Monthly Archives: October 2012

Pemphigus foliaceus, the most common autoimmune skin condition in dogs and cats, is characterized by pustules, erosions, and crusts. In this article, we focus on the diagnosis and treatment of pemphigus foliaceus in dogs and cats.

The signs of an attack on keratinocyte adhesion structures are clinically evident. When the tight bonds between superficial keratinocytes are affected, it manifests as vesicles and pustules. When the tight bonds between basilar keratinocytes and the skin’s basement membrane

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are affected, it manifests as bullae (large blisters) and ulcers.

In pemphigus foliaceus in people, the most common target of autoantibodies is the desmoglein 1 (DSG1) glycoprotein in the desmosome. The autoantibody response primarily involves IgG (IgG4 subclass). Initial studies in dogs with pemphigus foliaceus only rarely detected an IgG autoantibody response, but more recent work using different substrates in indirect immunofluorescence testing confirms that IgG autoantibodies are important in canine pemphigus foliaceus. However, DSG1 is not commonly targeted in pemphigus foliaceus in dogs ; it is not yet known which part of the desmosome is targeted in most canine pemphigus foliaceus cases. Early immunoblotting studies revealed that the target was a 148 kDa or 160 kDa protein. Immunoelectron microscopy shows that the site of autoantibody binding is in the extracellular region of the desmosome.

Genetic factors can influence the development of pemphigus foliaceus. In dogs, it is more frequently diagnosed in two breeds with closely related genotypes, Akitas and chows. Pemphigus foliaceus has also been reported in littermates. No breed disposition has been noted in feline pemphigus foliaceus. Sex and age appear to be unrelated to the development of pemphigus foliaceus in dogs and cats. The age of onset is variable and ranges from 1 to 16 years in dogs and less than 1 year of age4 to up to 17 years of age in cats.

Background  Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering

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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.

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MedWire News: Researchers have identified the primary target of the autoantibodies found in the serum of patients with the blistering skin disorder pemphigus vulgaris (PV).

PV patients develop antibodies against the proteins desmoglein (DSG)1 and 3, which help epidermal cells stick together and maintain the integrity of the skin, causing painful blistering on the skin and mucus membranes.

Giovanna Zambruno (Istituto Dermopatico dell’Immacolata, Rome, Italy) and colleagues found that the cis-adhesive interface of the DSG3 extracellular domain (EC)1 is the main target of the PV autoantibody (A)224 generated in the serum of patients with PV.

Existing therapies for the condition target the whole immune system, but this can cause problems with side effects and can result in patients being vulnerable to infections.

To pinpoint the trigger of the autoantibody production in PV more specifically, Zambruno and team isolated 15 immunoglobulin (Ig)G antibodies specific for DSG3 from two patients with the disorder.

Of these, three disrupted layers of skin cells in the laboratory and two were pathogenic when expressed in a murine passive transfer model.

The epitopes recognized by the pathogenic PV antibodies were isolated to the DSG3 EC1 and EC2 subdomains and a specific serologic assay was used to pinpoint the target of the PVA224 as being the cis-adhesive interface on EC1.

The researchers suggest that the autoreactivity seen in PV is due to somatic mutations that are generated by an antigen other than DSG3, as binding to DSG3 disappeared when the somatic mutations reverted to the germline sequence.

“The identification of an immunodominant region targeted by pathogenic antibodies has implications for diagnosis of PV and opens new perspectives toward the establishment of therapeutic approaches for treatment of PV patients,” write Zambruno and team in the Journal of Clinical Investigation.

“Finally, the germlined version of the PV autoantibodies may lead to the identification of the antigens that eventually lead to development of this life-threatening disease.”

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

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This study aimed to highlight the importance of routine screening for hyperglycemia and to develop a standardized, evidence-based approach for the management of pemphigus patients on prolonged systemic corticosteroid (CS) therapy. A cross-sectional study was conducted in two university-affiliated teaching hospitals using a referred sample of 200 patients with a confirmed diagnosis of pemphigus vulgaris, pemphigus foliaceus, or mucous membrane pemphigoid. All patients were receiving systemic CS therapy. A total of 150 patients responded to the survey. Six participants were excluded and 144 were included. The main outcome measure was blood glucose level to detect hyperglycemia. New-onset hyperglycemia was identified in 40% of patients who received CS therapy. None of the expected variables, including age, body mass index, family history of diabetes, corticosteroid dose, and duration of corticosteroid therapy, were independently associated with new-onset hyperglycemia. These findings indicate that the prevalence of CS-induced hyperglycemia in pemphigus patients is 40% and that in patients with pemphigus or MMP, CS therapy is associated with a markedly increased risk for hyperglycemia (odds ratio = 10.7, 95% confidence interval 1.38–83.50) compared with that of patients with the same diseases who do not receive CS therapy.

