Adhesion molecules and related proteins in Darier''s disease and Hailey–Hailey disease

We have used antibodies to plakoglobin and E-cadherin: the lectins, peanut agglutinin (PNA) and soybean agglutinin (SBA); and sera from patients with the autoimmune diseases pemphigus vulgaris (PV) or pemphigus foliaceus (PF), in an immunohistological study of Darier's disease and Hailey-Hailey disease. There was normal expression of plakoglobin, E-cadherin, lectins and pemphigus antigens at the periphery of keratinocytes in uninvolved skin. Clumps of plakoglobin were detected within acantholytic cells in Hailey-Hailey disease, whereas expression was diffuse in acantholytic cells in Darier's disease. This difference may reflect differences in the pathogenesis of acantholysis. E-cadherin expression was weak or absent at the periphery of some acantholytic cells; lectin binding was sometimes reduced around acantholytic cells, and pemphigus antibodies did not bind to the acantholytic cells involved skin in either disease. Internalization, conformational changes or proteolysis may alter the expression of extracellular epitopes by acantholytic cells.     

Relationship between keratinocyte adhesion and death: anoikis in acantholytic diseases

Abstract  Loss of attachment to the substratum may trigger apoptosis in epithelial cells (anoikis). It is less clear whether apoptosis may be triggered by disruption of cell-cell contacts, as happens in acantholytic diseases. Biopsy specimens were obtained from the border of skin lesions from four patients with pemphigus vulgaris (PV), four patients with pemphigus foliaceus (PF), three patients with Darier’s disease (DD), two patients with Darier’s-type Grover’s disease (GD), and two patients with benign familial pemphigus Hailey-Hailey disease (HH). Control skin was obtained from five healthy volunteers. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) and confocal laser scanning microscopy was employed to detect the nuclei containing fragmented DNA in apoptotic cells. In PV and PF, TUNEL-stained apoptotic keratinocytes were abundantly present in the regions of acantholysis and in the cohesive epidermis below the blisters. Apoptotic keratinocytes had pyknotic, condensed nuclei. In DD, GD and HH, the number of TUNEL-stained keratinocytes was lower, apoptotic keratinocytes were confined to the regions of dyskeratosis and acantholysis, and pyknosis was absent. In conclusion, disruption of cell-cell contacts in acantholytic skin disorders may in some cases cause apoptosis of keratinocytes. Further studies are needed to determine whether the observed differences in the pattern of apoptosis are due to targeting of different junctional elements (adherens junctions in PV and PF versus desmosomes in DD, GD and HH). Received: 21 January 1998     

Pemphigus vulgaris and herpesviruses: is there any relationship?

Background Pemphigus is an autoimmune disorder, which results from interaction of exogenous and endogenous factors. One of these environmental factors is viral infections particularly, herpesviruses. We aimed to detect the presence of HSV 1 and 2 (herpes simplex virus) and HHV8 (human herpesvirus 8) in our patients who were suffering from pemphigus vulgaris. Methods In this cross‐sectional study, 38 patients (19 male and 19 female patients) with pemphigus vulgaris were entered, 32 skins and six peripheral blood cells samples were obtained from the study population. Thereafter, the presence of HHV8 and HSV DNA were evaluated by using polymerase chain reaction (PCR). Results The mean age of patients was 45.05 ± 17.24 years (range: 16–81 years). Twelve patients mentioned history of herpes labial in the past (31.57%). Results of PCR test for detection of HSV and HHV8 DNA in all 32 skin samples and five peripheral blood samples and one case with skin and blood samples were reported negative. Conclusion Inability to detect HHV8 and HSV DNA in this study suggests that herpesviruses may be only occasional factors for development or exacerbation of pemphigus vulgaris.     

