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Pemphigus vulgaris (PV) is an auto-immune blistering skin disease characterized by flaccid blisters and painful erosions of mucous membranes and skin. Suprabasal blister formation results from a loss of epidermal cohesion induced by auto-antibodies against the desmosomal protein desmoglein 3. Treatment of PV currently consists of systemic glucocorticosteroids and adjuvant immunosuppressive drugs such as azathioprine, mycophenolate mofetil, cyclophosphamide or dapsone. Due to the low incidence of PV, there are insufficient data to conclude which treatment is the most effective and safest. Thus far, systemic tacrolimus (FK506, Prograf) has not yet been reported as adjuvant medication for PV. Here, we describe the successful use of systemic tacrolimus in 2 patients with recalcitrant PV of the oral mucosa. Tacrolimus was well tolerated, and clinical improvement allowed tapering of corticosteroids. Thus, oral tacrolimus may be a therapeutic alternative for patients with recalcitrant PV. [ABSTRACT FROM AUTHOR]

Abstract: Pemphigus vulgaris (PV) is a severe autoimmune bullous skin disease and is primarily associated with IgG against desmoglein 3 (dsg3), a desmosomal adhesion protein. In light of the recent association of autoreactive T helper (Th) 2 cells with active PV, the present study sought to relate the occurrence of Th2-regulated dsg3-specific autoantibody subtypes, i.e. IgE and IgG4, in 93 well-characterized PV patients. Patients with acute onset PV (n =37) showed the highest concentrations of serum IgE and IgG4 autoantibodies, which were significantly lower in PV patients in remission (n =14). Furthermore, there was a strong correlation between dsg3-reactive IgE and IgG4 in acute onset, but not in chronic active (n =42) or remittent patients. Additionally, intercellular IgE deposits were detected in the epidermis of acute onset PV. Thus, dsg3-specific IgE and IgG4 autoantibodies are related to acute onset disease which provides additional support to the concept that PV is a Th2-driven autoimmune disorder. [Copyright &y& Elsevier]

The article lists poster presentations related to pediatric dermatology including "The Effect of Breast Milk on the Healing of Diaper Dermatitis," "Vernix Caseosa: An Hydrophobic Layer," and "Congenital Lesions With the Hair Collar Sign."

Objectives/Hypothesis: We sought to investigate the role of desmoglein 3 in pathogenesis of sinonasal inverted papilloma (IP) and its malignant transformation. Methods: Fifteen subjects with sinonasal IP and 15 subjects of normal sphenoid sinus mucosa were enrolled. Each specimen was divided into two portions: one for mRNA expression analysis by real-time polymerase chain reaction, and the other for detection of targeted proteins by immunohistochemistry analysis. In addition, another 10 cases of IP with squamous cell carcinoma (SCC) were added for immunohistochemistry analysis. Results: The mRNA expression level of desmoglein 3 was significantly higher in IP tissues than in the normal sinus mucosa ( P < .001). In immunohistochemistry study, desmoglein 3 was detected in plasma membrane areas of IP and IP with SCC tissues, but no obvious expression was found in normal sinus mucosa (total score; both P < .001). Positive desmoglein 3 staining was strongly present in nearly all malignant transformation areas of IP with SCC cases (90%), but only in scattered areas of some cases of IP (53%) (total score; P < .001). Conclusions: Desmoglein 3 was overexpressed in IP and IP with SCC, and the overexpression was correlated with malignant transformation of IP. It may provide valuable insight into the pathobiology of this disease, and can potentially provide a venue to predict malignant transformation in sinonasal IP. Laryngoscope, 2010 [ABSTRACT FROM AUTHOR]

In patients with pemphigus vulgaris (PV), pathogenic immunoglobulin (Ig)G antibodies are most commonly directed against desmoglein 3 (Dsg3). It has recently been reported, however, that IgG anti-desmocollin 3 (Dsc3) antibodies are detected in some cases of pemphigus with or without IgG anti-Dsg3 antibodies. We present a case of pemphigus with IgG antibodies against Dsg3 and Dsc3. Subsequent studies showed that the cell surface distribution pattern of Dsc3 but not Dsg3 was altered, suggesting that suprabasal acantholytic blisters were induced by IgG anti-Dsc3 antibodies rather than IgG anti-Dsg3 antibodies. Our case suggests that anti-Dsc3 antibodies may be pathogenic in cases positive for the dual cadherin autoantibodies. [ABSTRACT FROM AUTHOR]

