Antibodies against desmoglein 1 in healthy subjects in endemic and nonendemic areas of pemphigus foliaceus (fogo selvagem) in Peru

BACKGROUND: Endemic pemphigus foliaceus or fogo selvagem is an autoimmune skin disease characterized by the presence of subcorneal superficial blisters and antibodies of the immunoglobulin G4 (IgG4) class specific for the desmosomal glycoprotein, desmoglein 1. In Peru, no studies have been published on the seroprevalence of antibodies against desmoglein 1 in healthy subjects from endemic foci. SUBJECTS AND METHODS: This was a cross-sectional study. The sample included 82 healthy subjects, 41 from the Pueblo Libre community, a focus of endemic pemphigus foliaceus, and 41 from a nonendemic urban area in Pucallpa City. Enzyme-linked immunosorbent assay (ELISA) was used to determine the presence of antibodies against desmoglein 1. Samples were processed and tested at the Department of Dermatology and Cutaneous Surgery, School of Medicine, University of Miami, Miami, Florida. RESULTS: It was found that 31.7% of healthy individuals (13 subjects) from the endemic focus had anti-desmoglein 1 antibodies. A statistically significant association was found between the distance from the endemic focus and the presence of antibodies against desmoglein 1 in subjects living within the endemic focus [Mantel-Haenszel odds ratio (OR), 3.34; P = 0.03; 95% confidence interval (CI), 1.06-10.48]. Agriculture as an occupation showed a statistically significant association with the presence of antibodies against desmoglein 1 (Mantel-Haenszel OR, 7.84; P < 0.001; 95% CI, 2.47-24.87). CONCLUSIONS: Antibodies against desmoglein 1 are present in healthy subjects exposed to an endemic focus of pemphigus foliaceus (fogo selvagem). Agriculture is associated with a high risk of development of antibodies against desmoglein 1 in the endemic focus of the Pueblo Libre community.     

Anti-desmoglein 1 antibodies in healthy related and unrelated subjects and patients with pemphigus foliaceus in endemic and non-endemic areas from Tunisia

Background  Pemphigus foliaceus is an autoimmune blistering skin disease characterized by the production of pathogenic IgG autoantibodies directed against desmoglein 1.
Aim  To determine the prevalence of anti-desmoglein 1 antibodies in healthy subjects and their distribution in the different regions of Tunisia and to better identify endemic areas of pemphigus foliaceus.
Methods  We tested, by enzyme-linked immunoserbent assay, sera of 270 normal subjects recruited from different Tunisian areas and 203 related healthy relatives to 90 Tunisian pemphigus foliaceus patients.
Results  Seventy-six patients (84.4%), 20 healthy controls (7.4%), and 32 relatives (15.76%) had anti-desmoglein 1 antibodies. In southern regions where pemphigus foliaceus is associated with a significant sex ratio imbalance (9 female : 1 male in the south vs. 2.3 : 1 in the north) and a lower mean age of disease onset (33.5 in the south vs. 45 years in the north), a higher prevalence of anti-desmoglein 1 antibodies in healthy controls was observed (9.23% vs. 5.71% in the north). Interestingly, the highest prevalence of anti-desmoglein 1 antibodies in healthy relatives (up to 22%) was observed in the most rural southern localities. More than half anti-desmoglein 1–positive healthy controls were living in rural conditions with farming as occupation, which suggests that this activity may expose the subjects to particular environmental conditions.
Conclusion  These results show that the endemic features of Tunisian pemphigus foliaceus are focused in these southern areas more than in other areas and that both environmental and genetic factors contribute to the disease.

Conflicts of interest

None declared.     

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.     

