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Endemic pemphigus over a century: Part II.

ABSTRACT: BACKGROUND:Endemic pemphigus foliaceus (EPF) is an autoimmune disease, classically occurring in a restricted geographic area. Foci of EPF have been described in several Central and South American countries, often affecting young people and Amerindians, with some female predilection. Although most American EPF cases have been documented in Brazil, cases have been reported in Peru, Paraguay, El Salvador and Venezuela. An additional variant of EPF has been described in El Bagre, Colombia, (El Bagre-EPF) affecting older men and a few post-menopausal females. Finally, one additional type of EPF has been described in nomadic tribes affecting females of child bearing age in Tunisia, Africa. AIMS:The main aim of this review is to summarize current knowledge about autoantigens, and immunologic and genetic studies in EPF. MATERIAL AND METHODS:We utilized a retrospective review of the literature, aiming to compile and compare the multiple geographic foci of EPF. RESULTS:The primary autoantigens in EPF are still considered to be desmogleins in the case of the Tunisian and all American cases, in contradistinction to plakins and desmogleins in El Bagre-EPF. Although several autoantigens are been suggested, their biochemical nature needs further elucidation. Current knowledge still supports the concept that an antibody mediated immune response represents the principal pathophysiology in all variants of EPF. CONCLUSION:A strong genetic susceptibility appears to contribute to disease development in several people affected by these diseases; however, no specific genes have been confirmed at present. We conclude that further investigation is necessary to define these disorders immunologically and genetically.

SUBMITTER: Abreu-Velez AM

PROVIDER: S-EPMC3354423 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Endemic pemphigus over a century: Part II.

Abréu-Vélez Ana María AM Roselino Ana Maria AM Howard Michael S MS Reason Iara J de Messias IJ

North American journal of medical sciences 20100301 3

<h4>Background</h4>Endemic pemphigus foliaceus (EPF) is an autoimmune disease, classically occurring in a restricted geographic area. Foci of EPF have been described in several Central and South American countries, often affecting young people and Amerindians, with some female predilection. Although most American EPF cases have been documented in Brazil, cases have been reported in Peru, Paraguay, El Salvador and Venezuela. An additional variant of EPF has been described in El Bagre, Colombia, ( ...[more]

PMID: 22624125

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Project description:Background:We have described a variant of endemic pemphigus foliaceus (EPF) in El Bagre area known as pemphigus Abreu-Manu. Our previous study suggested that Colombian EPF seemed to react with various plakin family proteins, such as desmoplakins, envoplakin, periplakin BP230, MYZAP, ARVCF, p0071 as well as desmoglein 1. Objectives:To explore whether patients affected by a new variant of endemic pemphigus foliaceus (El Bagre-EPF) demonstrated oral involvement. Materials and Methods:A case-control study was done by searching for oral changes in 45 patients affected by El Bagre-EPF, as well as 45 epidemiologically matched controls from the endemic area matched by demographics, oral hygiene habits, comorbidities, smoking habits, place of residence, age, sex, and work activity. Oral biopsies were taken and evaluated via hematoxylin and eosin staining, direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and immunohistochemistry. Results:Radicular pieces and loss of teeth were seen in in 43 of the 45 El Bagre-EPF patients and 20 of the 45 controls (P < 0.001) (confidence interval [CI] 98%). Hematoxylin and eosin staining showed 23 of 45 El Bagre-EPF patients had corneal/subcorneal blistering and lymphohistiocytic infiltrates under the basement membrane zone and around the salivary glands, the periodontal ligament, and the neurovascular bundles in all cell junction structures in the oral cavity; these findings were not seen in the controls (P < 0.001) (CI 98%). The direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and microarray staining displayed autoantibodies to the salivary glands, including their serous acini and the excretory duct cell junctions, the periodontal ligament, the neurovascular bundles and their cell junctions, striated muscle and their cell junctions, neuroreceptors, and connective tissue cell junctions. The autoantibodies were polyclonal. IgA autoantibodies were found in neuroreceptors in the glands and were positive in 41 of 45 patients and 3 of 45 controls. Conclusions:Patients affected by El Bagre-EPF have some oral anomalies and an immune response, primarily to cell junctions. The intrinsic oral mucosal immune system, including IgA and secretory IgA, play an important role in this autoimmunity. Our data contradict the hypothesis that pemphigus foliaceus does not affect the oral mucosa due to the desmoglein 1-desmoglein 3 compensation.