Introduction: Basal cell carcinoma (BCC) is the most common type of skin cancer and its incidence appears to be increasing. Objective: Reasons to undertake the study of desmoglein 3 protein (DSG3) expression in BCC were twofold: (i) DSG3-linked pemphigus vulgaris (PV), a life-threatening autoimmune blistering dermatosis, can coexist with malignancy, (ii) hair follicles, which physiologically express DSG3, apparently are involved in both PV pathogenesis (mature follicular cells) and BCC pathogenesis (stem cells of the bulge region of hair follicle). Material and methods: DSG3 expression was evaluated in BCC-affected areas in patients with BCC (22 specimens; BCC tumor), in non-BCC-affected epidermis in patients with BCC (21 specimens; control 1) and in more benign tumors than BCC (12 seborrheic keratosis specimens and 10 keratosis senilis specimens; control 2). The immunohistochemical staining on frozen sections was performed using monoclonal murine anti-DSG3 antibody. The digital microscopic image analysis with quantitative morphometric software was then used to measure the intensity of positive immunostaining signals of the DSG3 in the area of interest (tumor-affected, tumor-free). Results: There was significantly lower expression of DSG3 in BCC tumor compared to both control 1 and control 2. There was no significant difference of DSG3 expression in control 1 and control 2. Conclusions: Thus, it seems that DSG3 might have some role in BCC pathogenesis as its decreased expression in BCC-affected epidermis might reflect just locally invasive behavior of that tumor. Apparently, factors independent from DSG3 are capable to keep BCC cells in clusters, but are incapable to do the same as far as keratinocytes in PV are concerned. [ABSTRACT FROM AUTHOR]

Mucositis is a frequent problem after irradiation of the oral mucosa. To study the early effects of irradiation on the desmosomal adhesion complex, explants of keratinized oral mucosa were exposed to a single dose of 2 Gy gamma irradiation. Biopsies were obtained from the upper dental arch of nine young healthy non-smoking women undergoing minor oral surgery. The biopsies were incubated in a Transwell culture system and, after irradiation, fixed in formalin 24 h later. Morphometric measurements of epithelial thickness revealed that it was unaffected by exposure to ionizing rays. Immunofluorescence analysis of desmosomal cadherin expression (desmoglein 1/desmoglein 3) demonstrated that the distribution of desmoglein 1 was not affected, whereas the expression of desmoglein 3 decreased in the suprabasal layers of irradiated samples. It is suggested that this has consequences for the mechanical integrity of the mucosa and promotes the development of radiation mucositis. [ABSTRACT FROM AUTHOR]

Anti-desmoglein 3 and 1 autoantibodies are involved in the pathogenesis of pemphigus diseases. Our objective was to assess the value of ELISA in the diagnosis of pemphigus and its correlation with the severity of pemphigus vulgaris. Based on clinical presentation and histopathologic confirmation for the diagnosis of the pemphigus, 38 patients took part in the study. Sera of the patients were tested by desmoglein 1 and desmoglein 3 ELISA. Also, direct immunofluorescence was performed for all patients which revealed positive results in 36 patients (94.7%). ELISA was positive in 37 of 38 pemphigus patients (Sensitivity: 97.3%). The relationship between desmoglein 1 index values and skin severity was statistically significant (p<0.05). Desmoglein 3 index values increased with oral severity although this was not statistically significant. Iranian patients similar to Indian patients had higher positive anti-desmoglein 1 autoantibodies. Desmoglein-ELISA test is appropriate in the diagnosis of pemphigus. Desmoglein 1 index value is statistically correlated with the severity of pemphigus vulgaris. [ABSTRACT FROM AUTHOR]