Evaluation of desmoglein enzyme-linked immunosorbent assay (ELISA) in Indian patients with pemphigus vulgaris

OBJECTIVE: To evaluate the role of the enzyme-linked immunosorbent assay (ELISA) test for the detection of antibodies to desmoglein 1 (dsg1) and desmoglein 3 (dsg3) in the diagnosis of pemphigus vulgaris (PV), and its correlation with disease severity and clinical presentation (mucosal PV, cutaneous PV, mucocutaneous PV). METHODS: Twenty-seven active PV patients and 26 controls with other dermatologic disorders were included in the study. The severity of oral and cutaneous involvement was assessed and recorded. ELISA test for the measurement of anti-dsg1 and anti-dsg3 antibodies was performed (Medical and Biological Laboratories Co. Ltd., Nagoya, Japan). The cut-off ELISA value for both anti-dsg1 and anti-dsg3 was taken as 20. RESULTS: Of the 27 patients, 26 were ELISA positive for anti-dsg1 antibodies and 23 for anti-dsg3 antibodies. Of the controls, two were positive for anti-dsg1 and none for anti-dsg3 antibodies. The sensitivity and specificity of ELISA for anti-dsg1 in the diagnosis of PV were 96.3% and 92.3%, respectively. For anti-dsg3, they were 85.2% and 100%, respectively. The different morphologic types of PV could not be differentiated on the basis of antibody profile; however, a direct correlation between anti-dsg3 titers and the severity of oral disease was noted, and also between anti-dsg1 titers and the severity of cutaneous disease. CONCLUSIONS: ELISA (dsg1 and dsg3) is an efficient tool for confirming the diagnosis of PV. Specific antibody titers correlate with disease severity; however, desmoglein testing cannot differentiate between the various morphologic subtypes of PV.     

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.     

Analyses of autoantigens in a new form of endemic pemphigus foliaceus in Colombia

BACKGROUND: We previously described a new focus of endemic pemphigus foliaceus in rural areas of El Bagre, Colombia, with clinical and direct immunofluorescence characteristics of pemphigus erythematosus. OBJECTIVE: The aim of this study was to characterize autoantigen profiles for 34 serum samples obtained from patients with this condition. METHODS: Immunofluorescence, various immunoblot analyses with different antigen sources and detection methods, and immunoprecipitation were performed. RESULTS: Immunofluorescence with the use of human skin sections showed IgG autoantibodies against keratinocyte cell surfaces in all 34 serum samples. Some samples also showed weak reactivity with the basement membrane zone. The results of immunoblot and immunoprecipitation analysis indicated that all sera had antibodies reactive with desmoglein 1, the pemphigus foliaceus antigen. In addition, in various immunoblot assays, many sera reacted with several other proteins with molecular weights of 250 kd, 210 kd, and 190 kd, which appear to correspond to desmoplakin I, envoplakin, and periplakin, respectively. CONCLUSION: This endemic pemphigus disease in El Bagre showed immunologic features similar to pemphigus foliaceus or erythematosus. In addition, paraneoplastic pemphigus-like reactivity with various epidermal antigens was detected.     

A sensitive and restricted enzyme-linked immunosorbent assay for detecting a heterogeneous antibody population in serum from people suffering from a new variant of endemic pemphigus

