Pemphigus vulgaris and pemphigus foliaceus antibodies are pathogenic in plasminogen activator knockout mice.

Previous studies have suggested that urokinase plasminogen activator is required for blister formation in pemphigus vulgaris and pemphigus foliaceus. Other studies, however, have shown that downregulation of plasminogen activator does not inhibit blisters induced by pemphigus immunoglobulin G. To eliminate the possibility that small amounts of urokinase plasminogen activator might be sufficient for blister formation, we passively transferred pemphigus immunoglobulin G to urokinase plasminogen activator knockout neonatal mice. Pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused gross blisters and acantholysis in the superficial and suprabasal epidermis, respectively, to the same degree in knockout and control mice, demonstrating that urokinase plasminogen activator is not absolutely required for antibody-induced blisters. Some studies have shown elevated tissue-type plasminogen activator in pemphigus lesions. Tissue-type plasminogen activator, however, is not necessary for blister formation, because pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused blisters to the same degree in tissue-type plasminogen activator knockout and control mice. To rule out that one plasminogen activator might compensate for the other in the knockout mice, we bred urokinase plasminogen activator, tissue-type plasminogen activator double knockouts. After passive transfer of pemphigus foliaceus and pemphigus vulgaris immunoglobulin G these mice blistered to the same degree as the single knockout and control mice, and histology indicated blisters at the expected level of the epidermis. These data definitively demonstrate that plasminogen activator is not necessary for pemphigus immunoglobulin G to induce acantholysis in the neonatal mouse model of pemphigus.     

Pemphigus

Pemphigus is a group of organ-specific autoimmune mucocutaneous disorders with an established immunologic basis. The presence of intraepithelial blisters and erosions of the skin and variable involvement of the mucous membranes characterize its three major variants, pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Prior to the use of corticosteroids in the 1950s, the natural history of pemphigus vulgaris was relentless progression, with a 50% mortality at 2 years, and almost 100% at 5 years. Today, with mortality rates less than 5%, the focus has changed towards reducing corticosteroid side effects and maintaining optimal quality of life under treatment. This can be achieved by the appropriate use of steroid-sparing agents. This article addresses the comprehensive management of patients with pemphigus.     

Microscopic Nikolsky''s sign

Nikolsky's sign is a useful clinical sign in patients with active pemphigus. It does not however, indicate the level of split in the skin, and is seldom present in partially-treated patients. The purpose of this study was two fold: (i) to document the microscopic or subclinical counterpart of clinical Nikolsky's sign; and (ii) to improve the diagnostic yield of routine histopathology in pemphigus patients in whom the lesions are infected/old and are therefore not useful for histopathology, and when intact blisters are not present; this is particularly useful for institutions in which immunofluorescence facilities are not available. Pemphigus patients were allocated to one of two groups. Group A patients (n = 23) were subjected to manual tangential pressure over the perilesional skin before a biopsy specimen was taken from that site; group B patients (n = 14) were subjected to a biopsy without the tangential pressure technique. Group C consisted of 37 healthy volunteers who were subjected to the tangential pressure technique before a biopsy. Histopathological changes of pemphigus vulgaris or foliaceus were present in 73.9% patients in group A, 28.6% in group B and none in the control group C. Tangential pressure as described below can produce microscopic changes in the epidermis which are diagnostic of pemphigus. These changes are produced at the suprabasal level in pemphigus vulgaris and intraepidermally in pemphigus foliaceus. This technique is of value in those parts of the world where immunofluorescence facilities are not readily available.     

Validity of the EQ-5D in patients with pemphigus vulgaris and pemphigus foliaceus

Pemphigus is a group of autoimmune skin diseases that cause blisters and wounds on the skin and/or mucous membranes such as inside the mouth. It is an uncommon disease with around 15 new cases yearly per million people. The two most common clinical forms are pemphigus vulgaris and foliaceus. Pemphigus can still be life threatening, and the symptoms may cause significant difficulties for patients in their everyday life. This study, from Hungary, aimed to assess the health status and quality of life in patients with pemphigus vulgaris and foliaceus. The authors surveyed 109 pemphigus patients, and collected data on demographics and clinical characteristics. Quality of life was assessed by the EQ-5D general health status questionnaire. Overall, 50%, 43%, 43%, 42% and 19% of pemphigus patients reported problems regarding pain/discomfort, mobility, anxiety/depression, usual activities and self-care, respectively. Patients having skin and mucosal symptoms, a larger number of comorbidities (other diseases occurring alongside pemphigus) and more severe disease experienced greater impairment of quality of life. No difference was found in quality of life scores between pemphigus vulgaris and foliaceus patients or between females and males. This study demonstrates that the EQ-5D questionnaire is an accurate measure of quality of life in pemphigus patients. The EQ-5D questionnaire allows comparisons between patients across a broad range of disease areas and people without those diseases. The EQ-5D scores reported in this study can be useful for cost-effectiveness analyses of new pemphigus treatments such as rituximab, and might help to improve patients’ access to more effective medicines, in a condition for which only limited treatment options have been available so far.     

