the absence of clinical data. A retrospective study of 66 biopsies of pemphigus revealed that one third of them comprised histological signs of PNP; one of the corresponding sera reacted with mouse bladder epithelium. However, no evidence of a neoplastic disease was present in any of the patients, and Western blotting further excluded the diagnosis of PNP. These results suggest that some of the features considered characteristic of PNP are not strictly specific for this variety of pemphigus; hence this diagnosis cannot be reliably established by histology or immunofluorescence but requires biochemical studies.

Acantholysis↗
PubMed1987

T- and B-lymphocytes in pemphigus vulgaris. A clinico-immunological follow-up study of fifty patients with pemphigus vulgaris.

Peripheral blood T-lymphocytes, studied in 50 patients with pemphigus vulgaris by means of spontaneous (E) and active (EA) rosette-formation, were increased in active disease and gradually returned to normal after achieving clinical remission of pemphigus vulgaris. The portion of B-cells quantified by M-rosette formation was increased in active disease as well (19.9 +/- 3.0% vs. 10.8 +/- 1.6% in controls) (p less than 0.02) but returned to normal immediately after clinical remission was obtained. Levamisole in vitro suppressed E-, EA-, and M-rosette formation in all the patients examined with active disease. The subsets of T-cells in 10 non-treated patients with active pemphigus vulgaris and 5 patients with a long-term steroid maintained remission of the disease were studied using OKT series monoclonal antihuman antibodies. A statistically significant increase in the percentage of OKT3+ cells (p less than 0.05) and a considerable increase in OKT4+ cell count (p less than 0.002) were registered in patients with active pemphigus vulgaris, compared with controls. In five patients with 2-9 years' remission the percentage of OKT3+, OKT4+, OKT5+ and OKT8+ cells did not significantly differ from controls.

Adult↗
PubMed1984

Penicillamine-induced pemphigus. Immunoglobulin from this patient induces plasminogen activator synthesis by human epidermal cells in culture: mechanism for acantholysis in pemphigus.

The incubation of cultured epidermal cells with IgG obtained from a 56-year-old man with penicillamine-induced pemphigus resulted in an increase in extracellular and intracellular plasminogen activator. This suggests that penicillamine-induced pemphigus and spontaneously occurring pemphigus share common pathophysiologic processes in the induction of blister formation.

Acantholysis↗
PubMed2002

Isotypes and antigenic profiles of pemphigus foliaceus and pemphigus vulgaris autoantibodies.

In this study we systematically characterized isotype profiles and antigenic and tissue specificity of antidesmoglein autoantibodies from patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) using enzyme-linked immunoabsorbent assays (ELISA), indirect immunofluorescence (IIF) staining, and immunoblotting (IB). In PF, we found that IgG1 antidesmoglein-1 (Dsg1) reacts with a linear epitope(s) on the ectodomain of Dsg1, while its IgG4 counterpart recognizes a conformational epitope(s). These two subclasses of anti-Dsg1 are both capable of recognizing tissues from monkey esophagus and adult human skin, but IgG1 is not able to react with mouse skin, which may explain why this isotype of anti-Dsg1 failed to induce PF-like lesions in the passive transfer animal model. In mucosal PV patients, we found that both IgG1 and IgG4 only recognized monkey esophagus tissue by IIF, except in one patient, indicating that these antibodies react with a unique conformational epitope(s) that is present in mucosal but not skin tissue. In generalized PV, IgG1 anti-Dsg3 autoantibodies appeared to recognize a linear epitope(s) on the Dsg3 ectodomain. In contrast, IgG4 anti-Dsg3 antibodies recognized both linear and conformational epitopes on the Dsg3 molecule. Interestingly, the IgG1 anti-Dsg3 antibodies failed to react with human and mouse skin tissues, suggesting that this subclass of autoantibodies may not play an essential role in the development of PV suprabasilar lesions. In summary, we conclude that this study further elucidates the pathological mechanisms of PF and PV autoantibodies by revealing their distinct isotype and antigenic profiles. This information may help us to better understand the autoimmune mechanisms underlying the development of pemphigus.

Animals↗
PubMed1998

Neonatal pemphigus vulgaris associated with mild oral pemphigus vulgaris in the mother during pregnancy.

We report a neonate with immunofluorescence-proven pemphigus vulgaris. The condition presented at birth with widespread skin erosions and ulceration of the oral mucosa. Histopathological and immunofluorescence studies confirmed pemphigus vulgaris. The mother had mild oral pemphigus vulgaris treated during pregnancy with topical corticosteroids. All the neonate's skin erosions had crust formation at day 2 but healed completely within 2 weeks.

Autoimmune Diseases↗
PubMed1999

The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid.

Seven patients with mild pemphigus vulgaris (n = 3) or pemphigus foliaceus (n = 4) were treated with a very potent topical corticosteroid alone. Clobetasol propionate 0.05% cream was applied to mucosal lesions and involved skin twice a day for at least 15 days, then progressively tapered. Pemphigus was considered to be controlled if healing of lesions was obtained, with a 75% decrease in the number of new lesions per week without addition of any systemic treatment. In all seven patients, the disease was controlled initially with healing of cutaneous lesions within 15 days, while healing of mucosal lesions took at least 1 month. In four patients, remission was maintained with topical corticosteroid alone for a mean 19-month follow-up. In three patients, relapse occurred after 2-11 months, requiring a systemic treatment.

Administration, Topical↗
PubMed2000

Paraneoplastic pemphigus with circulating antibodies directed exclusively against the pemphigus vulgaris antigen desmoglein 3.

A patient with follicular B-cell lymphoma presented with erythroderma associated with cutaneous and mucosal blisters. Histologic and direct immunofluorescence analysis of lesional skin showed a typical pattern of paraneoplastic pemphigus (PNP). Interestingly, indirect immunofluorescence on rat bladder was negative and immunoblot analysis of the patient's serum on epidermal extracts demonstrated antiepidermal antibodies that only recognized the pemphigus vulgaris antigen desmoglein 3, with no antibodies directed against the different proteins of the plakin family. To our knowledge this has never been reported in the literature. It exemplifies the overlap between pemphigus vulgaris and PNP and the pathogenic role of anti-desmoglein 3 antibodies in PNP. Moreover, it underscores the need to consider clinical, histologic, and immunologic features for the diagnosis of PNP.

Autoantibodies↗