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PubMed2003

Tumour necrosis factor-alpha polymorphism as one of the complex inherited factors in pemphigus.

The aim of our study was to analyse a significance of tumour necrosis factor (TNF)-alpha promoter gene polymorphisms in relation to the HLA-DR locus in genetic predisposition to pemphigus. TNF-alpha gene polymorphisms in position -238 and -308 were identified using a modified polymerase chain reaction-restriction fragment length polymorphism method in 53 patients with pemphigus (38 with pemphigus vulgaris, 15 with pemphigus foliaceus) and 87 healthy controls. The HLA-DRB1 locus was typed using the polymerase chain reaction SSO method in all the patients and 152 population controls. Carriers of the TNF-alpha polymorphic -308 A allele were found to be more frequent in the pemphigus foliaceus group in comparison with the control group (odds ratio (OR) = 8.12; p = 0.0005). A significant association between HLA-DRB1*04 (OR = 3.86; pcor = 0.0001) and DRB1*14 (OR = 8.4; pcor = 0.0001) and pemphigus vulgaris was found. In this group of patients a decreased frequency of HLA-DRB1*07 (OR = 0.08; pcor = 0.006) was also identified. We have shown for the first time a positive association of TNF-alpha polymorphism in position -308 with pemphigus foliaceus.

Female↗
PubMed1991

Treatment of pemphigus.

Ninety-eight cases of various types of pemphigus were treated between 1978-1987. Sixty-one cases were pemphigus vulgaris (PV), 22 cases were pemphigus foliaceus, generalized type (PFG) in which one case developed pemphigus vegetans, 11 cases were pemphigus foliaceus localized type (PFL), and four cases were pemphigus erythematosus (PE). Fifteen mild cases of PV and three mild PFG were treated with corticosteroid (prednisolone or prednisone) alone, and dapsone or cyclophosphamide (CP) were added as treatment failed in two cases of each. Dapsone alone was used effectively in three cases of mild PV. Eight cases of moderate and three cases of severe PV, as well as five cases of moderate PFG, failed to respond to corticosteroid alone but were cleared by the addition of CP. Thirty-two moderate cases of PV and PFG treated with a combination of corticosteroid 60 mg/day plus initial CP and 14 severe cases of PV and PFG treated with corticosteroid 120 mg/day plus initial CP, resulted in clearing skin lesions in 2 months. Azathioprine or chlorambucil were substituted in three cases who developed CP toxicity. Addition of gold sodiumthiomalate in six refractory cases when the above regimens failed, caused a complete remission in two and partial control in four. Higher dosage of prednisolone or prednisone more than 120 mg/day has never been used. Eleven cases of PFL and four cases of PE were treated with uneventfully good results. Intercellular antibody titers became negative within 4.67 months except in refractory cases, however, the treatment was continued for at least 3 years. Herpes simplex superimposed infection was more common than herpes zoster infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Genetic factors in pemphigus.

Epidemiological studies performed in different ethnic populations and family studies, notably based on a partial phenotype of the autoimmune process, indicate that genetic factors are involved in the occurrence of pemphigus. However, the precise heritability remains uncertain in the absence of twin concordance rate studies. Among the different strategies available to identify genetic factors participating in autoimmune disease susceptibility, only population studies based on case-control design have been performed in pemphigus. These studies consistently showed that MHC locus, in particular HLA class II alleles, are associated with pemphigus vulgaris and pemphigus foliaceus. Other genes of the MHC locus may also participate in disease susceptibility as shown by studies using microsatellite markers across different regions of the MHC. It is likely that other non-MHC genes are involved in the pathogenesis of pemphigus. In particular, involvement of a polymorphic variant of desmoglein 1 gene was shown to be associated with pemphigus foliaceus and to interact in an epistatic manner with MHC class II genes to contribute to the autoimmune process. Other candidate genes to which a role can be assigned in the disease pathogenesis should be considered to design case-control or family-based association studies. Genome scan studies which require a large number of multiplex families to reach statistical power, should also be considered in the endemic form of pemphigus foliaceus because of the high number of familial cases.

Alleles↗
PubMed1997

HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese.

