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Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lübeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases. Considerable advances have been made in describing incidences and prevalences of these diseases and linking comorbidities with autoantibody reactivities and clinical variants, for example, dipeptidyl peptidase-IV inhibitor-associated noninflammatory bullous pemphigoid. Although new entities are still being described, diagnosis of most autoimmune blistering diseases can now be achieved using standardized and widely available serological test systems. Various experimental mouse models of pemphigus and pemphigoid disease are increasingly being used to understand mechanisms of central and peripheral tolerance and to evaluate more specific treatment approaches for these disorders, such as molecules that target autoreactive T and B cells and anti-inflammatory mediators, that is, dimethyl fumarate, phosphodiesterase 4, and leukotriene B4 inhibitors in pemphigoid disorders, and chimeric antigen receptor T cells in pemphigus. Very recent experimental data about the immunopathology and the determinants of autoantibody formation and keratinocyte susceptibility in pemphigus were discussed. With regard to cellular mechanisms leading to the loss of cell-cell adhesion, new ideas were shared in the field of signal transduction. Major steps were taken to put the various partly contradictory and controversial findings about the effects of pemphigus autoantibodies and other inflammatory mediators into perspective and broaden our view of the complex pathophysiology of this disease. Finally, two investigator-initiated multicenter trials highlighted doxycycline and dapsone as valuable medications in the treatment of bullous pemphigoid., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Paraneoplastic pemphigus (PNP) is a multiorgan disease characterized by antibodies against plakins, desmogleins and the α2-macroglobulin-like-1 (A2ML1) protein, in association with an underlying neoplasm. Accurate diagnosis relies on the demonstration of these autoantibodies in serum., Objectives: To evaluate the value of different laboratory techniques in the serological diagnosis of PNP., Methods: We performed immunoblotting, envoplakin (EP) enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) on rat bladder, radioactive immunoprecipitation and a nonradioactive combined immunoprecipitation-immunoblot assay. Additional assays included BP180 ELISA and BP230 ELISA. We included the sera of 19 patients with PNP and 40 control subjects., Results: The sensitivities were 63% for anti-EP ELISA, 74% for rat bladder IIF, 89% for immunoblotting, 95% for radioactive immunoprecipitation and 100% for nonradioactive immunoprecipitation. Specificities ranged from 86% to 100%. The BP180 and BP230 ELISAs had low sensitivity and specificity for PNP. The combination of rat bladder IIF and immunoblot showed 100% sensitivity and specificity. The analysis of sequential PNP sera showed that antibody titres may decrease over time, possibly resulting in negative outcomes for EP ELISA and rat bladder IIF studies., Conclusions: The detection of autoantibodies against EP and periplakin, or A2ML1 by immunoprecipitation is most sensitive for PNP. The combination of rat bladder IIF and immunoblotting is equally sensitive and highly specific, and represents an alternative valuable and relatively easy approach for the serological diagnosis of PNP., (© 2013 British Association of Dermatologists.)

Background: Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering disease that is characterized by superficial blistering of the skin, and according to the current perspective is caused by autoantibodies directed against desmoglein (Dsg) 1., Objectives: To examine early acantholysis in the skin of patients with PF at an ultrastructural level., Methods: Two Nikolsky-negative (N-), five Nikolsky-positive (N+) and two lesional skin biopsies from immunoserologically defined patients with PF were studied by light and electron microscopy., Results: We found no abnormalities in N- PF skin, whereas all the N+ skin biopsies displayed intercellular widening between desmosomes, a decreased number of desmosomes and hypoplastic desmosomes in the lower epidermal layers. Acantholysis was present in two of five N+ biopsies, but only in the upper epidermal layers. The lesional skin biopsies displayed acantholysis in the higher epidermal layers. Hypoplastic desmosomes were partially (pseudo-half-desmosomes) or completely torn off from the opposing cell., Conclusion: We propose the following mechanism for acantholysis in PF: initially PF IgG causes a depletion of nonjunctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of nonjunctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic desmosomes and a decreased number of desmosomes. In addition, antibodies might promote disassembly of desmosomes. In the upper layers of the epidermis, where Dsg3 is not expressed and cannot compensate for Dsg1 loss, ongoing depletion of Dsg1 will finally result in a total disappearance of desmosomes and subsequent acantholysis., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists 2012.)