A 6‐year treatment experience for pemphigus: retrospective study of 69 Chinese patients

There is a lack of data on treatment and prognosis of pemphigus in China. The aim of this study was to evaluate long‐term follow‐up and prognosis of pemphigus. Forty‐seven inpatients with pemphigus vulgaris (PV) and 22 with pemphigus foliaceus (PF) were recruited in this retrospective study. The average age at onset was 51.6 and 54.9 years in PV and PF, respectively. High‐dose systemic steroids were administered in 47 PV and 21 PF, of which 18 PV and 8 PF with adjuvant therapies. CD4 lymphocytopenia was found in 5 PV and 2 PF patients at admission and successfully treated by intravenous thymopentin daily. During a mean follow‐up of 37.1 months, 41 PV and 19 PF reached remission, 30 PV and 9 PF relapsed, 4 PV and 2 PF died. Major causes of death were relapse of pemphigus due to discontinuation of oral steroids by the patients themselves (four cases) and severe infections (two cases, one with severe CD4 lymphocytopenia). The 1‐year mortality rate of PV and PF was 8.5% and 4.5%, respectively. Cox regression analysis indicated that age at onset of pemphigus was an independent risk factor related to the elevated mortality. Our report confirmed the high mortality rate of pemphigus in a Chinese population and stressed that patient education was urgently needed to prevent relapses and deaths.     

副肿瘤天疱疮2例报告及与HHV-8关系初探

目的 报告副肿瘤天疱疮2例，并对其与Castleman病、人类疱疹病毒－8之间的关系进行初探。方法 采用PCR法进行HHV－8检测。结果 2例病人外周血及肿瘤组织共4份标本均为阴性。结论 这2例副肿瘤天疱疮无HHV8感染。     

Herpes simplex virus 1 and cytomegalovirus are associated with pemphigus vulgaris but not with pemphigus foliaceus disease

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are blistering autoimmune diseases that depend on interaction between genetic and environmental factors. Viral infections, like herpes simplex viruses 1 and 2 (HSV1/2), cytomegalovirus (CMV), Epstein‐Barr virus and dengue virus, could trigger or exacerbate pemphigus. IgM and IgG antibodies against these viruses in serum from PV and PF, their relatives and controls were determined. HSV1/2 expression was evaluated by direct immunofluorescence (DIF) and qPCR in affected or not oral mucosa from PV patients compared with uninjured PF mucosa. IgG anti‐HSV1 was higher in the PV group compared with all groups. IgG anti‐CMV resulted higher in PV group compared with PF patients and PV relatives. HSV1 was confirmed by DIF and qPCR on oral samples from patients with PV. Lack of HSV1 expression in the oral mucosa of patients with PF corroborate that immunosuppressive therapy cannot be the main cause for HSV1 replication in PV disease.     

A Clinicopathological Study of Pemphigus in Eastern India with Special Reference to Direct Immunofluorescence

Background:Pemphigus is a group of chronic autoimmune vesico-bullous disorders in which the epidermis and the basement membrane zone are the focus of attack resulting in cutaneous and mucosal blister formation. Direct immunofluorescence (DIF) test is a very sensitive test for the diagnosisAim:To study the clinico histopathological patterns of pemphigus in eastern India. The study also aims to correlate DIF with clinical and histologic findings as well as severity of skin involvement [scoring systems].Results:In our study Pemphigus vulgaris (PV) was the predominant type with 32 cases followed by 8 cases of pemphigus foliaceus (PF) and a single case of IgA pemphigus. Mean age at presentation was late middle age. Majority of the patients, 26 (63.41%) initially had cutaneous involvement followed by mucosal involvement. In this study group 36 (87.80%) patients showed acantholytic cells on histopathological examination. Most patients of PV showed suprabasal blister 20 (62.50%) followed by intraspinous 5 (15.62%) and subcorneal 5 (15.62%) blister. In majority 28 (87.50%) of the PV patients IgG and C3 antibodies were deposited throughout the epidermis. The strength of antibody positivity was strong in most of the patients (71.87%). In cases of PF mostly IgG 6 (75%) antibodies were deposited in the upper epidermis. DIF intensity had poor correlation with disease activity/severity except in PF.Conclusion:Almost 85.36% cases of pemphigus were diagnosed clinicopathologically. But 6 cases couldn’t be diagnosed accurately on clinicopathological basis and in them DIF was confirmatory. Two cases of pure mucosal PV and 1 case of IgA pemphigus was confirmed by DIF. Two cases of bullous pemphigoid clinico-histologically mimicking PV were also excluded by DIF. So it appears from our study that DIF is confirmatory for diagnosis of pemphigus in all cases.     