It has previously been demonstrated that susceptibility to pemphigus vulgaris is associated with human leukocyte antigen (HLA)-DR4 serologic specificity among Ashkenase Jews, and with DR4 as well as DR6 (DR14) in other ethnic groups. We genotyped HLA-DRB1, DQA1, DQB1, and DPB1 alleles in 16 patients with pemphigus by polymerase chain reaction-restriction fragment length polymorphism, to find evidence of potential HLA class II allele associations with pemphigus in Japanese patients who have a relatively homogeneous ethnic background. All nine patients with pemphigus vulgaris and five of seven patients with pemphigus foliaceus carried one or two alleles of HLA-DRB1*04 (*0403, *0406) and HLA-DRB1*14 (*1401, *1405, *1406) subtypes. Sequence analysis of these DRB1*04 and DRB1*14 alleles revealed the amino acid homology of phenylalanine at position 26 and valine at position 86 with the DRB1*0402 allele that reportedly confers a strong susceptibility to pemphigus vulgaris in Ashkenazi Jews. Thus our findings, together with previous HLA studies on pemphigus vulgaris patients of different ethnic groups, suggest that HLA-DRB1*04 and DRB1*14 alleles are commonly associated with pemphigus vulgaris across racial barriers. These HLA-DRB1 alleles are likely to be also associated with pemphigus foliaceus. Further studies on more diverse ethnic populations will be helpful in determining the significance of the association between certain amino acid residues of the class II molecules and disease susceptibility to pemphigus vulgaris as well as pemphigus foliaceus.

Adult↗
PubMed1999

Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases.

BACKGROUND: Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are potentially severe diseases. In drug-resistant PV and pemphigus foliaceus, long-term adjuvant treatment with extracorporeal photochemotherapy (photopheresis, ECP) has been reported to induce remission. Only limited numbers of patients have been reported so far. No information about the effectiveness in drug-resistant BP is available. PATIENTS AND METHODS: Seven patients with drug-resistant autoimmune bullous diseases have been referred to the photopheresis center of Jena (3 x PV, 3 x BP, 1 x pemphigus foliaceus). The age ranged from 31 to 85 years. ECP was performed on 2 consecutive days once a month. Oral 8-methoxypsoralen was used as photosensitizer. Previous immunosuppressive treatment with either prednisolone or prednisolone/ azathioprine was continued. RESULTS: Complete remission (absence of skin or mucous membrane lesions) was achieved in the 6 patients with PV and BP after 1-4 cycles. In the patient suffering from pemphigus foliaceus, a partial remission (> 50% improvement) was observed; in all except this patient, the immunosuppressive treatment could be tapered. Long-term remission was achieved. No severe side effects were observed. The treatment was well tolerated. CONCLUSIONS: Short-time ECP is an effective and safe adjuvant treatment for patients with drug-resistant autoimmune bullous diseases. It can induce remission and allows dose tapering of the immunosuppressive drugs.

Adult↗
PubMed1994

The human genes for desmogleins (DSG1 and DSG3) are located in a small region on chromosome 18q12.

Desmoglein is a transmembrane glycoprotein component of desmosomes in vertebrate epithelial cells. Two of the three currently known desmogleins are the autoantigens of autoimmune skin blistering diseases, pemphigus vulgaris and pemphigus foliaceus, in which autoantibodies cause the loss of cell adhesion of keratinocytes with resultant blister formation. In this study, the genes for two autoantigens (DSG1 for pemphigus foliaceus and DSG3 for pemphigus vulgaris) were mapped on band q12 of human chromosome 18 by fluorescence in situ hybridization. Furthermore, both genes were localized on a 320-kb genomic fragment separated by pulsed-field gel electrophoresis. These results suggest the possibility of a cluster for the desmoglein gene family on chromosome 18.

Animals↗
PubMed1977

HLA-A10 in pemphigus among Japanese.

The frequency of the major histocompatibility antigen, HLA-A10, was significantly increased (corrected P less than .025) in 43 unrelated patients with pemphigus vulgaris (41.9%) and in 25 patients with pemphigus foliaceus (48.0%), when compared with 60 unrelated healthy controls (16.7%). No significant correlations with other HLA or differences between pemphigus vulgaris and pemphigus foliaceus were observed. Both forms of pemphigus were considered to link with the HLA-A10.

Female↗
PubMed2001

Antibodies to desmogleins 1 and 3, but not to BP180, induce blisters in human skin grafted onto SCID mice.