Abstract: We have previously demonstrated that serum autoantibodies of patients with pemphigus vulgaris (PV) may affect desmoglein 3 (Dsg3)-mediated adhesion by decreasing its half-life and inducing Dsg3 cleavage. Here we sought to gain more insights into the role of Dsg3-targetting IgG in acantholysis. To do so, alterations of keratinocyte morphology and cell–cell adhesion strength were investigated in the presence of PV serum, PV IgG, and IgG purified from PV patients’ sera against linear epitopes of Dsg3 (anti-Dsg3-L IgG). Changes in Dsg3 protein levels were assessed by Western blotting. Results showed that both PV serum and PV IgG were able to induce acantholysis and decrease the total amount of Dsg3 in cell lysates. Polyclonal anti-Dsg3-L IgG displayed Dsg3-depleting activity solely when used at 1μg/ml, i.e. under non-physiologic conditions. Furthermore, cell–cell detachment induced by PV IgG and anti-Dsg3-L IgG seemed to precede the loss of Dsg3 from keratinocytes, suggesting that depletion/degradation of Dsg3 represents a late event in acantholysis. Collectively, the data presented here demonstrate that PV IgG recognizing non-conformational epitopes of Dsg3 are pathogenic when administered on doses largely exceeding those found in PV sera. [Copyright &y& Elsevier]

We have previously demonstrated that serum of patients with pemphigus vulgaris induces reduction of desmoglein 3 (Dsg3) half-life in keratinocytes (FEBS Lett 2006: 580: 3276). This phenomenon seems to occur as a consequence of the progressive depletion of Dsg3 from desmosomes. Here we reported that reduction of full-length Dsg3 may be due to its progressive cleavage, leading to the formation of two fragmentation products with apparent molecular masses of about 60 kDa (fragment 1) and 70 kDa (fragment 2), as revealed by Western blotting. Unexpectedly, analysis of fragmentation pattern suggested cleavage to occur intracellularly. Consistently, fragment 1 was shed and localized within the cytosol, as shown by living cell immunofluorescence microscopy. Total amounts of full-length plakoglobin and Dsg1 were apparently unchanged. Taken together, our findings provide evidence that proteolytic processing of Dsg3 can lead to depletion of Dsg3 from the cell. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is considered to be an autoimmune disease affecting skin and mucous membranes. Traditionally, PV autoantibodies are thought to recognize antigens located in the intercellular substance (ICS) of keratinocytes; antigens represented mainly by the desmosomal cadherin desmoglein 3 (Dsg3). Accordingly, titres of anti-ICS and anti-Dsg3 immunoglobulin G (IgG) are considered to be major laboratory criteria when making a diagnosis of PV. In this paper, we demonstrated for the first time that PV IgG bind antigen(s) expressed on the surface of peripheral blood mononuclear cells (PBMC), as revealed by immunofluorescence studies. This novel autoantigen is immunoprecipitated by PV IgG as a 130 000 molecular weight protein. However, Western blot analysis of the immunocomplexes failed to show reactivity with anti-Dsg3 monoclonal and polyclonal antibodies. Taken together, our data provide strong evidence that PV autoimmunity targets a 130 000 antigen other than Dsg3 on PBMC. This shifting from epidermis to blood cells may open new perspectives for a better understanding of pemphigus autoimmunity and more rational approaches to its treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the specific matrix metalloproteinases (MMPs) targeting desmoglein 3 (Dsg3) in apoptotic keratinocytes. Method: Inhibitor studies on cultured keratinocytes and Western blot analysis. Results: Blocking of MMP-9 activity strongly reduces shedding of Dsg3 from cell surface. MMP-2 has a less relevant role in the cleavage of Dsg3 while other MMPs, such as MMP-1, -3, and -8, do not target Dsg3. Conclusion: Apoptic keratinocytes impair the extracellular domain of cell surface Dsg3 by MMP-9 activity. The discovery of a specific targeting of Dsg3 could be useful to understand the pathophysiology of diseases in which Dsg3 is affected. [ABSTRACT FROM AUTHOR]