Pemphigus

Pemphigus is an infrequent, organ-specific, autoimmune bullous disease, which affects the skin, mucous membranes and appendages. Histopathologically, it is characterized by acantholysis. Pemphigus has classically been divided into two major groups, pemphigus vulgaris and pemphigus foliaceus, with their respective clinical variants pemphigus vegetans and pemphigus erythematosus. In recent years, new variants of pemphigus have been described: paraneoplastic pemphigus, IgA pemphigus and pemphigus herpetiformis. This article reviews the epidemiology, etiopathogenesis, clinical symptoms, diagnosis, treatment and prognosis of pemphigus. Advances in molecular biology techniques have made it possible to more precisely identify the different antigens against which antibodies are directed, and to fine-tune ELISA diagnostic techniques. Treating pemphigus vulgaris and foliaceus with general steroids has modified their prognosis; it is estimated that mortality in recent decades is less than 10 %. Managing the clinical complications that appear during the evolution of the pemphigus has contributed to reducing morbidity and mortality.     

Postpemphigus acanthomata: a sign of clinical activity?

Background Pemphigus is a group of vesiculobullous disorders in which the blisters usually heal with hyper- or hypopigmentation. The appearance of acanthomata at sites of previous blisters has been noted in some cases. Methods All cases of pemphigus admitted to the Madras Medical College hospitals during a 2-year period from March 1993 to March 1995 were taken into the study and screened for the presence of acanthomata. Results Fifty-two cases of pemphigus were identified, 47 of pemphigus vulgaris and five of pemphigus foliaceus; and of these 13 developed acanthomata when the blisters healed. Ten of these cases were of pemphigus vulgaris and three were of pemphigus foliaceus; biopsy of these lesions showed hyperkeratosis, acanthosis, papillomatosis, and intraepidermal clefting. Immunofluorescence carried out in two of these acanthomata also showed intercellular fluorescence. Conclusions The occurrence of acanthomata in healed lesions of pemphigus is not uncommon; because histopathologic and immunofluorescence evidence of disease activity is present, cases of this sort require careful follow-up.     

Autoantibodies against desmoglein 2 are not pathogenic in pemphigus

BackgroundAnti-desmoglein 1 and 3 autoantibodies justify acantholysis in pemphigus; however, the pathogenesis of anti-desmoglein 2 is hypothetical.ObjectiveTo compare the participation of desmogleins 1, 2 and 3 through the production of serum autoantibodies, and protein and gene expression in the skin/mucosa of patients with pemphigus foliaceus and pemphigus vulgaris.MethodsThe autoantibodies were titrated by ELISA in 202 samples of pemphigus foliaceus, 131 pemphigus vulgaris, 50 and 57 relatives of patients with pemphigus foliaceus and pemphigus vulgaris, respectively, and 114 controls. Protein and gene expressions were determined by immunohistochemistry and qPCR in the skin/mucosa of 3 patients with pemphigus foliaceus and 3 patients with pemphigus vulgaris.ResultsHigher titers of anti-desmoglein 2 (optical density) resulted in pemphigus foliaceus and pemphigus vulgaris, when compared to controls (0.166; 0.180; 0.102; respectively; p < 0.0001). There was a correlation between anti-desmoglein 2 and anti-desmoglein 1 titers in pemphigus foliaceus (r = 0.1680; p = 0.0206). There was no cross-reaction of anti-desmoglein 2 with desmoglein 1 and 3. Protein overexpression of desmoglein 2 was observed in intact and lesional skin of patients with pemphigus compared to the skin of controls. Internalization granules of desmoglein 1 and 3, but not of desmoglein 2, were observed in lesions of pemphigus foliaceus and pemphigus vulgaris, respectively. Gene overexpression of desmoglein 2 was observed in the mucosa.Study limitationsSmall sample size for the statistical analysis of protein and gene expression.ConclusionAutoantibodies against desmoglein 2 are not pathogenic in pemphigus; protein and gene overexpression of desmoglein 2 in the skin and mucosa may be involved in acantholysis repair.     