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Background  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein (Dsg) adhesion proteins. Previous studies have shown an IgG4 > IgG1 predominance of anti-Dsg 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 patients with pemphigus.

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

Methods  IgG subclasses and Dsg-specific IgG1 and IgG4 were quantitated in patients with PV and PF, and in sera from age-matched controls using a subclass enzyme-linked immunosorbent assay. The effectiveness of IgG4 depletion in blocking IgG pathogenicity in PV was determined using a keratinocyte dissociation assay.

Results  Dsg-specific antibodies comprised a median of 7·1% and 4·2% of total IgG4 in patients with PV and PF, respectively, with eightfold and fourfold enrichment in IgG4 vs. IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in patients with PV and PF compared with 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  Dsg-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some patients with pemphigus. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.

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Background  Promoter polymorphisms of the macrophage migration inhibitory factor gene are associated with increased production of macrophage migration inhibitory factor. Elevated levels of macrophage migration inhibitory factor have been observed in the sera of patients with pemphigus vulgaris. More than this, macrophage migration inhibitory factor promoter gene polymorphism has been found to confer increased risk of susceptibility to chronic inflammatory diseases.

Objective  We investigated whether there is an association between promoter polymorphism of the macrophage migration inhibitory factor gene and pemphigus vulgaris.

Methods  One hundred and six patients with pemphigus vulgaris, and a control panel of one hundred healthy volunteers were genotyped for a single nucleotide polymorphism identified in the 5′-flanking region at the position −173 of the gene, using polymerase chain reaction–restriction fragment length analysis.

Results  We found a notably high prevalence of C/C genotype in our nation but no significant difference was observed between patients and controls.

Conclusion  The result of this study using a large and well documented trial of patients showed that macrophage migration inhibitory factor −173G-C polymorphism is not associated with pemphigus vulgaris; but as the role of macrophage migration inhibitory factor in the inflammatory process has not been delineated in detail and the prevalence of C/C genotype is notably higher in our nation, this finding merits more consideration.

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Pemphigus vulgaris (PV) is an autoimmune disease in which the body’s immune system develops antibodies to two of its own proteins, the desmogleins DSG1 and DSG3 that help maintain the integrity of the skin. The immune attack causes painful blisters on the skin and mucus membranes that can lead to infections. Current therapies are geared towards suppressing the entire immune system, but this is problematic as it causes many side effects and leaves the patient vulnerable to infection.

To identify better therapeutic targets, researchers at the Institute for Research in Biomedicine in Bellinzona, Switzerland, identified the portions of DSG1 and DSG3 that are targeted by antibodies. In the study, published this month in the Journal of Clinical Investigation, Antonio Lanzavecchia and colleagues collected immune cells from PV patients and isolated the antibodies to determine which ones were involved in PV. By studying the antibodies, they were able to identify regions of DSG3 that are the primary target of the immune sysm. These findings could help with new ways to diagnose and treat PV.

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We evaluated the effectiveness of mizoribine, a newly developed immunosuppressive agent, as an adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus. Eleven pemphigus patients (eight pemphigus vulgaris and three pemphigus foliaceus) received the combination therapy of prednisolone and mizoribine. Complete remission was observed in three of the eight patients with pemphigus vulgaris and in one of the three patients with pemphigus foliaceus. The four patients with complete remission had a rapid clinical response and achieved remission at a median of 11.8 months. Partial remission was achieved in two of the three patients with pemphigus foliaceus. The median time to achieve partial remission was 16.0 months. Six (55.6%) of the 11 patients with pemphigus had complete or partial remission and were able to taper their prednisolone. The cumulative probability of having a complete remission was 64.3% at 19 months of follow-up using Kaplan–Meier analysis. The effectiveness of the additional mizoribine therapy could be attributed to its corticosteroid-sparing properties as well as its immunosuppressive effects. The serum concentration titer of mizoribine was around 1.0 μg/mL 2 hours after administration. Patients who were not improved by the additional mizoribine might require a continuously higher dose of mizoribine to achieve effective therapy.

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Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease of skin and mucous membranes caused by autoantibodies that bind to the cadherin-type cell-cell adhesion molecules desmoglein 3 (DSG3) and DSG1, the main constituents of desmosomes, and cause the loss of keratinocyte cell adhesion. The critical role of autoantibodies in PV pathogenesis is supported by the observations that the disease activity correlates with anti-DSG3 antibody titers , that newborns of mothers with active PV exhibit blisters caused by the placental transfer of maternal antibodies, and that pemphigus-like lesions are induced in neonatal mice by passive transfer of anti-DSG3 IgG from PV patients.