We showed previously that primary keratinocytes selected for low desmoglein 3 (Dsg3) expression levels exhibited increased colony-forming efficiency and heightened proliferative potential relative to cells with higher Dsg3 expression levels, characteristics consistent with a more ‘stem/progenitor cell-like’ phenotype. Here, we have confirmed that Dsg3dim cells derived from cultured primary human adult keratinocytes have comparability with α6 bri/CD71dim stem cells in terms of colony-forming efficiency. Moreover, these Dsg3dim cells exhibit increased reconstituting ability in in vitro organotypic culture on de-epidermalized dermis (DED); they are small, actively cycling cells, and they express elevated levels of various p63 isoforms. In parallel, using the two immortalized keratinocyte cell lines HaCaT and NTERT, we obtained essentially similar though occasionally different findings. Thus, reduced colony-forming efficiency by Dsg3bri cells consistently was observed in both cell lines even though the cell cycle profile and levels of p63 isoforms in the bri and dim populations differed between these two cell lines. Dsg3dim cells from both immortalized lines produced thicker and better ordered hierarchical structural organization of reconstituted epidermis relative to Dsg3bri and sorted control cells. Dsg3dim HaCaT cells also show sebocyte-like differentiation in the basal compartment of skin reconstituted after a 4-week organotypic culture. No differences in percentages of side population cells (also a putative marker of stem cells) were detected between Dsg3dim and Dsg3bri populations. Taken together our data indicate that Dsg3dim populations from primary human adult keratinocytes and long-term established keratinocyte lines possess certain stem/progenitor cell-like properties, although the side population characteristic is not one of these features. [ABSTRACT FROM AUTHOR]

Abstract: Defects of cell–cell adhesion underlie disruption of epithelial integrity observed in patients with pemphigus vulgaris (PV), an autoimmune disease characterized by severe mucosal erosions and skin blisters. Pathogenic PV autoantibodies found in patients’ sera target desmoglein 3 (Dsg3), a major component of the desmosome, but how does this phenomenon affect Dsg-dependent adhesion and lead to acantholysis still remains controversial. Here, we show that PV serum determines a reduction of Dsg3 half-life in HaCaT keratinocytes, although the total amount of Dsg3 remains unchanged. Immunofluorescence studies suggest that PV IgG exert their effect prevalently by binding non-desmosomal Dsg3 without causing its massive internalization. Furthermore, PV IgG targeting desmosome-assembled Dsg3 do not induce depletion of Dsg3 from the adhesion sites. Conversely, incorporation of PV IgG-Dsg3 complexes into new forming desmosomes appears perturbed. With our study, the basic biochemical changes of Dsg3 in an in vitro model of PV have been defined. [Copyright &y& Elsevier]

Human systemic lupus erythematosus (SLE) and its murine model, MRL Ipr/Ipr mice, are well known to develop a wide range of symptoms, such as glomerulonephritis, dermatitis, and arthritis, as an immune-complex disease. However, the deposition of circulating immune complex does not fully explain the tissue specificity of disease. Tissue-specific autoantigens may also be involved in tissue inflammation. In this study, desmoglein 3 (Dsg3), a major component of epidermal desmosomes, was identified as a skin-specific autoantigen. Several murine models of skin inflammation were found to develop autoantibodies to Dsg3 tightly correlated with disease aggravation, especially in MRL Ipr/Ipr mice. Furthermore, SLE-prone skin disease-free FcγRIIb-deficient mice developed skin inflammation upon immunization with Dsg3. Taken together with histological studies, we concluded that skin-specific Dsg3 serves as an autoantigen in chronic skin inflammatory diseases accompanied by mast cell degranulation, including both murine SLE and other autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Background Pemphigus vulgaris (PV, OMIM 169610) is a severe blistering disorder of the skin and mucous membranes, caused by the production of autoantibodies directed against the epithelial adhesive protein desmoglein 3. Although an association between PV and HLA class II alleles has been established, the genetic factors predisposing to the disease remain poorly understood, the rarity of PV hampering the recruitment of substantial patient cohorts. Objectives To investigate DSG3 as a candidate PV susceptibility gene. Methods We examined five DSG3 single nucleotide polymorphisms (rs8085532, rs3911655, rs3848485, rs3794925 and rs1466379) in two case–control datasets respectively originating from the U.K. (62 PV patients, 154 controls) and northern India (28 patients, 98 controls). Results In the U.K. sample, we observed a significant association between PV and the DSG3*TCCTC haplotype (Fisher's exact test P = 0·002). A related haplotype (DSG3*TCCCC) was associated with PV in the Indian dataset ( P = 0·002). We also found that all British and Indian patients bearing DSG3 risk haplotypes carried at least one copy of a PV-associated HLA allele. Conclusions These results suggest that genetic variation of DSG3 may be an additive risk factor predisposing to PV and warrant further investigations of this gene. [ABSTRACT FROM AUTHOR]