We recently described a new variant of endemic pemphigus foliaceus (EPF) in El Bagre, Colombia, that resembles Senear-Usher syndrome and identified autoantibodies to desmoglein 1 (Dsg1), as well as to multiple known and unknown antigens including plectins, in the serum of these patients. Here, we developed a cost-effective ELISA assay capable of detecting the heterogeneous antibody population observed in these EPF patients, and useful for serum epidemiological studies. A protein extract obtained from trypsin-digested fresh bovine skin and further purified on a concanavalin A matrix was used as antigen. This extract contains an important conformational epitope (a 45 kDa tryptic fragment of the Dsg1 ectodomain), which is recognized by antibodies in serum from patients with all varieties of pemphigus foliaceus (PF), and from half of those with pemphigus vulgaris with active clinical disease. The cut-off and threshold values were normalized using human serum obtained from both endemic and non-endemic areas for PF. The efficiency of this ELISA was tested using 600 serum samples from controls and patients diagnosed with EPF, non-endemic PF and other bullous diseases. The overall sensitivity and specificity of the assay were determined to be 95% and 72%, respectively, with reproducibilities of 98% (intraassay) and 95% (interassay). Comparing the ELISA with other tests to detect EPF autoantibodies, this ELISA was the most sensitive, followed by direct immunofluorescence (DIF), indirect immunofluorescence using anti-IgG4 monoclonal antibodies and immunoprecipitation (IP), respectively. The most specific assay was IP, followed by DIF. Immunoblotting to Dsg1 exhibited both poor sensitivity and poor specificity, although plectins were well visualized. We conclude that this ELISA is an excellent tool for field serological studies, allowing testing of multiple serum samples simultaneously and for detecting, with appropriate restriction and sensitivity, the heterogeneous antibody population seen in patients with this variant of EPF. Finally, autoantibody serum levels obtained with this ELISA correlated well with the clinical activity and extent of disease in patients with El Bagre EPF.Abbreviations BMZ Basement membrane zone - BP Bullous pemphigoid - BP180 Bullous pemphigoid 180 kDa antigen - ConA Concanavalin A - CPF Cazanaves pemphigus foliaceus - DIF Direct immunofluorescence - ELISA Enzyme-linked immunosorbent assay - EPF Endemic pemphigus foliaceus - IB Immunoblotting - IIF Indirect immunofluorescence - IP Immunoprecipitation - mAb Monoclonal antibody - PBS Phosphate-buffered saline - PBS^– Phosphate-buffered saline lacking divalent cations - PF Pemphigus foliaceus - PV Pemphigus vulgaris - SLE Systemic lupus erythematosus This paper is part of the doctoral (PhD) thesis of Ana María Abréu Vélez, MD, while at the University of Antioquia.     

Prevalence of Metabolic Syndrome and its components in a Brazilian sample of pemphigus patients

BACKGROUND

Pemphigus foliaceus and pemphigus vulgaris are endemic in the northeastern region of São Paulo State, Brazil. They are treated mainly with systemic corticosteroids, which may provoke osteoporosis; atherosclerosis, higher blood pressure, insulin resistance, glucose intolerance, hyperlipidemia and abdominal obesity. These side effects of corticoids also constitute criteria for the diagnosis of metabolic syndrome.

OBJECTIVE

The prevalence of metabolic syndrome and each component of metabolic syndrome in Pemphigus foliaceus and pemphigus vulgaris groups was compared with Brazilian casuistic samples.

METHODS

Data of 147 patients (pemphigus foliaceus 48.9% and pemphigus vulgaris 51.1%) were compiled from medical records regarding metabolic syndrome and its components, and included in the analysis.

RESULTS

There was no significant difference regarding the prevalence of metabolic syndrome in pemphigus groups compared with the Brazilian casuistic samples. The analysis of each component of metabolic syndrome showed a higher prevalence of: higher blood pressure in male subjects with pemphigus vulgaris, and in pemphigus foliaceus in both genders; diabetes mellitus in both genders for pemphigus vulgaris and pemphigus foliaceus; obesity in females for pemphigus vulgaris and pemphigus foliaceus, and hypertriglyceridemia in both genders for pemphigus vulgaris and pemphigus foliaceus groups that were statistically significant compared to the Brazilian reports. Furthermore, the study noted a higher incidence of cardiovascular events in both genders in pemphigus foliaceus and pemphigus vulgaris groups than in Brazilian casuistic samples.

CONCLUSION

The components of metabolic syndrome are more numerous in pemphigus when compared with Brazilian casuistic samples. Future studies are necessary to assure that metabolic syndrome may be associated with pemphigus per se, including a greater casuistic sample of patients who have not taken corticoids.     