The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.     

天疱疮抗体结合靶抗原的定位研究

目的 研究天疱疮抗体铺皮细胞间抗原在超微结构水平的部位。方法 采用ＬＲＷｈｉｔｅ树脂为包埋剂,用金标记包一直接和间接免疫电镜技术,观察天疱疮患者皮损中ＩｇＧ的沉积部位和患者血清中ＩｇＧ型自身抗体结构正常人皮肤的部位。结果 寻常型天疱疮和落叶型天疱疮的直接和间接免疫电镜均在表皮细胞间的桥粒部位觅金颗粒沉积,在非桥数部位的角质形成细胞间未金颗粒沉积。结论寻常型天疱疮和落叶型天疱疮的靶抗原均是桥粒成分,     

Pemphigus

Pemphigus diseases comprise a group of autoimmune disorders which are characterized by intraepidermal blisters and autoantibodies to components of desmosomes. Desmosomes mediate adhesion between neighbouring keratinocytes. A common feature of pemphigus diseases are intercellular deposits of IgG or, less frequently, of IgA within the epidermis. The group of pemphigus diseases includes pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, pemphigus herpetiformis, pemphigus erythematosus, paraneoplastic pemphigus, drug-induced pemphigus, and IgA pemphigus. Using molecular tools, some of the autoantigens in these diseases have been characterized. In pemphigus vulgaris, autoantibodies are directed to desmoglein 3 and in pemphigus foliaceus to desmoglein 1. Target antigens in IgA pemphigus are desmocollin 1 and desmoglein 3. In paraneoplastic pemphigus, autoantibodies react with a complex of various proteins, including desmoplakin 1 and 2, BP230, envoplakin, periplakin, plectin, desmoglein 3, and a yet uncharacterized 170 kD protein. This review summarizes new insights into the immunopathogenesis and diagnosis of pemphigus diseases.     

Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients.

Pemphigus refers to a group of autoimmune blistering skin diseases, mainly identified as pemphigus vulgaris and pemphigus foliaceus, both characterized by the presence of autoantibodies against keratinocyte adhesion molecules, leading to loss of cell-cell adhesion with consequent blister formation. Pemphigus vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6 whereas no data are available on pemphigus foliaceus, except for the endemic Brazilian form (fogo selvagem), which is reported to be associated with DR1 and DR4. We here report human leukocyte antigen molecular typing on a total of 87 patients, 61 with pemphigus vulgaris and 26 with pemphigus foliaceus, versus 128 healthy matched controls. Generic typing showed an increase of DRB1*04 and DRB1*14 and a decrease of DRB1*07 in both pemphigus vulgaris and pemphigus foliaceus patients. Molecular subtyping of DR4+ and DR14+ subjects showed a highly significant association between the DRB1*1401 and both pemphigus vulgaris (p < 0.0001) and pemphigus foliaceus patients (p < 0.0001) together with a significant increase of the linked DQB1*0503 (pemphigus vulgaris p < 0.0001; pemphigus foliaceus p < 0.0001). Moreover, whereas the association between DRB1*0402 and pemphigus vulgaris (p < 0.0001) has been confirmed, no significant association between a specific allele of the DR4 group and pemphigus foliaceus, has been found. Therefore, at least in Italian patients, pemphigus vulgaris and pemphigus foliaceus share DRB1*1401 and DQB1*0503, as susceptible human leukocyte antigen alleles, whereas DRB1*0402 is only found associated with pemphigus vulgaris. The observation that both diseases, pemphigus vulgaris and pemphigus foliaceus, carry the same susceptible human leukocyte antigen alleles has been interpreted as a common genetic background predisposing to pemphigus as, like in other autoimmune disorders, it is not sufficient to explain the onset of the disease on the basis of the sole aforementioned alleles. Other linked genes and/or environmental factors should play a facilitating role in the outbreak of pemphigus, either pemphigus vulgaris or pemphigus foliaceus.     

