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Fogo Selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeterminate Chagas disease was identified in a Brazilian Amerindian population of high risk for FS. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. The profile of anti-Dsg1 antibodies showed positive results in 15 of 40 FS sera and in 33 of 150 sera from healthy individuals from endemic FS sites, and no cross-reactivity between Chagas disease and FS was observed.

Authors: Sousa JX, Diaz LA, Eaton DP, Hans-Filho G, Lanzani de Freitas E, Delgado L, Ichimura LM, Cristaldi F, Orlandi R, Kesper N, Umezawa ES, Rivitti EA, Aoki V, The Cooperative Group on Fogo Selvagem Research Abstract Fogo Selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeterminate Cha…

from MedWorm: Pemphigus

Background -  Glucocorticoids as sole therapy for pemphigus foliaceus (PF) in cats are not always successful, and it is common to need additional immunomodulating agents to manage the disease. Hypothesis/Objectives -  This retrospective study evaluated the use of modified ciclosporin as an adjuvant or sole immunomodulating drug in cats with PF and compared their response to PF cats managed with chlorambucil. Animals -  Fifteen client-owned cats diagnosed with PF that received ciclosporin and/or chlorambucil as part of their treatment and had adequate follow-up to assess treatment response were evaluated. Methods -  Records were reviewed from feline PF patients presented between the years of 1999 and 2009. Cats were divided into two treatment groups: those treated with ciclosporin and those treated with chlorambucil. Most cats in both groups also received concurrent systemic glucocorticoids. Each group contained six patients. Three cats were treated with both medications and are discussed separately. Time to disease remission, remission-inducing glucocorticoid dose, maintenance or final glucocorticoid dose, disease response and adverse effects were assessed. Results -  There was no significant difference in remission times or disease response between groups. All six patients maintained with ciclosporin for PF management were weaned off systemic glucocorticoids, while glucocorticoid therapy was stopped in only one of the six cats receiving chlorambucil. Conclusions and clinical importance -  Modified ciclosporin is effective in the management of feline pemphigus foliaceus and is glucocorticoid sparing. PMID: 22731616 [PubMed – as supplied by publisher] (Source: Veterinary Dermatology)

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 1 (Dsg1).

Objectives  To examine early acantholysis in skin of PF patients at an ultrastructural level.

Methods  Two Nikolsky negative (N-), five Nikolsky positive (N+) and two lesional skin biopsies of immunoserological defined PF patients were studied by light and electron microscopy.

Results  We found no abnormalities in N- PF skin, whereas all 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 non-junctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of non-junctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic 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.

Background:  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein adhesion proteins. Previous studies have shown an IgG4>IgG1 predominance of anti-desmoglein antibodies in pemphigus; however, no studies have examined total serum IgG4 levels in pemphigus. IgG4 is induced by chronic antigen stimulation, which could occur with persistent skin blistering and potentially elevate the total serum IgG4 relative to other IgG subclasses in pemphigus patients.

Objectives:  The primary aim of the study was to quantitate total and desmoglein-specific IgG subclasses in pemphigus patients.

Methods:  IgG subclasses and desmoglein-specific IgG1 and IgG4 were quantitated in PV, PF, and age-matched normal sera using a subclass ELISA. The effectiveness of IgG4 depletion in blocking PV IgG pathogenicity was determined using a keratinocyte dissociation assay.

Results:  Desmoglein-specific antibodies comprised a median of 7.1% and 4.2% of total IgG4 in PV and PF patients, with 8-fold and 4-fold enrichment in IgG4 versus IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in PV and PF patients compared to age-matched controls (p=0.004 and p=0.005, respectively). IgG4 depletion of PV sera reduced pathogenicity in a keratinocyte dissociation assay and showed that affinity-purified IgG4 is more pathogenic than other serum IgG fractions.

Conclusions:  Desmoglein-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some pemphigus patients. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.