Comparative study of pemphigus vulgaris and pemphigus foliaceus in Singapore

This is a retrospective study of all patients diagnosed to have pemphigus in our centre over a 3 year period. The case records of all patients with pemphigus from January 1995 to December 1997 were analysed. Fifty patients were diagnosed to have pemphigus during the study period. The diagnoses were pemphigus vulgaris in 31 patients, pemphigus foliaceus in 16, paraneoplastic pemphigus in two and IgA pemphigus in one. The average titre of anti-intercellular antibodies in patients with pemphigus vulgaris (1:96) was higher than the titre in patients with pemphigus foliaceus (1:69). The average initial dose of prednisolone required for disease control in patients with pemphigus vulgaris (62 mg/day) was significantly higher than that required for patients with pemphigus foliaceus (44 mg/day). In our study population, pemphigus vulgaris is a more severe and chronic disease than pemphigus foliaceus, as reflected in the higher titre of anti-intercellular antibodies, higher dose of systemic corticosteroids required for control of the disease, the longer duration to achieve complete remission and longer follow-up period.     

Sensitivity of indirect immunofluorescence and ELISA in detecting intercellular antibodies in endemic pemphigus foliaceus (Fogo Selvagem)

BACKGROUND: Since 1967 dermatology has used the classic technique of indirect immunofluorescence (IFI) for the detection of autoantibodies against antigens of the skin in diseased people with endemic pemphigus foliaceus. Thirty years later enzyme-linked immunosorbent assays--ELISA (rDsg1 and rDsg3) appeared as a viable option. A group of highly recognized researchers have concluded that ELISA is a simple, sensitive and highly specific method, allowing for diagnostic differentiation between pemphigus vulgaris (PV) and endemic pemphigus foliaceus (EPF). Scientific literature certifies that both ELISA and IIF bear high sensitivity in spite of the fact that a direct comparison between the ELISA and IIF tests has never been performed. OBJECTIVES: This study was conducted to compare the sensitivity of these tests in detecting antibodies in the EPF. MATERIAL AND METHODS: Thirty-two serum samples were collected from patients with EPF. The control serum of 15 healthy individuals was tested to detect the presence of antibodies of EPF by indirect immunofluorescence and ELISA (rDsg1 and rDsg3). The IIF was performed, taking human skin as a substrate. RESULTS: Antibodies in patients with EPF were detected more commonly by the ELISA (rDsg1) (91%) compared with IIF (81%). CONCLUSIONS: The ELISA (rDsg1) is slightly more sensitive than IIF in detecting antibodies related to EPV. However, according to our results, we do not currently possess a test with 100% accuracy in differentiating EPF from PV. Although previous studies have associated Dsg3 with PV, the tests performed during this study showed that 12% (4/32) of patients with EPF (cutaneous diseases only) also had Dsg3 antibodies.     

A subset of pemphigus foliaceus patients exhibits pathogenic autoantibodies against both desmoglein-1 and desmoglein-3

In pemphigus vulgaris the major pathogenic antibody binds desmoglein-3, and mediates mucosal disease. Development of cutaneous disease is associated with acquisition of antibodies to desmoglein-1. In pemphigus foliaceus, and its endemic form, fogo selvagem by contrast, the major pathogenic antibody recognizes desmoglein-1 and mediates cutaneous disease only. In this study, we sought to determine the prevalence of antibodies to desmoglein-3 in patients with pemphigus foliaceus and fogo selvagem. We produced recombinant desmoglein-1 and desmoglein-3, and used them in highly sensitive and specific enzyme-linked immunosorbent assays, as well as immunoprecipitation assays. We detected antibodies to desmoglein-3 in 19 of 276 patients with pemphigus foliaceus and fogo selvagem, who had cutaneous disease only. We showed that these antibodies to desmoglein-3 could be absorbed in a concentration-dependent manner by desmoglein-3 but not by desmoglein-1. Also antibodies to desmoglein-1 could be absorbed in a concentration-dependent manner by desmoglein-1 but not desmoglein-3. This suggests that two separate species of antibody are present rather than one antibody capable of cross-reacting with both desmoglein-1 and desmoglein-3. Finally, it was shown that affinity-purified antibodies to desmoglein-3 from patients with pemphigus foliaceus and fogo selvagem induced a pemphigus vulgaris-like skin disease in mice by passive transfer. These results suggest that a subset of patients with pemphigus foliaceus and fogo selvagem have antibodies to desmoglein-3 that may be involved in the pathogenesis of their cutaneous disease.     