The role of human herpesvirus-6, Epstein–Barr virus and cytomegalovirus infections in the etiopathogenesis of different types of cutaneous drug reactions

Background Recently, it has been recognized that drug‐induced hypersensitivity syndrome (DIHS) is associated with reactivation of human herpesvirus‐6 (HHV‐6), Epstein–Barr virus (EBV) and cytomegalovirus (CMV). However, whether those viruses have a role in the development of cutaneous drug reactions (CDRs) other than DIHS is not known. Objective To investigate the role of HHV‐6, EBV and CMV infections in the etiopathogenesis of different types of CDRs. Methods Eighteen patients with diagnosis of CDR according to the clinical and histopathological findings were evaluated. Real‐time polymerase chain reaction (PCR) was used for the detection of EBV, CMV, and HHV‐6 DNA in lesional skin biopsy specimens; EBV and CMV DNA in serum samples; and HHV‐6 DNA in peripheral blood mononuclear cells. Results The genome of HHV‐6 was detected only in the lesional skin of two patients with DIHS. Epstein–Barr virus and CMV DNA in the skin lesions, EBV and CMV genomes in the serum samples, and HHV‐6 DNA in the peripheral blood mononuclear cells were negative in all patients. Limitations The patient population was small and did not include all types of CDRs. Also, we had only two patients with DIHS. We had not been able to measure the increase in anti‐viral IgG titers in serial serum samples. Conclusion Epstein–Barr virus and CMV infections do not seem to have a role in the etiopathogenesis of CDRs including DIHS. The association between HHV‐6 infection and CDRs is likely to be limited to DIHS.     

Ultrastructural binding site of pemphigus foliaceus autoantibodies: comparison with pemphigus vulgaris

We studied in vivo binding sites of pemphigus foliaceus (PF) auto-antibodies by immuno-gold labelling technique, and compared them with those of pemphigus vulgaris (PV). In early acantholytic lesions of PF, the bound antibodies indicated by 5 nm protein A-colloiclal gold particles were observed on the surface of keratinocytes, with particular affinity for desmosomes and separated attachment plaques. Nondesmosomal cell surfaces were sparsely labeled with the gold particles. A similar binding pattern was seen in the epidermal sheets obtained from a PV patient utilizing the Nikolsky phenomenon. These findings indicate that both PF and PV antigen-antibody complexes are densely located on the desmosomal areas in early pemphigus lesions, suggesting the pathogenic importance of functional impairment of desmosomes by the autoantibodies.     

Prurigo pigmentosa: a clinicopathological study and analysis of associated factors

Background Prurigo pigmentosa (PP), a rare inflammatory disease of the skin, is mostly reported in the ethnic Japanese population. Its pathogenesis remains unclear. The chronic and recurrent nature of PP implies a possible role of viral infection in the pathogenesis. The anti‐inflammatory mechanism of doxycycline, which is well documented as a good treatment for PP, is related to the suppression of interleukin expression. Methods We identified and retrospectively analyzed 16 biopsy‐proven and criteria‐matched patients over a seven year period at a single medical center. DNA extracted from formalin‐fixed, paraffin‐embedded specimens was analyzed for herpes simplex virus‐1 (HSV‐1), HSV‐2, and human herpes virus‐6 (HHV‐6) DNA by polymerase chain reaction. Immunohistochemistry was performed to determine the interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8) expression in PP skin lesions. Results Clinicopathological findings in the ethnic Chinese population are similar to those reported in Japanese studies. All patients had a good response to doxycycline treatment, with a mean duration of use of 2.4 weeks. However, recurrence was noted in six patients. HSV‐1, HSV‐2, and HHV‐6 DNA in PP skin lesions were negative. Immunohistochemistry showed IL‐6 (P = 0.035) to be more strongly expressed in PP skin lesions. There was no statistical significance of elevated IL‐8 expression in PP (P = 0.123). Conclusions Prurigo pigmentosa is not uncommon in the ethnic Chinese population. There was no evidence of herpes virus DNA in PP skin lesions. Increased expression of IL‐6 in PP skin lesions may explain the effects of doxycycline in terms of its anti‐inflammatory properties.     