Pemphigus and bullous pemphigoid (BP) are blistering skin diseases associated with IgG autoantibodies to desmosomal and hemidesmosomal components. When autoantibodies to desmogleins 1 and 3 from patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) or rabbit antibodies against the murine hemidesmosomal component BP180 are passively transferred into neonatal mice, they induce blisters in the skin of the mice. To develop an animal model that would duplicate the findings in the skin of the patients more closely, full-thickness human skin from healthy volunteers was grafted onto SCID mice. Injection of the purified IgG fraction from the serum of PF and PV patients led to subcorneal and suprabasal splits in the human grafts and human IgG was deposited intercellularly in the upper and lower layers of the epidermis, respectively. Interestingly, anti-BP180 autoantibodies purified from the serum of BP patients and from a rabbit immunized with recombinant human BP180 strongly bound to the basement membrane zone of the grafts (n=32), fixed murine complement, led to the recruitment of neutrophils to the upper dermis of the graft, but did not induce subepidermal blisters. We report a novel experimental model for PF and PV which should greatly facilitate further studies to dissect the immunopathological mechanisms in these diseases. Specifically, this model can be used to identify pathogenically relevant epitopes on human desmogleins 1 and 3 and to develop novel strategies for the treatment of pemphigus.

Animals↗
PubMed2003

Recent advances in the study of the pathophysiology of pemphigus.

Recent rapid advances in the basic research into pemphigus have provided many insights into its pathophysiology. In particular, a recently developed enzyme-linked immunosorbent assay (ELISA) for desmogleins 1 and 3 (Dsg1 and Dsg3), antigens for pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively, has led to great progress in the diagnosis and classification of pemphigus, as well as in understanding its pathomechanisms. Studies with the anti-Dsg1 and anti-Dsg3 antibodies have indicated that there are two types of PV, the mucosal dominant type and the mucocutaneous type. The same ELISA has identified the antigens in pemphigus herpetiformis. The autoantigens detected by this ELISA correlate well with the clinical features in pemphigus patients in showing the shift between PV and PF. In addition, the Dsg compensation theory proposed by Stanley and Amagai can reasonably explain the different depths of skin lesions and the different occurrences of skin and oral mucosal lesions between PV and PF. Furthermore, a complicated profile of autoantigens in paraneoplastic pemphigus (PNP) has been indicated in various biochemical studies, and IgG anti-Dsg1 and anti-Dsg3 antibodies have been detected in serum from all the PNP patients by the above ELISA. On the other hand, serum from subcorneal pustular dermatosis type IgA pemphigus patients have been shown to react with Dsc1, another type of desmosomal cadherin, by a novel cDNA transfection method. In addition, IgA anti-Dsg1 and anti-Dsg3 antibodies have been detected in a few patients with IgA pemphigus by an ELISA for IgA antibodies. Various autoimmune bullous diseases, including several types of pemphigus, are the only diseases in which the pathogenic role of circulating autoantibodies has been confirmed using the newborn mouse animal model. Therefore, studies of the pathophysiology of pemphigus are extremely important as a paradigm for research into various types of autoimmune diseases in other fields.

Animals↗
PubMed2005

Cutaneous type pemphigus vulgaris: a rare clinical phenotype of pemphigus.

Pemphigus is an autoimmune blistering disease of the skin, mucous membranes, or both. There are two main categories of pemphigus: pemphigus foliaceus (PF) and pemphigus vulgaris (PV). PV is further subdivided into mucosal dominant and mucocutaneous types, according to the extent of cutaneous lesions. These classes of pemphigus have distinct histopathologic and serologic findings, with most cases falling into these subtypes. We report 4 cases that clinically showed blisters and erosions in the skin only, without mucosal involvement. Histologic examination of cutaneous lesions demonstrated suprabasilar acantholysis, a typical finding for PV. These patients had predominant anti-desmoglein 1 (Dsg1) IgG autoantibodies as well as anti-Dsg3 IgG autoantibodies, as determined by enzyme-linked immunosorbent assay. The desmoglein compensation theory posits that this rare phenotype can be produced by pathogenically weak anti-Dsg3 IgG in the presence of potent anti-Dsg1 IgG autoantibodies. Thus, cutaneous type PV without apparent mucosal involvement is observed as a rare clinical and histologic expression of pemphigus. This expression can be a transient phenotype that may develop from, or evolve into, other subtypes of pemphigus.

Autoantibodies↗
PubMed2001

Bullous pemphigoid sera react specifically with various domains of BP230, most frequently with C-terminal domain, by immunoblot analyses using bacterial recombinant proteins covering the entire molecule.