A Clinicopathological Study of Pemphigus in Eastern India with Special Reference to Direct Immunofluorescence

Background:Pemphigus is a group of chronic autoimmune vesico-bullous disorders in which the epidermis and the basement membrane zone are the focus of attack resulting in cutaneous and mucosal blister formation. Direct immunofluorescence (DIF) test is a very sensitive test for the diagnosisAim:To study the clinico histopathological patterns of pemphigus in eastern India. The study also aims to correlate DIF with clinical and histologic findings as well as severity of skin involvement [scoring systems].Results:In our study Pemphigus vulgaris (PV) was the predominant type with 32 cases followed by 8 cases of pemphigus foliaceus (PF) and a single case of IgA pemphigus. Mean age at presentation was late middle age. Majority of the patients, 26 (63.41%) initially had cutaneous involvement followed by mucosal involvement. In this study group 36 (87.80%) patients showed acantholytic cells on histopathological examination. Most patients of PV showed suprabasal blister 20 (62.50%) followed by intraspinous 5 (15.62%) and subcorneal 5 (15.62%) blister. In majority 28 (87.50%) of the PV patients IgG and C3 antibodies were deposited throughout the epidermis. The strength of antibody positivity was strong in most of the patients (71.87%). In cases of PF mostly IgG 6 (75%) antibodies were deposited in the upper epidermis. DIF intensity had poor correlation with disease activity/severity except in PF.Conclusion:Almost 85.36% cases of pemphigus were diagnosed clinicopathologically. But 6 cases couldn’t be diagnosed accurately on clinicopathological basis and in them DIF was confirmatory. Two cases of pure mucosal PV and 1 case of IgA pemphigus was confirmed by DIF. Two cases of bullous pemphigoid clinico-histologically mimicking PV were also excluded by DIF. So it appears from our study that DIF is confirmatory for diagnosis of pemphigus in all cases.     

天疱疮患者皮损局部异位淋巴结构的病理学特征

目的 探讨天疱疮患者皮损处浸润淋巴细胞病理学特征及其与外周血抗桥粒黏蛋白（Dsg）1/Dsg3抗体滴度的相关性。方法 对2014—2016年上海交通大学医学院附属瑞金医院皮肤科93例寻常型和落叶型天疱疮患者的组织病理片进行分析。计算每例 × 50镜下淋巴细胞总数,定义为淋巴细胞密集程度指数。采用酶联免疫吸附试验（ELISA）测定天疱疮患者血清中抗Dsg1/Dsg3抗体滴度。统计淋巴细胞密集程度指数与抗体滴度间相关性。对其中8例寻常型和8例落叶型天疱疮患者的皮损样本进行免疫组化染色,分析CD3+ T细胞、CD20+ B细胞、CD138+ 浆细胞的分布。结果 在93例病理切片中,Grade1、Grade2、Grade3淋巴细胞聚集出现概率分别为100.00%、68.09%、10.64%,寻常型（56例）和落叶型天疱疮（37例）比较,Grade1?3淋巴细胞聚集出现概率差异无统计学意义。淋巴细胞的密集程度在寻常型和落叶型天疱疮患者比较,差异无统计学意义,与天疱疮患者血清中特异性抗Dsg1和抗Dsg3 的抗体滴度无相关性。在16例天疱疮病例中,全部有CD3+ T细胞出现,15例有CD20+ B细胞,12例有CD138+ 浆细胞存在。16例切片中,Grade1?3淋巴细胞聚集区域中均含有大量的CD3+ T细胞,而含有CD20+ B细胞的淋巴细胞聚集占总数的52.80% ± 5.78%,含有CD138+ 浆细胞的淋巴细胞聚集占总数的34.59% ± 7.42%。CD3+ T细胞、CD20+ B细胞、CD138+ 浆细胞在寻常型（8例）和落叶型天疱疮（8例）分布差异无统计学意义。结论 天疱疮患者皮损处普遍出现不同程度的淋巴细胞浸润,可能形成异位淋巴结构,参与皮损的形成和加重。     