In the skin, DSG3 is mainly expressed in the basal and suprabasal layers, while DSG1 is predominantly expressed in the upper epidermal layers. In contrast, in noncornified stratified epithelia, such as the oral mucosa, DSG3 is highly expressed throughout the epithelium, while DSG1 is expressed at a much lower level. The differential expression pattern of DSG1 and DSG3 is responsible for clinical variants of pemphigus: antibodies to DSG3 are present in the mucosal form, while antibodies to both DSG3 and DSG1 are associated with mucocutaneous lesions.

DSG3 is a calcium-binding membrane glycoprotein with an extracellular domain comprising 5 distinct subdomains (EC1–EC5), and it is synthesized as proprotein, which is processed in the Golgi apparatus by removal of a propeptide before transporting to the cell surface. The cleavage of the propeptide occurs upstream of a conserved tryptophan residue in the EC1 subdomain, unmasking residues critical for the formation of homophilic interactions with DSG3 on opposing cells. Several studies have shown that polyclonal antibodies in PV serum react primarily with the aminoterminus of DSG3 in the EC1 and EC2 subdomains (amino acids 1–161).

The isolation of pathogenic mAbs is instrumental for addressing questions as to the mechanism that induces the autoreactive response and drives blister formation in PV patients. Amagai and coworkers isolated from an active mouse model of PV a pathogenic antibody, AK23, which causes loss of cell adhesion by binding to the EC1 subdomain of DSG3 that is involved in the formation of the trans-adhesive interface. A number of human anti-DSG pathogenic and nonpathogenic mAbs were isolated as single-chain variable-region fragments (scFvs) from a PV patient . Similarly to the AK23 mAb, the pathogenic activity of these human antibodies was mapped to the aminoterminal region of EC1, which is masked by the propeptide . Taken together, the human and mouse data suggest that pathogenic antibodies bind primarily to EC1 and disrupt the keratinocyte adhesion by interfering with the trans-adhesive interface of DSG3.

In this study, we isolated from 2 PV patients several IgG autoantibodies that bind DSG3. These antibodies carried high levels of somatic mutations that were required for binding to DSG3. The epitopes recognized by 3 pathogenic antibodies were mapped to the EC1 and EC2 subdomains in regions that are expected to be involved in cis-adhesive interactions. This region was found to be the primary target of serum autoantibodies in PV patients. These results identify the cis-adhesive interface as the immunodominant region targeted by pathogenic antibodies in PV and suggest that autoreactivity relies on somatic mutations triggered by an unrelated antigen.

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We report a case of neutropenic ulceration in a 42-year-old woman receiving azathioprine for pemphigus vulgaris. She developed multiple indolent ulcers involving the nose, neck, and back, after about 6-8 weeks following commencement of azathioprine 50 mg daily. The ulcers were large, disfiguring, dry, and with basal necrotic slough. They were painless and did not discharge pus. The absolute neutrophil count was severely depressed initially, but normalized following azathioprine withdrawal. Swab culture revealed colonization with Klebsiella pneumoniae and the ulcers healed with local debridement, treatment with imipenem, and topical application of mupirocin. However, nasal disfigurement persisted. Neutropenic ulceration is known to be associated with azathioprine therapy but we report this case because of the unusual presentation-indolent cutaneous ulcers. Early recognition of the problem and drug withdrawal can prevent complications like disfigurement.

Neutropenia is characterized by an abnormally low number of neutrophils in the blood. Neutrophils normally comprise 45-75% of circulating white blood cells, and neutropenia is diagnosed when the absolute neutrophil count falls to <1500/ μL. Slowly developing neutropenia often goes undetected and is generally discovered when the patient develops sepsis or localized infections.

There are many causes of neutropenia, and immunosuppressants are a common iatrogenic cause. Azathioprine is an immunosuppressant drug that is being used for nearly 50 years now in organ transplantation and in diseases with suspected autoimmune etiology. Dermatologists use azathioprine as a steroid-sparing agent in various dermatoses such as psoriasis, immunobullous diseases, photodermatoses, and eczematous disorders. [1] The drug has been used in ulcerative autoimmune disorders such as Crohn’s disease and pyoderma gangrenosum. On the other hand, it has also been implicated as a cause of ulceration associated with neutropenia. [2] Most reports of neutropenic ulceration document involvement of the buccal mucosa and oral cavity.  We report a case of multiple severe cutaneous ulcers associated with long-term azathioprine use in a patient with pemphigus vulgaris.

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