Our labs are pursueing the goal of exactly defining the qualities of peptide antigenicity, immunogenicity and pathogenicity in order to develop safe specific immunotherapies by utilizing specific portions of disease-associated-proteins (DAPs). Using as a model the Pemphigus vulgaris antigen (PVA) desmoglein 3 (Dsg3), we have studied the murine humoral response against the Dsg3 amino acid 49-60 peptide sequence, previously characterized as sequence having low similarity to the mouse proteome. The results show that the low-similarity Dsg349-60 REWVKFAKPCRE peptide does not elicit pathogenic antibodies. [ABSTRACT FROM AUTHOR]

ABSTRACT Tufted hair folliculitis (THF) is a rare disease which is characterized by the emergence of multiple hairs from widely dilated follicular orifices surrounded by an inflammatory infiltrate resulting in scarring alopecia. The pathogenesis is not yet fully understood. Although colonization with Staphylococcus aureus could not always be detected and systemic treatment with antibiotics alone is not sufficient, this microorganism is considered to play an important role. Around 30 patients with THF have been reported since the first publication. We present a patient with pemphigus vulgaris who developed THF. To our knowledge, this is the fourth case with an association of these two entities. Amongst other causing mechanisms, the autoimmune reaction may play an important role for the development of THF. [ABSTRACT FROM AUTHOR]

The desmoglein plays an important part in the formation of desmosomes. We constructed recombinant adenoviruses containing desmoglein 1 and desmoglein 3 derivatives partly lacking the extracellular domain (desmoglein 1ΔEC and desmoglein 3ΔEC, respectively), and full-length desmoglein 1 and desmoglein 3 and studied the involvement of desmoglein 1 and desmoglein 3 in desmosome formation. During low-level expression of desmoglein 3ΔEC in transduced HaCaT cells, keratin insertion at cell–cell contact sites was only partially inhibited and desmoplakin was partially stained at cell–cell contact sites. Low-level expression of desmoglein 1ΔEC, however, resulted in complete inhibition of keratin insertion at the cell–cell contact sites, and desmoplakin was stained in perinuclear dots. These results indicate the dominant-negative effect of desmoglein 1ΔEC on desmosome formation was stronger than that of desmoglein 3ΔEC. Desmoglein 1ΔEC coprecipitated plakoglobin to approximately the same extent as desmoglein 3ΔEC. Therefore, we conclude that the dominant-negative effect of desmoglein 1ΔEC is not simply due to plakoglobin sequestration. On the other hand, during low-level expression of full-length desmoglein 3 and desmoglein 1, they both colocalized with desmoplakin. During high-level expression, however, keratin insertion at cell–cell contact sites was inhibited in desmoglein 1 but not in desmoglein 3, and desmoplakin was stained at cell–cell contact sites in desmoglein 3 but not in desmoglein 1. These data suggest desmoglein 1 and desmoglein 3 expressed at low level were incorporated into desmosome but at high-level expression, desmoglein 1 disrupted desmosomes but desmoglein 3 did not. Our findings provide biologic evidence that desmoglein 1 and desmoglein 3 play a different functional role in cell–cell adhesion of keratinocytes. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by autoantibodies against the desmosomal cadherins, desmogleins 1 and 3 (Dsg1, Dsg3) of which Dsg3 plays a major pathogenic role. We have previously generated a novel active disease mouse model for PV, which was produced by the transfer of splenocytes from Dsg3–/– mice, immunized with recombinant mouse Dsg3, into Rag2–/–-immunodeficient mice that express Dsg3. In this study, we undertook a further analysis of these PV model mice using electron microscopy (EM). We compared the ultrastructure of the epithelia of PV model mice with that of Dsg3–/– mice to highlight the mechanisms of blister formation in PV. These PV model mice showed the ultrastructural phenotype of PV, which is characterized by suprabasal acantholysis, rows of tombstone basal keratinocytes and half-desmosomes. Additionally, patchy hair loss was observed in PV model mice as in Dsg3–/– mice, and the ultrastructure of the telogen hair follicles was indistinguishable between PV model mice and Dsg3–/– mice. These results demonstrate that anti-Dsg3 autoantibodies interfere with the cell-cell adhesion of keratinocytes in PV model mice. In conclusion, our model mice closely represent the disease phenotype of PV at the ultrastructural level and can therefore be utilized not only as a clinical disease model but also to study the molecular mechanisms involved in blister formation in PV. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous disease associated with production of IgG autoantibodies to desmoglein 3, a 130 kDa epidermal protein. To further characterize the epitope(s) of pemphigus vulgaris antigen we established two human-human hybridoma by fusion of the peripheral blood mononuclear cells with a human and mouse heterohybridoma. These hybridomas designated as MAb Dsg-3: 06 and MAb Dsg-3: 10 and stable in culture and demonstrated yield of monoclonal antibodies specific for pemphigus vulgaris. Immunofluorescence, immunoblot, ELISA assays demonstrated that both the monoclonal antibodies bind to the intercellular cement substance and to 130 kDa protein present in the skin and specifically binds to recombinant desmoglein 3 protein, but not to desmoglein 1 protein. The IgG subclass distribution study demonstrated that both the antibodies are of IgG1 subclass in nature. Both the antibodies were non-pathogenic as demonstrated in vitro by their inability to produce acantholysis in normal human skin in organ culture or in vivo by the induction of disease in neonatal BALB/c mice. The relevance and value of these monoclonal antibodies in the pathogenesis of pemphigus vulgaris is discussed. [ABSTRACT FROM AUTHOR]