By immunoblot analyses of normal human epidermal extracts, the 230 kDa bullous pemphigoid antigen (BP230) is recognized by most bullous pemphigoid sera. By polymerase chain reaction using keratinocyte cDNA library as a template, we successfully amplified 3 cDNAs of about 3 kb, which covered whole human BP230 molecule. By inserting the cDNAs into bacterial expression vector pGEX, we prepared 3 different recombinant glutathione-S-transferase-fusion proteins, which roughly presented N-terminal domain, central rod domain and C-terminal domain of BP230. By immunoblotting using these 3 recombinant proteins, we demonstrated that the majority of bullous pemphigoid sera reacted clearly with multiple recombinant proteins of BP230, most frequently with C-terminal domain. We also examined sera of pemphigus vulgaris, pemphigus foliaceus and herpetiform pemphigus that showed BP230-like protein band by immunoblotting of epidermal extracts, as well as paraneoplastic pemphigus, for reactivity with the 3 recombinant proteins. In the study, we found that only very few of these non-bullous pemphigoid sera reacted with some of the recombinant proteins. These results indicate that the BP230 is specifically reacted by bullous pemphigoid sera, and that the immunoblotting using the BP230 recombinant proteins should be a useful tool for the diagnosis of bullous pemphigoid.

Antibodies, Monoclonal↗
PubMed2003

Protein A immunoadsorption: a novel and effective adjuvant treatment of severe pemphigus.

BACKGROUND: Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering skin diseases usually treated with high-dose systemic corticosteroids and other immunosuppressants that may cause severe side-effects. Plasmapheresis also has been demonstrated to be of benefit in the treatment of pemphigus. In contrast to plasmapheresis, staphylococcal protein A immunoadsorption (PA-IA) specifically removes immunoglobulin from the circulation, allows treatment of larger plasma volumes, and does not require the substitution of plasma components. OBJECTIVES: To determine the effectiveness and side-effects of PA-IA in patients with severe pemphigus. METHODS: Five patients with severe pemphigus (PV, n = 4; PF, n = 1) were treated by PA-IA. Three of these patients had been refractory to various treatment regimens. In addition to PA-IA, methylprednisolone, 0.5 mg x kg-1 body weight day-1 was given initially and subsequently tapered. RESULTS: In all patients, a dramatic clinical improvement was seen within 2 weeks after initiation of therapy. Patients were free of lesions after 3, 4, 4, 10 and 21 weeks of treatment, respectively. Concurrently, autoantibody levels decreased rapidly. CONCLUSIONS: PA-IA is a rational, effective, and safe adjuvant therapy for severe pemphigus and warrants wider use for this indication. A controlled study should compare side-effects and effectiveness of PA-IA with other treatment options for pemphigus.

Adjuvants, Immunologic↗
PubMed1980

Immunohistochemical findings in a patient with penicillamine pemphigus.

This report describes the immunofluorescence (IF) findings in sequential skin biopsies and serum obtained during a follow-up study of a patient who developed pemphigus lesions after D-penicillamine treatment of arthritis. The distribution in the skin of IgG, IgM and C3 varied with the date, type and site of the biopsy sample. Thus IF patterns showed features of (a) pemphigus vulgaris, (b) pemphigus foliaceus and (c) pemphigus erythematosus. Indirect IF examination indicated the presence of circulating intercellular epithelial antibody of both the IgG and IgM class.

Complement C3↗
PubMed2004

Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common subepidermal immunobullous disease, characterized by circulating IgG autoantibodies targeting BP180 and BP230 hemidesmosomal proteins. Several immunological studies have demonstrated that the membrane proximal noncollagenous domain NC16a of BP180 is the immunodominant region targeted by BP autoantibodies. Recently, a commercial BP180 NC16a-specific enzyme-linked immunosorbent assay (ELISA) has become available for detecting pathogenic anti-BP180 autoantibodies in BP sera. However, it remains unclear whether the diagnostic potential of the ELISA is equivalent to that of the 'gold-standard' diagnostic technique of immunofluorescence (IF). OBJECTIVES: To examine the usefulness of a commercially available BP180-NC16a ELISA in the initial serodiagnosis of BP. METHODS: Sera from a large cohort of patients with BP (n = 102) and control subjects (age- and sex-matched normal volunteers, n = 60; pemphigus foliaceus, n = 18; pemphigus vulgaris, n = 16) were assayed by BP180-NC16a ELISA. All BP sera were obtained at presentation before initiation of systemic immunosuppressive therapy. The values of IgG antibody levels measured by ELISA were compared with those measured by indirect IF on salt-split skin. Results Receiver operating characteristic analysis was used to calculate the cut-off value for the ELISA in the diagnosis of BP which maximizes both sensitivity and specificity, and to estimate the diagnostic accuracy of the ELISA as represented by the area under the curve (AUC = 0.965). A cut-off value of 9 was associated with a sensitivity of 89% (91 of 102 BP sera showed a positive result) and a specificity of 98%. Fifty-eight of 60 normal controls and all the pemphigus sera showed a negative result. There was a correlation between the mean ELISA values and indirect IF titres (Spearman rank correlation 0.286; P = 0.004). CONCLUSIONS: Our results suggest that the BP180-NC16a ELISA is a useful tool for the detection of pathogenic anti-BP180 IgG autoantibodies at the initial disease stage of BP. Because it is not only highly sensitive and specific, but is also easy to perform, is objective, and semiquantitative, the ELISA may provide valuable information for the accurate and reliable serodiagnosis of BP.