Evaluation of cases of pemphigus vulgaris and pemphigus foliaceus from a reference service in Pará state,Brazil

BACKGROUND

Pemphigusis a bullous, rare and chronic autoimmune disease. There are two major forms of pemphigus: vulgaris and foliaceus. Epidemiological data and clinical outcome in patients diagnosed in the Brazilian Amazon states are still rare.

OBJECTIVES

To study the occurrence of the disease during the study period and analyze the epidemiological profile of patients, the most common subtype of pemphigus, and the clinical evolution of patients.

METHODS

Retrospective analysis of medical records of hospitalized patients with pemphigus foliaceus and pemphigus vulgaris in the period from 2003 to 2010 in Dermatology Service of Hospital Fundação Santa Casa de Misericórdia do Pará, Belém, Northern Brazil.

RESULTS

We found a total of 20 cases of pemphigus during the study period, 8 of which were of foliaceus pemphigus and 12 of vulgaris pemphigus. Pemphigus foliaceus had the predominance of male patients (75%), showed satisfactory clinical evolution, and was characterized by absence of pediatric cases. Pemphigus vulgaris affected more women (66.7%), showed mean hospital stay of 1 to 3 months (50%), and there were three cases of death (25%). The prescribed immunosuppressive drugs included prednisone with or without combination of azathioprine and/or dapsone. Sepsis was associated with 100% of the deaths.

CONCLUSIONS

The occurrence of the disease is rare, there are no familiar/endemic outbreaks in the sample. Evolution is usually favorable, but secondary infection is associated with worse prognosis. The choice of best drugs to treat pemphigus remains controversial.     

Tunisian endemic pemphigus foliaceus is associated with the HLA-DR3 gene: anti-desmoglein 1 antibody-positive healthy subjects bear protective alleles

Background  Pemphigus foliaceus is an autoimmune blistering skin disease that partly results from genetic factors, especially human leucocyte antigen (HLA) class II genes.
Objectives  The aim of the study was to determine the HLA DR/DQ markers of susceptibility and protection in the Tunisian endemic form.
Methods  Genomic DNA from 90 patients with pemphigus foliaceus recruited from all parts of the country and matched by age, sex and geographical origin with 270 healthy individuals, was genotyped.
Results  Firstly, when the whole patient population was studied, DRB1*03 , DQB1*0302 and DRB1*04 alleles were significantly associated with the disease while a significant decrease of, in particular, DRB1*11 and DQB1*0301 was observed in patients compared with controls. DRB1*0301 was the dominant allele in DR3-positive patients and controls, while DRB1*0402 was found in 42% of DR4-positive patients. Secondly, when the HLA DR/DQ allele distribution was studied after dividing patients according to their geographical origin, the southern group, which consisted exclusively of patients with the endemic form of the disease, showed the same associations as the whole pemphigus foliaceus population, particularly with DRB1*03 . In the northern group, only the DRB1*04 and DQB1*0301 alleles were found to be associated. Interestingly, anti-desmoglein 1 antibody-positive healthy controls did not carry susceptibility alleles but, in contrast, most carried negatively associated alleles.
Conclusions  These observations indicate that a particular genetic background characterizes the Tunisian endemic form of pemphigus foliaceus and that HLA class II genes control the pathogenic properties of the autoimmune response rather than the initial breakage of B-cell tolerance.     

Varicella-zoster virus (VZV) and alpha 1 antitrypsin: a fatal outcome in a patient affected by endemic pemphigus foliaceus

Background 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. Case report 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. Materials and methods We performed studies utilizing hematoxylin and eosin, immunohistochemistry, and direct immunofluorescence techniques on tissues from several organs. Results 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. Conclusion 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.     