Paraneoplastic pemphigus (PNP) is a distinct autoimmune blistering disease that can affect multiple organs other than the skin. It occurs in association with certain neoplasms, among which lymphoproliferative diseases are most commonly associated. The clinical presentation of PNP consists typically of painful, severe oral erosions that may be accompanied by a generalised cutaneous eruption and systemic involvement. The eruption may be of different morphology, consisting of lesions that resemble pemphigus, pemphigoid, erythema multiforme or graft versus host disease, as well as lesions resembling lichen planus. Similarly, the histological findings also show considerable variability. PNP is characterised by the presence of autoantibodies against various antigens: desmoplakin I (250 kd), bullous pemphigoid antigen I (230 kd), desmoplakin II (210 kd), envoplakin (210 kd), periplakin (190 kd), plectin (500 kd) and a 170-kd protein. This 170-kd protein has recently been identified as alpha-2-macroglobulin-like-1, a broad range protease inhibitor expressed in stratified epithelia and other tissue damaged in PNP. The prognosis of PNP is poor and the disease is often fatal. Immunosuppressive agents are often required to decrease blistering, and treating the underlying malignancy with chemotherapy may control autoantibody production. The prognosis is better when PNP is associated with benign tumours and these should be surgically excised when possible.

Autoimmune bullous diseases (ABDs) are organ-specific autoimmune diseases, in which blisters on the skin and mucous membranes develop through binding of pathogenic autoantibodies to target antigens. There are two major ABD groups: the pemphigus group, showing autoantibodies to desmosomal components; and the subepidermal ABD group, showing autoantibodies to hemidesmosomal components in the epidermal basement membrane zone. Recent immunological, biochemical and molecular biological studies revealed many new autoantigens, including desmocollins, various plakin family proteins and integrins. A revised ABD classification includes new disease entities such as paraneoplastic pemphigus, IgA pemphigus and anti-laminin γ1 pemphigoid. In addition to systemic corticosteroids and various immunosuppressive agents, various adjuvant therapies for ABDs have developed. Among them, intravenous immunoglobulin (IVIG) is a promising therapy, although the therapeutic mechanisms are still unknown. Various disease models for ABDs have developed, particularly for pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa acquisita (EBA), and these have provided insights into the pathogenesis of various ADBs that suggest possible new treatment strategies. However, the fundamental mechanisms in disruption of immune-tolerance are still unknown. EBA shows autoimmunity to type VII collagen, the major component of anchoring fibrils, and EBA pathogenesis has been studied in various disease models. Previous studies suggested that, following binding of autoantibodies to type VII collagen, activation of complement, cytokine release, neutrophil migration, Fcγ receptors (FcgRs) and metalloproteinases play important roles in induction of subepidermal blisters. In this issue of the Journal of Pathology, Kasperkiewicz and colleagues reveal important roles of activating FcgRIV and inhibitory FcgRIIB in EBA pathogenesis that were recognized by conducting elegant studies using both genetic analysis and functional animal model methods. The expression equilibrium of the activating and inhibitory FcgRs can be modulated towards the inhibitory FcgRIIB by IVIG therapy, resulting in beneficial clinical effects of IVIG in EBA and other autoimmune skin-blistering diseases. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

This report describes the clinical presentations and treatment responses of three children with PV, as confirmed according to histology and indirect immunofluorescence studies. In all three cases, oral prednisone used in conjunction with mycophenolate mofetil (MMF) resulted in complete clinical remission, during which all pharmacotherapy was successfully discontinued. Resolution of the skin and mucosal blistering tended to occur quickly with prednisone, and after initiation of treatment with MMF, discontinuation of all pharmacotherapy was achieved within a range of 10 to 30 months in the three patients. One patient experienced a recurrence of genital lesions 19 months after discontinuation of therapy, but the condition remitted within 2 weeks with topical corticosteroid therapy. At the time of this report, the duration of complete remission ranged from 6 to 19 months. In summary, combination therapy with prednisone and MMF for pediatric PV appears to be a safe and effective approach that is associated with durable remission.

Herpes virus infections are well known infectious complications of pemphigus and bullous pemphigoid. We describe pathologic findings utilizing autopsy tissue from several organs from a patient affected by a new variant of endemic pemphigus in El Bagre, Colombia, South America.

We describe a patient by a new variant of endemic pemphigus foliaceus from El Bagre that was receiving high-dosage immunosuppressants when hospitalized and died suddenly following contact with a second patient affected by chicken pox.