Summary Background Pemphigus vulgaris (PV) is a severe autoimmmune skin disorder induced by antibodies against desmoglein (Dsg) 3 on epidermal keratinocytes. Objectives To establish an active animal model of PV to analyse the T-cell-regulated production of pathogenic antibodies in vivo . Methods Immunodeficient SCID mice were injected with peripheral blood lymphocytes (PBL) from an HLA-DRB1*0402/DQ8+ patient with PV or a DRB1*0402/DQ8+ healthy donor, with or without subsequent injections of human Dsg3 or preincubation of PBL with Dsg3. Results Human immunoglobulins (2·7–18·5 mg mL-1 ) were detected in all the mice after 8 weeks. Only one of 30 PBL-treated mice developed IgM against Dsg3 and showed intercellular IgM deposits in skin, nostrils and tongue. In contrast, in a previous study, 41% of SCID mice injected with PBL from patients with PV developed anti-Dsg3 antibodies in vivo . Conclusions Our inability to reproduce these findings may be due to the transfer of slightly lower numbers of PBL (20 × 106 vs. 25–30 × 106 ). [ABSTRACT FROM AUTHOR]

Background IgG autoantibodies against desmoglein (Dsg) 3 play a key part in the pathogenesis of pemphigus vulgaris (PV), the most severe autoimmune bullous disorder. Objectives To determine whether immunoglobulin isotypes other than IgG are detectable in the sera of patients with PV and whether a particular immunoglobulin subtype is associated with a distinct clinical phenotype of PV. Methods Sera from 41 patients with acute-onset, chronic active, and remittent PV disease with mucosal and cutaneous lesions were assayed against a baculovirus-expressed Dsg3 protein by immunoblot analysis. Results In acute-onset PV, Dsg3-reactive IgG1 was detected in nine of 15 (60%), IgG4 in 14 of 15 (93%), IgA in nine of 15 (60%) and IgE in two of 15 (13%) sera. In chronic active PV, Dsg3-reactive IgG1 was detected in 11 of 18 (61%), IgG4 in 16 of 18 (89%), IgA in 13 of 18 (72%) and IgE in two of 18 (11%) sera. In contrast, sera from patients with remittent PV disease contained only Dsg3-reactive IgG1 in six of eight (75%) and IgG4 in four of eight (50%) cases, but not Dsg3-reactive IgA or IgE. Conclusions In extension of previous findings, our study demonstrates that, in addition to IgG autoantibodies, IgA and occasionally IgE autoantibodies reactive with Dsg3 are present in acute and chronic active PV. The detection of Dsg3-reactive autoantibodies of the IgG4, IgA and IgE subclasses in active PV provides additional evidence that PV is a T-helper 2-regulated autoimmune disorder. [ABSTRACT FROM AUTHOR]