Cytokine pattern in blister fluid and sera of patients with pemphigus

BACKGROUND: Pemphigus is a chronic auto-immune blistering disease with four main variants, i.e. pemphigus vulgaris (PV), foliaceus (PF), erythematosus (PE) and vegetans. The common histological feature of this disease is acantholysis. OBJECTIVE: The aim of this study was to compare levels of some cytokines in blister fluid and sera of patients with pemphigus, using as control blister fluid of patients with bullous pemphigoid (BP) and bullous contact dermatitis (BCD). METHODS: Using an immuno-enzymatic assay (ELISA), we tested 16 sera and 6 blister fluids of patients with various forms of pemphigus (13 with PV, 1 with PF, 2 with PE), the sera of 16 healthy control subjects, 5 blister fluids of patients with BP and 5 blister fluids of patients with BCD, for the presence of some cytokines (IL-10, IL-8 and IFN-gamma). Intercellular antibodies were searched for and titred; desmoglein 1 and 3 antibody levels were independently evaluated to compare them with the severity of both cutaneous and oral involvement. RESULTS: The levels of IL-10 in the sera of patients with pemphigus were below the detection limits. IL-8 was significantly increased only in 4 samples of sera from pemphigus patients compared with controls, while IFN-gamma was detected at low levels in almost all patients compared with sera of controls. The cytokine levels in blister fluid of patients with pemphigus were significantly higher than in the sera. There was a difference between the expression of cytokines in blister fluid of control patients with BP and BCD compared with those of pemphigus patients. CONCLUSION: This report discusses the anti-inflammatory role played by IL-10 in the chronic form of pemphigus and the hypothesis of a possible role of IL-8 in neutrophil and lymphocyte-monocyte recruitment.     

Complement and antibody deposition in Brazilian pemphigus foliaceus and correlation of disease activity with circulating antibodies

Brazilian pemphigus foliaceus is a blistering skin disease endemic to central and southern areas of South America. In this study of skin biopsy specimens from 14 patients we present evidence that complement and immunoglobulins were present by direct immunofluorescence in the epidermal intercellular spaces in all patients. Eight of 14 patients had granular deposits of C3 in the basement membrane zone. By indirect immunofluorescence, serum samples from all 19 patients tested demonstrated the presence of circulating IgG autoantibody. Autoantibodies deposited in the intercellular spaces in titers ranging from 1:10 to more than 1:1280, and the titers drastically decreased during treatment. This is the first study to demonstrate complement deposition in the skin in Brazilian pemphigus foliaceus.     

Elevated expression of CD23 on peripheral blood B lymphocytes from patients with bullous pemphigoid: correlation with increased serum IgE

BACKGROUND: Increased serum IgE levels are occasionally found in patients with severe bullous pemphigoid (BP). CD23, a low affinity Fc receptor for IgE, is mainly expressed on mature B lymphocytes. Studies have suggested that serum levels of soluble CD23 (sCD23) correlate with serum IgE levels and disease severity in BP. OBJECTIVE: The purpose of our study is to examine whether the expression of CD23 is elevated in BP and whether this expression correlates with serum IgE levels and disease severity. METHODS: We measured CD23 expression on B cells from patients with active BP, pemphigus vulgaris, pemphigus foliaceus, and atopic dermatitis (AD), as well as healthy control subjects, using a flow cytometer. Serum levels of IgE and sCD23 were also measured. RESULTS: The expression of CD23 was significantly higher in BP patients compared with healthy control subjects (P < 0.05), whereas the levels were normal in the other bullous diseases. CD23 expression tended to be higher in severe BP compared with moderate BP, and the levels in severe BP were comparable to the levels in AD. Furthermore, CD23 expression correlated positively with serum IgE levels (P < 0.002), and the IgE levels were significantly higher in severe BP than in moderate BP (P < 0.01 ). CD23 expression in BP did not correlate with sCD23 levels. CONCLUSIONS: These results suggest that the up-regulated surface CD23 on B cells may be involved in IgE synthesis and inflammatory events in BP.