Clinical and immunological profile of umbilical involvement in pemphigus vulgaris and pemphigus foliaceus

Background. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune vesicobullous disorders with IgG autoantibodies directed against desmoglein (Dsg)1 and 3, which lead to intraepidermal acantholysis. Aim. To characterize the clinical and immunological profile of patients with PF or PV with umbilical involvement. Methods. In total, 10 patients (7 women, 3 men; age range 24–70 years, disease duration 3–16 years) diagnosed with either PV (n = 5) or mucocutaneous PF (n = 5) were assessed according to their clinical features, histopathology and immunological findings [direct and indirect immunofluorescence (DIF and IIF) and ELISA with recombinant Dsg1 and Dsg3]. Results. Erythema, erosions, crusts and vegetating skin lesions were the main clinical features of the umbilical region. DIF of the umbilical region gave positive results for intercellular epidermal IgG and C3 deposits in eight patients and for IgG alone in the other two. Indirect immunofluorescence with IgG conjugate showing the typical pemphigus pattern was positive in all 10 patients, with titres varying from 1 : 160 to 1 : 2560. ELISA with recombinant Dsg1 gave scores of 24–266 in PF and 0–270 in PV. Reactivity to recombinant Dsg3 was positive in all five patients with PV (ELISA 22–98) and was negative in all PF sera. Conclusions. All 10 patients with pemphigus with umbilical presentation had the clinical and immunopathological features of either PF or PV. This peculiar presentation, not yet completely elucidated, has rarely been reported in the literature. A possible explanation for this unique presentation may be the presence of either novel epitopes or an association with embryonic or scar tissue located in the umbilical‐cord region.     

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.     

No evidence for a role of human herpesvirus type 8 in sarcoidosis: molecular and serological analysis

The aim of this study was to analyse the association between human herpesvirus type 8 (HHV8) and sarcoidosis. Using nested polymerase chain reaction (PCR), we tested the presence of HHV8 DNA sequences in 13 skin specimens and peripheral blood mononuclear cells from eight patients suffering from sarcoidosis. We also looked for the presence of HHV8 antibodies in the sera of 28 patients with sarcoidosis using three techniques: two indirect immunofluorescence assays and an enzyme-linked immunosorbent assay with recombinant capsid protein fragment encoded by open-reading frame 65. HHV8 PCR analysis was negative while HHV8 serological studies showed an overall prevalence of 18% among patients suffering from sarcoidosis: 43% in patients from sub-Saharan Africa, 17% in patients from Northern Africa, 12.5% in patients from the French West Indies and 0% in French patients. In conclusion, our results do not indicate an association between HHV8 and sarcoidosis but reflect the seroepidemiology of this virus in different geographical regions.     

Pemphigus in Korea: clinical manifestations and treatment protocol

Pemphigus, a rare, chronic blistering disease of the skin and mucous membranes with severe morbidity and occasional mortality, is the most common autoimmune bullous disease in Korea. The purpose of this study was to evaluate the clinical features and propose a treatment strategy for patients with pemphigus. A retrospective analysis was conducted of 51 pemphigus patients seen between 1993 and 2001. Pemphigus vulgaris (PV) was the most common type with 32 cases, followed by 19 cases of pemphigus foliaceus (PF). The male to female ratio was 1:1.3, with females predominating, particularly among PV patients (PV, 1:1.5; PF, 1:1.1). The average ages at onset of PV and PF were 44.3 and 51.0 years old, respectively. Mucosal involvement was noted in 27 cases (84.4%) of PV but in only 3 cases (15.8%) of PF. Most patients initially received relatively low to intermediate doses (0.3-1.0 mg/kg/day) of prednisolone, and 23 (71.9%) PV patients and 10 (52.6%) PF patients also received immunosuppressive agents. Oral prednisolone and azathioprine (100 mg/day) formed the mainstay of treatment for our patients (47.1%). At the time of writing, 25.5% (13/51) of patients are in complete remission, and 72.5% (37/51) are undergoing maintenance therapy. One patient died due to sepsis during the treatment. For the treatment of pemphigus, a course of the lowest possible corticosteroid dosage in combination with immunosuppressive agents appears to be effective and less toxic than a high corticosteroid dosage.     