We performed studies utilizing hematoxylin and eosin, immunohistochemistry, and direct immunofluorescence techniques on tissues from several organs.

We detected the presence of varicella zoster virus, as well as strong positivity for α-1 antitrypsin in the heart, kidneys, spleen, liver, skin, brain, lungs, pancreas, small and large intestines, and skeletal muscle. In regard to structural damage in the kidney and heart, we believe the observed damage is associated with the presence of autoantibodies to these organs, since both of them are rich in plakins and El Bagre-EPF patients present significant antibodies to plakin molecules.

In patients with endemic pemphigus foliaceus, we recommend complete isolation of the patient when receiving high dosages of systemic immunosuppressive agents. We further suggest the clinical possibility of a synergistic, fatal interaction between active pemphigus foliaceus, varicella zoster virus, herpes simplex virus, immunosuppressive agents, and a systemic activation of α-1 antitrypsin. Thus, we suggest adequate bed spacing, barrier nursing, and preventative testing for α-1 antitrypsin activation are warranted in these patients to address these complications.



Background:  Pemphigus vulgaris (PV) is an autoimmune blistering skin disorder characterized by the presence of suprabasal acantholysis and autoantibodies against desmoglein 3. There are two different clinical forms: mucocutaneous (MCPV) or mucosal (MPV). However, it is not clear how PV lesions in oral, ear, nose and throat (OENT) areas produced by the very dynamic of the anatomical structures involved in the functions of the aerodigestive tract.

Objectives:  To investigate the pattern of OENT manifestations in PV, and their relationship with physiological traumatic mechanisms in stratified squamous epithelium structures.

Patients:  A prospective analysis of 40 patients diagnosed with MCPV (22 patients) or MPV (18 patients) was carried out in the University Clinic of Navarra. OENT manifestations were evaluated in all patients endoscopically. OENT involvement was divided into anatomical areas.

Results:  The most frequent symptom was pain, mainly on oral mucosa (87,5%). Buccal mucosa (90%), posterior wall of pharynx (67.5%), upper edge of epiglottis (85%) and nasal vestibule (70%) were the areas most frequently affected in the OENT mucosa. These localizations were related to physiological traumatic mechanisms in polystratified squamous epithelium structures.

Conclusions:  OENT endoscopy should be included in the examination of all PV patients. To know the most frequent localizations of active lesions on OENT mucosa in PV will help us to interpreter more efficiently the findings from OENT endoscopy. Also, information related to traumatic physiological mechanisms on OENT areas must be offered to patients in order to avoid the appearance of new active PV lesions.


Source: Study of Oral, Ear, Nose, and Throat Involvement…

Bullous pemphigoid (BP) is an autoimmune blistering skin disease. Auto-antibodies to BP180 and BP230 can be detected by indirect immunofluorescence (IIF) on different substrates (oesophagus, salt-split-skin, BP180-antigen dots, BP230-transfected cells) and ELISA. Here, we compared test characteristics of these test systems. We analyzed sera from BP patients (n=60) in whom the clinical diagnosis had been confirmed histopathologically. The control cohort comprised sera from patients with other autoimmune-associated (n=22) or inflammatory (n=35) skin diseases. All samples were tested by IIF (EUROIMMUN™ Dermatology Mosaic) and ELISA (EUROIMMUN and MBL). Anti-BP180 is best detected with BP180-antigen dots by IIF (sensitivity: 88%; specificity: 97%). As compared to IIF, the differences with both BP180 ELISA techniques are small though. Likelihood ratios (LRs) for positive and negative test results are >10 and between 0.1 and 0.2, respectively, for all test systems. Detection of anti-BP230 is highly variable (sensitivity range 38-60%; specificity range 83-98%). Only the IIF test reveals a LR for positive test results >10. Since the LRs for a negative test are all ~0.5, negative test results for anti-BP230 antibodies do not help to exclude BP. In conclusion, the multi-parameter IIF test reveals a good diagnostic performance in BP. Since this test simultaneously allows for the detection of anti-Dsg1 and anti-Dsg3 antibodies, involved in pemphigus foliaceus and vulgaris, a single test-incubation may be sufficient to differentiate between the most frequent autoimmune blistering diseases.

Copyright © 2012 Elsevier B.V. All rights reserved.