Background Pemphigus vulgaris (PV) and foliaceus (PF) are characterized by antibodies to the desmosomal proteins desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. Past studies using indirect immunofluorescence (IIF) as a measure of pemphigus antibody levels have failed to demonstrate consistently a relationship between disease severity and IIF titres. However, IIF is not able to measure separately Dsg1 and 3 antibodies, unlike enzyme-linked immunosorbent assays (ELISA), which utilize recombinant proteins. Objectives To compare independently Dsg1 and 3 antibody levels with the severity of both cutaneous and oral involvement in PV and PF. Patients and methods Four hundred and twenty-four serum samples were analysed from 80 subjects with PV and 24 with PF. IgG antibodies to Dsg1 and 3 were measured by ELISA. For every sample analysed, the associated severity of skin and oral disease were graded from 0 to 3; quiescent, mild, moderate and severe. Results A relationship between Dsg1 antibodies and skin severity was demonstrated such that a 10-unit increase in Dsg1 ELISA value was associated with a 34% chance of having a higher severity score [95% confidence interval (CI), 25–45%, P < 0·0005]. This was observed in both PV and PF. Oral severity was associated with Dsg3 antibody levels and a 10-unit increase in the Dsg3 ELISA value was associated with a 25% chance of a higher oral severity score (CI 17–33%, P < 0·0005). We were unable to demonstrate a relationship between Dsg1 antibodies and oral severity, even after adjusting for the effect of Dsg3 antibodies. Similarly, there was no relationship between Dsg3 antibodies and skin severity. Conclusions This study suggests that the clinical phenotype of pemphigus, in particular the balance of skin and oral disease, is determined principally by the quantities of Dsg1 and 3 autoantibodies, respectively. [ABSTRACT FROM AUTHOR]

Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous blistering disease characterized by IgG autoantibodies that bind to various epithelia and immunoprecipitate a complex of 250, 230, 210, 190 and 170 kDa proteins. A recent study has suggested that PNP patients have antidesmoglein (Dsg) 3 autoantibody and that the antibody plays a pathogenic role in PNP. We report a 72-year-old woman with PNP associated with thymoma and adenocarcinoma of the lung. Diagnosis of PNP was made by the characteristic clinical, histological and immunopathological findings, as well as immunoprecipitation of characteristic 230, 210 and 190 kDa proteins. Using enzyme-linked immunosorbent assay with baculovirus-expressed recombinant proteins, the patient’s serum was negative against both Dsg 3 and Dsg 1. This finding is unusual, and it suggests that the target antigen, which is involved in acantholysis, may be other than Dsg 3 in this case. [ABSTRACT FROM AUTHOR]

Background Pemphigus vulgaris (PV) is characterized by pathogenic autoantibodies to desmoglein (Dsg) 3, but additional antibodies to Dsg1, the pemphigus foliaceus antigen, are detectable in some cases. Objectives To investigate the clinical significance of the presence of both Dsg 1 and 3 antibodies. Methods In 79 subjects with PV, enzyme-linked immunosorbent assays were used to detect IgG autoantibodies reactive with the ectodomain of Dsg1 and Dsg3. Results There was a clear association between the clinical phenotype and the Dsg antibody profile. All subjects had Dsg3 autoantibodies and 61% had coexisting Dsg1 antibodies (Dsg3+/Dsg1+). PV limited entirely to the mucosal surfaces was seen only in Dsg3+/Dsg1– patients, while additional Dsg1 antibodies (Dsg3+/Dsg1+) predicted cutaneous in addition to mucosal involvement. Although minor cutaneous involvement was observed in most Dsg3+/Dsg1– patients, severe cutaneous involvement was seen only in Dsg3+/Dsg1+ patients. Dsg1 antibodies were detectable early in the course of disease and their appearance did not relate to the use of systemic therapy. The proportion of Dsg1+ patients was higher in those of Indian origin compared with white northern Europeans (P < 0·05). Conclusions These data suggest that the presence of Dsg1 antibodies is predictive of a potentially more severe disease and that genetic factors may determine the Dsg antibody profile. [ABSTRACT FROM AUTHOR]