Background: Rituximab, an anti-CD20 antibody, was shown in open series studies to be effective in treating pemphigus at a dose of 4 × 375 mgm(-2) as approved for B-cell malignancies., Objectives: We investigated whether a lower dose of rituximab is also effective for pemphigus., Methods: Patients with pemphigus were treated with a single course of two infusions of rituximab (500 mg each) at an interval of 2 weeks. Clinical consensus late end points, B-cell number, desmoglein 1 and desmoglein 3 indices were monitored., Results: We enrolled 15 patients in the study: three with pemphigus foliaceus (PF) and 12 with pemphigus vulgaris (PV). The follow-up was 32-152 weeks (median 94). All 15 patients responded to therapy. Eight patients achieved complete remission in a median period of 5 weeks (four on minimal therapy, four off therapy). Seven patients achieved partial remission in a median period of 34·5 weeks (five on minimal therapy, two off therapy). Relapses (40%) were seen between 53 and 103 weeks (median 97) after start of therapy. B-cell numbers dropped to <1% after first infusion, and remained undetectable in patients with sustained remission. The antidesmoglein 1 index correlated well with the clinical severity in PF, but this was less obvious in PV., Conclusions: A low dose of rituximab is an effective and safe treatment for pemphigus. Relapses may occur, mostly at the end of the second year. Cost-effectiveness studies with a long follow-up are required to determine the proper dosage of this expensive drug in pemphigus., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

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., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

We present a case of immunobullous disease with an impressive acquired palmoplantar keratoderma (PPK) and unique antigenicity. The palms of the patient showed hyperkeratotic ridges with a tripe pattern that decreased with the amelioration of the immunobullous condition. The histopathology of perilesional skin (blister) demonstrated eosinophilic spongiosis and suprabasal blistering as in pemphigus vulgaris. In palmar skin, acantholysis, intraepidermal pustules, papillomatosis and marked hyperkeratosis were observed. Direct and indirect immunofluorescence displayed intraepidermal intercellular IgG staining as well as linear IgG staining along the epidermal basement membrane zone. Immunochemical assays revealed IgG antibodies to the desmosomal protein desmocollin 3 and to the hemidesmosomal proteins BP230 and LAD-1. Affinity-purified antidesmocollin 3 serum IgG bound to monkey oesophagus in the typical pemphigus pattern. Desmocollins are transmembrane proteins of the desmosome. Desmosome diseases may cause hereditary PPK. In our patient with acquired PPK, we hypothesize that the antibodies to desmocollin 3 were, apart from their role in eliciting the pemphigus-like blistering disease, also implicated in the pathogenesis of the PPK.

Background: Pemphigus is a bullous mucocutaneous autoimmune disease characterized by IgG autoantibodies to desmoglein (Dsg) 1 and/or Dsg3. Occasionally direct immunofluorescence of pemphigus skin reveals IgA depositions with an intraepidermal intercellular pattern in addition to the IgG deposition., Objectives: To investigate if pemphigus patients, in addition to having IgG autoantibodies, also generate IgA antibodies to Dsg1 and/or Dsg3., Patients/methods: Sera of 100 pemphigus patients and 36 bullous pemphigoid controls were tested by IgA enzyme-linked immunosorbent assay (ELISA) to the recombinant extracellular domains of Dsg1 and Dsg3. The patients were selected on clinical grounds and positive IgG ELISA index values for Dsg1 and/or Dsg3. They were divided into four groups: patients having IgG to only Dsg1 (n=34), patients having IgG to both Dsg1 and Dsg3 (n=31), patients having IgG to only Dsg3 (n=27) and patients who had paraneoplastic pemphigus (PNP) (n=8)., Results: IgA antibodies to Dsg1 were found in 13 (38%) of the patients with IgG to Dsg1, in five (16%) of the patients with IgG to both Dsg1 and Dsg3, in four (15%) of the patients with IgG to Dsg3 and in none of the PNP patients. IgA antibodies to Dsg3 were found in one (3%) of the patients with IgG to Dsg1, in 18 (58%) of the patients with IgG to both Dsg1 and 3, in 18 (67%) of the patients with IgG to Dsg3, and in four (50%) of the PNP patients. Immunofluorescence analysis demonstrated intraepidermal intercellular staining IgA antibodies in serum and intercellular IgA deposits in skin of IgA ELISA-positive patients, although to a lesser extent than by ELISA., Conclusions: This study shows that in a considerable number of supposedly IgG-mediated pemphigus patients IgA to Dsg1 and Dsg3 is also present. In most cases the antigen specificity of the IgA follows the antigen specificity of the IgG, although in a small number of cases IgA is present against the Dsg not recognized by IgG.