Polymorphisms of HLA class II antigens in 33 Japanese pemphigus patients]

The HLA class II antigens in 33 Japanese pemphigus patients were investigated by both serologic and restriction fragment length polymorphism (RFLP) analyses: 17 cases of pemphigus vulgaris (PV), 13 cases of pemphigus foliaceus (PF), 3 cases of unclassified pemphigus. In serologic typing, DR2 was absent in PV. DR5, DRw6, DRw12, and DRw52 were positively associated with PV. DQw1 was positively associated with PF. RFLP analyses showed that DRw6 PV patients had a disease-associated restriction fragment representing DQw5, the same association as that found in DRw6 Jewish PV patients. On the other hand, all 13 PF patients were serologically typed for DQw1, which could not be further subdivided into DQw5 by RFLP analyses. These results suggest that Japanese and Jewish PV patients may be immunogenetically closely related to each other, but Japanese PV patients appear to be immunogenetically different from Japanese PF patients.     

Four mild but refractory cases of pemphigus foliaceus successfully treated with intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is a potential second line of therapy for pemphigus, with increasing evidence of its effectiveness and safety, although oral corticosteroids remain the first treatment for pemphigus. IVIG is usually applied in severe cases of pemphigus, particularly pemphigus vulgaris (PV). Pemphigus foliaceus (PF) caused by immunoglobulin PF autoantibodies to desmoglein 1 (Dsg1) is usually milder than PV. However, PF cases are occasionally resistant to corticosteroids and require long‐term treatment to control the disease, leading to various adverse effects. IVIG was used in patients with relatively mild PF, who were resistant to therapies with corticosteroids and dapsone. We assessed the disease severity by Pemphigus Disease Area Index (PDAI) and measured anti‐Dsg1 antibody indices by enzyme‐linked immunosorbent assay, before and 4 months after IVIG. Four Japanese female PF patients (57.3 ± 8.6 years) were treated with a single cycle of IVIG (400 mg/kg per day for five consecutive days) in combination with the previous therapies. Within 1–2 months of addition of IVIG, all PF cases showed remarkable improvement of skin lesions, and PDAI also markedly decreased. For 2 years after IVIG, no apparent exacerbation was observed. Anti‐Dsg1 antibody indices decreased in all cases during the 2 years. IVIG could be a potential treatment for not only severe cases of PV but also mild and refractory cases of PF. IVIG may trigger the shift from intractable condition to remission via non‐pathogenic anti‐Dsg1 antibodies or some mechanisms excluding anti‐Dsg1 antibody.     

Enteric‐coated mycophenolate sodium in the treatment of refractory pemphigus

Background One of the major goals of pemphigus therapy is to reduce the patient’s cumulative exposure to systemic corticosteroids. To investigate the efficacy of enteric‐coated mycophenolate sodium (EC‐MPS), 10 patients with active, refractory pemphigus vulgaris (PV) or foliaceous (PF) were treated with EC‐MPS (1440 mg daily) and prednisone (75 mg daily) over 18 months. Observations Following EC‐MPS/prednisone therapy, disease progression was inhibited between days 30 and 45 in 9/10 patients (8 PV; 1 PF). At 18 months, 8/9 PV patients had clinically quiescent disease; EC‐MPS therapy was no longer required in two patients as a result of disease remission. The remaining PV patient showed no response to treatment. The PF patient also had clinically quiescent disease but with high levels of anti‐desmoglein‐1. ECMPS dose was reduced to 720 mg daily in 4/9 patients by month 6. Average daily prednisone requirement decreased to 25 mg at 6 months and to 15 mg at 18 months. Three adverse events were reported: headache (two cases; one mild and one moderate) and significant increase in blood glucose (one case; moderate). Conclusions Enteric‐coated mycophenolate sodium is effective and safe as an adjuvant therapy in patients with refractory pemphigus and may be effective even in patients whose disease is unresponsive to azathioprine.     