Aged↗
PubMed1981

HLA-DR antigens in pemphigus among Japanese.

The frequency of HLA-DR4 was significantly increased at P less than 0.02 in 37 unrelated pemphigus patients (62.2%), when compared with unrelated 73 healthy controls (30.1%). This antigen was more frequently found in pemphigus foliaceus (70.6%) than pemphigus vulgaris (55.8%).

Gene Frequency↗
PubMed1979

Association of pemphigus chronicus with pregnancy.

The evolution of pemphigus chronicus has been studied in 3 pregnant women. In the first patient, pemphigus vulgaris appeared 2 years prior to pregnancy. In the other 2 patients the disease began during pregnancy. Both women were treated with corticosteroids during their pregnancy which was normal as was delivery. A complete remission was seen in the first case 7 years following cortocosteroid therapy, and 8 months after therapy in the second case. Prolonged corticosteroid administration had no adverse effects on the fetus. The occurrence of pemphigus chronicus in the Republic of Macedonia during the past 15 years was only 0.14% of all patients referred to the Department of Dermatology. Female patients with this disease slightly outnumbered males. All forms of pemphigus seen in this period were diagnosed both clinically and histologically. The total number of cases was 53, of which pemphigus vulgaris was 74.4%, pemphigus vegetans 7%, pemphigus foliaceus 9.3% and pemphigus seborrhoicus 9.3%. We present our cases of pemphigus in pregnant women with regard to the fact that only few such cases have been published.

Adrenal Cortex Hormones↗
PubMed2005

Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.

Numerous mechanisms of action have been proposed for intravenous Ig (IVIG). In this study, we used IgG passive transfer murine models of bullous pemphigoid (BP), pemphigus foliaceus (PF), and pemphigus vulgaris (PV) to test the hypothesis that the effect of IVIG in autoantibody-mediated cutaneous bullous diseases is to accelerate the degradation of pathogenic IgG by saturation of the MHC-like Fc receptor neonatal Fc receptor (FcRn). BP, PF, and PV are organ-specific antibody-mediated diseases in which autoantibodies target the hemidesmosomal antigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively. Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, PF, and PV disease phenotypes, respectively. We found that FcRn-deficient mice were resistant to experimental BP, PF, and PV. Circulating levels of pathogenic IgG in FcRn-deficient mice were significantly reduced compared with those in WT mice. Administration of high-dose human IgG (HDIG) to WT mice also drastically reduced circulating pathogenic IgG levels and prevented blistering. In FcRn-deficient mice, no additional protective effect with HDIG was realized. These data demonstrate that the therapeutic efficacy of HDIG treatment in the pemphigus and pemphigoid models is dependent on FcRn. Thus, FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases.

Animals↗
PubMed2001

Dominant autoimmune epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins.

Desmoglein (Dsg) is a cadherin-type adhesion molecule found in desmosomes. Dsg1 and Dsg3 are the target Ags in the autoimmune blistering diseases pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively. To map conformational epitopes of Dsg1 and Dsg3 in PF and PV, we generated Dsg1- and Dsg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg1-specific residues by baculovirus expression. The swapped domains were portions of the N-terminal extracellular domains of Dsg1 (1-496) and Dsg3 (1-566), which have similar structures but distinct epitopes. The binding of autoantibodies to the mutant molecules was assessed by competition ELISAs. Domain-swapped molecules containing the N-terminal 161 residues of Dsg1 and Dsg3 yielded >50% competition in 30/43 (69.8%) PF sera and 31/40 (77.5%) PV sera, respectively. Furthermore, removal of Abs against the 161 N-terminal residues of Dsg1 by immunoadsorption eliminated the ability of PF sera to induce cutaneous blisters in neonatal mice. Within these N-terminal regions, most of the epitopes were mapped to residues 26-87 of Dsg1 and 25-88 of Dsg3. Furthermore, a point-mutated Dsg3 molecule containing Dsg1-specific amino acid substitutions (His(25), Cys(28), Ala(29)) reacted with anti-Dsg1 IgG, thus defining one of the epitopes of Dsg1. Using the predicted three-dimensional structure of classic cadherins as a model, these findings suggest that the dominant autoimmune epitopes in both PF and PV are found in the N-terminal adhesive surfaces of Dsgs.

Autoantibodies↗