Antibody deposits in Tzanck smears in pemphigus vulgaris

Forty-three patients, including 24 males and 19 females between 5 and 62 years of age, having pemphigus vulgaris (27), pemphigus foliaceus (1), bullous pemphigoid (3), chronic benign bullous dermatosis of childhood (2) and herpes zoster (10) were included in this study. Tzanck smears were prepared from the floor of the blisters in these patients by deroofing the bullae, and the slides were stored without fixation at room temperature for 1 to 10 days. Immunofluorescence staining was done with FITC-conjugated anti-human IgG. Twenty-one cases having pemphigus vulgaris and 1 case having pemphigus foliaceus showed bright green fluorescence on the membrane of acantholytic cells. No epithelial cells were seen in smears from bullous pemphigoid and chronic benign bullous dermatosis of childhood, whereas epithelial cells were seen in 10 cases of herpes zoster. These stained negative with anti-IgG. Storage of the prepared smears for 1–10 days did not seem to affect the results of immunofluorescence. Tzanck smears can be used as an easy substitute for skin/mucosal biopsy for the direct immunofluorescence test.     

Mucocutaneous pemphigus vulgaris carrying high-titre antidesmoglein 1 antibodies with skin lesions resembling pemphigus erythematosus

Patients with pemphigus vulgaris (PV) who have both antidesmoglein (Dsg)1 and anti-Dsg3 antibodies usually develop flaccid blisters on skin and mucous membranes. We report a case of PV with crusting skin lesions resembling pemphigus erythematosus, the localized variant of pemphigus foliaceus (PF). Notably, the patient had high titres of anti-Dsg1 IgG, as assessed by ELISA. We then established an in vitro model of pemphigus, and found that patient's serum was able to induce suprabasilar acantholysis in mouse skin culture. However, epidermal splitting also occurred within the granular layer, suggesting that the pathogenic potential of such a high-titre anti-Dsg1 serum was intermediate between PV and PF. Thus, the levels of anti-Dsg1 antibodies could play a role in determining the clinical phenotype of pemphigus.     

Nonendemic pemphigus foliaceus presenting as fatal bullous exfoliative erythroderma

Pemphigus foliaceus is a cutaneous autoimmune blistering disease that is characterized by lower morbidity and mortality than those observed in pemphigus vulgaris or paraneoplastic pemphigus. However, erythrodermic forms of the endemic variant of pemphigus foliaceus have been associated with a higher mortality. We report a case of nonendemic pemphigus foliaceus that presented as fatal bullous exfoliative erythroderma, and thus, we will emphasize the inclusion of this entity in the differential diagnosis and the use of skin direct immunofluorescence in the evaluation of patients with erythroderma.     

Pemphiguserkrankungen bei Kindern und Jugendlichen

The pemphigus diseases, which include some of the most severe bullous autoimmune skin reactions, are seen predominantly in middle-aged and elderly individuals. Only endemic pemphigus foliaceus in South America most frequently affects juveniles and children. All non-endemic pemphigus diseases, including paraneoplastic pemphigus, have been reported to occur in adolescents and even very rarely in children younger than 10 years. Pemphigus vulgaris in pregnancy represents a frequently overseen medical problem and may result in fetal growth retardation, intrauterine death, premature delivery and – in about 30% – in neonatal pemphigus vulgaris of the newborn. Contrary to pemphigus vulgaris, the transplacental crossing of autoantibodies against desmoglein1 in pregnant women with pemphigus foliaceus hardly ever leads to neonatal skin lesions in the offspring. This phenomenon can be explained by differences in the distribution and cross-compensation of the pemphigus antigens desmoglein3 and 1 in neonatal and adult skin or mucosa, respectively.     

Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus

Pemphigus is an autoimmune blistering disease characterized by circulating autoantibodies directed against the keratinocyte cell surface. The two variants, pemphigus foliaceus and pemphigus vulgaris, can be distinguished at the molecular level by immunochemical studies. The large majority of patients with pemphigus develop the disease spontaneously; however, there is a small group of patients who develop pemphigus after treatment with certain medications, of which penicillamine and captopril are the best documented. Most patients with drug-induced pemphigus have circulating and/or tissue bound epidermal cell surface autoantibodies; however, the molecular specificity of these autoantibodies has not been studied. We performed immunoprecipitation studies utilizing extracts of 125I-labeled suction blister epidermis and the sera of three patients with drug-induced pemphigus foliaceus (two due to penicillamine and one due to captopril) and one patient with captopril-induced pemphigus vulgaris. We found that the three patients with drug-induced pemphigus foliaceus had circulating autoantibodies that are directed against the pemphigus foliaceus antigen complex and that the one patient with drug-induced pemphigus vulgaris had circulating autoantibodies that are directed against the pemphigus vulgaris antigen complex. This study demonstrates that autoantibodies from drug-induced pemphigus patients have the same antigenic specificity, on a molecular level, as do autoantibodies from other pemphigus patients.     