Klinik und Immunpathologie bei 48 Patienten mit Pemphigus

Background and Objective. Pemphigus is a rare intraepidermal autoimmune bullous disease. Two major variants, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are distinguished. The aim of this study was to document the clinical and immunpathological findings in all pemphigus patients who were diagnosed in the Department of Dermatology at the University of Würzburg over the past 10 years. Patients/Methods. Based on a retrospective study, clinical and immunpathological findings in 48 patients with pemphigus were recorded. All patients had positive findings by direct and/or indirect immunfluorescence microscopy. Results. Between January 1989 and August 1998, 48 patients were diagnosed with pemphigus at our institution; 31 patients had PV and 17 PF. The average age (±standard deviation) of PV patients was 55 (±17) and of PF patients 60 (±12) years. All PV patients showed involvement of mucous membranes and in 65% of cases, the skin was also involved. In contrast, PF patients had involvement only of the skin. By direct immunfluorescence microscopy, intercellular deposits of IgG and C3 were detected in 89% and 78% of PV cases, respectively. In PF, intercellular deposits of IgG were found in 94% and of C3 in 75% of cases. By indirect immunfluorescence microscopy on monkey esophagus, 94% of the PV and 88% of the PF patients revealed circulating serum antibodies. In 30 patients, we characterized the immune response by ELISA using recombinant desmoglein 1 and 3. All PF sera showed autoantibodies against desmoglein 1 and all PV sera against desmoglein 3. In PV with both mucous membrane and skin involvement, antibodies to both desmoglein 3 and 1 were detected. Conclusions. Our results confirm the correlation of the autoantibody profile with the clinical phenotype of pemphigus.     

The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with the changes in autoantibody profile assessed by an enzyme-linked immunosorbent assay

BACKGROUND: There are a number of reports of pemphigus with clinical shifting between pemphigus foliaceus (PF) and pemphigus vulgaris (PV). On the other hand, a novel enzyme-linked immunosorbent assay (ELISA) against recombinant baculoproteins of desmoglein 1 (Dsg1) (PF antigen) and Dsg3 (PV antigen) has been established and found to be extremely sensitive and specific. OBJECTIVES: To characterize the change in the antibody profiles in a series of pemphigus cases with mixed features of PF and PV by various methods, including the novel ELISA. Patients/methods Sera were obtained from eight cases undergoing a shift between PF and PV and three cases of coexistent PF and PV. The autoantigens were analysed by ELISA, as well as by immunofluorescence using normal human skin sections and immunoblotting using normal human epidermal extracts. RESULTS: The results of the ELISA, immunofluorescence and immunoblotting studies showed that the transition between PF and PV correlates well with the changes of autoantibodies against either Dsg1 or Dsg3. CONCLUSIONS: The clinical phenotype at each stage is defined by the anti-Dsg antibody profile in the serum of these pemphigus patients showing mixed features of PF and PV. In addition, ELISA using recombinant baculoproteins was particularly useful in distinguishing PF and PV.     

IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis

Background In pemphigus circulating IgG is present with the desmosomal cadherins desmoglein (Dsg) 1 and 3. In the epidermis of patients, this IgG deposits in a pattern that is often partly granular and does not reflect the normal Dsg distribution. Objective To understand why the IgG deposits in a granular pattern in the skin of patients with pemphigus. Patients/Methods We analysed the distribution of IgG and desmosomal adhesion molecules in skin biopsies of 18 patients with pemphigus vulgaris (PV) and 10 with pemphigus foliaceus (PF) by double staining immunofluorescence. The effect of IgG on desmosomal proteins was studied in an in vitro skin model. Results In PF skin Dsg1, but not Dsg3, was aberrantly distributed in the same partly granular pattern as the IgG. Vice versa, in skin of PV patients with anti‐Dsg3 antibodies, Dsg3, but not Dsg1, colocalized with the granular IgG. Plakoglobin also coclustered with IgG and Dsg, but this was far more prominent with Dsg1 than with Dsg3. In areas of heavy Dsg1 clustering, but not in areas of heavy Dsg3 clustering, intercellular widening between keratinocytes was present. Patient IgG, but not Fab fragments, induced the same Dsg clustering in vitro. Conclusions The IgG‐induced clustering of the Dsg autoantigens underlies the granular IgG deposition in patient skin. In PF and in mucocutaneous PV, Dsg1 clustering, but not Dsg3 clustering, correlates with nonacantholytic intercellular widening between desmosomes. In the patient the Dsg becomes sequestered from desmosomal components which fits in with the desmoglein nonassembly depletion hypothesis, indicating that targeted nonjunctional Dsg is no longer available to be incorporated into desmosomes and this leads to disturbed assembly, and Dsg‐depleted desmosomes.