The case history of a 61-year-old male patient is described, who presented with severe stomatitis, conjunctivitis and leukocytosis. The diagnosis chronic lymphocytic leukemia (CLL) stage A (0) was made, for which no treatment was necessary. Progression of stomatitis and conjunctivitis and erythosquamous skin lesions with bullae and vesiculae formation developed. Under the diagnosis of bullous pemphigoid the patient was treated with corticosteroids. The histologic and immunofluorescence examination of a skin biopsy was compatible with this diagnosis, and antibodies to skin could not be detected in a first serum sample. Pseudomonas was cultured from all lesions, the corticosteroids were stopped and antibiotic treatment was started, without clear effect. Because of progression of skin lesions and debilitation, the patient finally declined all treatment and died five weeks after admission. Post-mortem examination showed enlarged lymphnodes in the cervical, aortal en iliacal areas, with histology confirming the diagnosis of CLL. Indirect immunofluorescence with the second serum sample showed auto-antibodies in high titer directed against the intercellular epithelial substance. Immunoblot studies showed binding with the classic target antigens in paraneoplastic pemphigus. Re-examination of the histologic skin specimen and the result of direct immunofluorescence were in retrospect compatible with the diagnosis of paraneoplastic pemphigus.

A patient is described who initially presented with pemphigus vulgaris, limited to the oral cavity, and weight loss. Although the various laboratory studies pointed to the diagnosis of paraneoplastic pemphigus (PNP), the underlying neoplasm was not detected until 6 months later, when the patient developed shortness of breath and routine physical examination on admission revealed an abdominal mass, which eventually was proven to be an epithelioid leiomyosarcoma. In spite of radical excision of the tumour and intensive treatment of the dyspnoea, the patient died of respiratory failure 19 months after the PNP had been diagnosed. Early diagnosis of PNP is stressed to possibly prevent fatal pulmonary involvement.

A patient is described who initially presented with an acrovesicular eczema which subsequently developed into erythema multiforme with histopathological features of bullous pemphigoid. Although the various laboratory studies pointed to the diagnosis of paraneoplastic pemphigus (PNP), the underlying neoplasm was not detected until 6 months later, when the biopsies of an oral lesion showed the presence of an underlying non-Hodgkin lymphoma.

Background Paraneoplastic pemphigus (PNP) is a malignancy-associated autoimmune disease in which circulating autoantibodies recognize various polypeptides that constitute the desmosomes and hemidesmosomes of epithelial structures. Objectives To determine whether PNP is associated with autoreactivity against the armadillo-repeat-containing plakophilin-3 (PKP3) protein. Methods HEK293 cells were transiently transfected with either a pEF6/myc-His or a pEGFP-N2 construct, both encoding human PKP3 (protein products of 85 kDa and 115 kDa, respectively). Protein lysates were made in Laemmli buffer. The proteins were separated by gel electrophoresis, transferred to filters and probed with five PNP sera, four pemphigus vulgaris sera, two pemphigus foliaceus sera, five bullous pemphigoid sera, one cicatricial pemphigoid serum and one linear IgA dermatosis serum. A mouse monoclonal anti-PKP3 antibody raised against a 20-amino acid peptide of human PKP3 was used as a positive control. Results Autoreactivity against both 85-kDa and 115-kDa recombinant PKP3 protein products was detected in all five PNP sera and in one pemphigus vulgaris serum. None of the sera of patients with basement membrane zone bullous diseases reacted with the PKP3 protein products. The presence of autoantibodies against PKP3 in PNP sera was subsequently confirmed in human epidermal lysate blots. Conclusions This is the first report of PKP3 reactivity in bullous disorders, which was present in all the PNP sera tested. The presence of PKP3 reactivity in one patient with pemphigus vulgaris is not unexpected as the desmosome is also targeted in this disease. [ABSTRACT FROM AUTHOR]