Autoimmune bullous skin diseases. Part 1: Clinical manifestations

Autoimmune bullous skin diseases are characterized by autoantibodies against adhesion molecules of the skin. Pemphigus is a disorder with an intraepidermal loss of adhesion and is characterized by fragile blisters and erosions. Pemphigus vulgaris often shows extensive lesions of the oral mucosa, while pemphigus foliaceus is commonly restricted to cutaneous involvement with puff pastry-like scale formation. Paraneoplastic pemphigus is obligatorily associated with malignancies and often presents as hemorrhagic stomatitis with multiforme-like exanthems. IgA pemphigus typically presents with pustules and annular plaques but not with mucosal involvement. The clinical spectrum of the pemphigoids includes tense blisters, urticarial plaques, and prurigo- like eczematous lesions. Pemphigoid gestationis mostly occurs during the last trimester of pregnancy and mucous membrane pemphigoid primarily involves the oral mucosa and conjunctivae and leads to scarring. Linear IgA bullous dermatosis manifests with tense blisters in a "cluster of jewels"-like pattern in childhood and is more heterogeneous in adulthood. Classical epidermolysis bullosa acquisita shows extensive skin fragility. Dermatitis herpetiformis is associated with gluten-sensitive enteropathy and manifests clinically with severe itching and papulovesicles on the extensor surfaces of the extremities and the lumbosacral area. The intention of the review is to demonstrate the heterogeneous clinical spectrum of autoimmune bullous disorders.     

History of pemphigus

The modern concept of pemphigus divides it into variants: pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus (Senear-Usher syndrome), and pemphigus herpetiformis. These conditions are all related by the fact that they are all bullous diseases at some time during their clinical course and are histologically characterized by acantholysis. In pemphigus vulgaris and pemphigus vegetans, acantholysis is generally above the basilar cell layer (suprabasilar) or in the lower half of stratum spinosum. In pemphigus foliaceus, pemphigus herpetiformis and pemphigus erythematosus, acantholysis occurs in the granular cell layer or upper stratum spinosum. Autoantibodies to the intercellular cement substance of the epidermis are present in all the variants.

The changes in the concept of pemphigus over time has been reviewed.^1,2 The term “pemphigus,” itself, was first proposed by Boissier de Sauvages in his classification of skin diseases.³ He described pemphigus maior as an acute, febrile, blistering disease lasting only two weeks. Today, the diagnosis would probably be erythema multiforme.

Wichmann^4,5 was the first to describe pemphigus as a chronic bullous disease; he used the term, febris bullosa, to describe bullous eruptions of short duration. Unfortunately, few authors agreed with Wichmann's more restricted concept, and continental dermatologists continued to use the term pemphigus for a wide range of vesicular or bullous diseases. For example, Gilibert,⁶ in his monograph on pemphigus, included almost every disease with bullae in his classification. His “chronic pemphigus” most closely corresponds to the modern concept of pemphigus. Von Martius⁷ had an equally liberal definition of pemphigus, dividing it into 97 types.

Willan had a much more restricted view of the disease. In his classification of skin diseases, pemphigus vulgaris was a febrile, bullous eruption of short duration.⁸ He applied the term “pompholyx duitinus” to a chronic, bullous eruption, without inflammation and fever, similar to the modern concept of pemphigus vulgaris.     

Bilateral herpes simplex virus keratitis in a patient with pemphigus vulgaris

Pemphigus is a group of chronic blistering diseases in which acantholysis and blister formation occur within the epidermis. Immunoglobulins and complement are found in the circulation and are bound to the cell surfaces of keratinocytes. Pemphigus is classified into several types hut may he divided into two major variants, pemphigus vulgaris and pemphigus foliaceus. The primary skin lesion of pemphigus vulgaris which was often fatal before the introduction of systemic glucocorticoid therapy, is a flaccid, fragile blister which can occur anywhere. The most common skin lesions arc erosions, which are often painful; suprabasal elefting within the epidermis is also present. In the majority of these patients, painful mucous membrane erosions will be the first symptom, while sometimes the conjunctiva is affected but corneal involvement is very rare.