Project description:Pemphigus foliaceus (PF) is considered to be caused by the combined effects of susceptibility genes and environmental triggers. The polymorphisms of Toll-like receptors (TLRs) genes have been associated with the risk of various autoimmune diseases. The aim of this study was to evaluate the potential association of TLR2-3-4 and 7 gene polymorphisms with Tunisian PF. Fourteen polymorphisms were analyzed in 93 Tunisian PF patients compared to 193 matched healthy controls: rs5743703-rs5743709 and (GT)n repeat (TLR2); rs5743305, rs3775294, and rs3775291 (TLR3), rs4986790 and rs4986791 (TLR4); and rs3853839 (TLR7). Our results showed that the genetic factors varied depending on the epidemiological feature stratification. In fact, in the whole population, no association with the susceptibility to PF was found. The TLR2 GT repeat seems to be closely associated with PF risk in patients originated from the endemic localities (group 3); the GT18 allele and the heterozygous genotype GT18/GT19 seem to confer risk to endemic PF (P = 0.02; OR = 2.3 [1.1-4.9] and P = 0.0002, OR = 20 [2.5-171], respectively). In contrast, the GT23 repeat could be considered as protector allele (P = 0.02, OR = 0.2 [0.06-0.87]). Furthermore, medium GT alleles which induce high promoter activity were also significantly more frequent in patients versus short or long GT repeats (P = 0.0018 with OR = 3.26 [1.5-7]). On the other hand, the TLR3-rs574305 AA genotype and A allele were significantly more frequent in patients whose age of the onset was above 35 years (group 2) (P = 0.038, OR = 1.78 and P = 0.009, OR = 3.92, respectively). Besides, the TLR4>rs3775294 A allele was found to be protector only in patients with sporadic features (groups 2 and 4) (P = 0.03, OR = 0.57 [0.3-0.9] and P = 0.006, OR = 0.24 [0.08-0.74], respectively). No statistically significant difference was observed in the genotypic and allelic frequencies of TLR-4 and TLR-7 gene polymorphisms. The present data suggest that TLR2and TLR3 polymorphisms are significantly associated with increased susceptibility to PF in the Tunisian population.

Project description:Epitope spreading is an important mechanism for the development of autoantibodies (autoAbs) in autoimmune diseases. The study of epitope spreading in human autoimmune diseases is limited due to the major challenge of identifying the initial/primary target epitopes on autoantigens in autoimmune diseases. We have been studying the development of autoAbs in an endemic human autoimmune disease, Brazilian pemphigus foliaceus (or Fogo Selvagem (FS)). Our previous findings demonstrated that patients before (i.e. preclinical) and at the onset of FS have antibody (Ab) responses against other keratinocyte adhesion molecules in addition to the main target autoantigen of FS, desmoglein 1 (Dsg1), and anti-Dsg1 monoclonal Abs (mAbs) cross-reacted with an environmental antigen LJM11, a sand fly saliva protein. Since sand fly is prevalent in FS endemic regions, individuals in these regions could develop Abs against LJM11. The anti-LJM11 Abs could recognize different epitopes on LJM11, including an epitope that shares the structure similarity with an epitope on Dsg1 autoantigen. Thus, Ab response against this epitope on LJM11 could be the initial autoAb response detected in individuals in FS endemic regions, including those who eventually developed FS. Accordingly, this LJM11 and Dsg1 cross-reactive epitope on Dsg1 could be the primary target of the autoimmune response in FS. This investigation aimed to determine whether the autoAb responses against keratinocyte adhesion molecules are linked and originate from the immune response to LJM11. The anti-Dsg1 mAbs from preclinical FS and FS individuals were employed to determine their specificity or cross-reactivity to LJM11 and keratinocyte adhesion molecules. The cross-reactive epitopes on autoantigens were mapped. Our results indicate that all tested mAbs cross-reacted with LJM11 and keratinocyte adhesion molecules, and we identified an epitope on these keratinocyte adhesion molecules which is mimicked by LJM11. Thus, the cross-reactivity could be the mechanism by which the immune response against an environmental antigen triggers the initial autoAb responses. Epitope spreading leads to the pathogenic autoAb development and ensuing FS among genetically susceptible individuals.

Dataset Information

Endemic pemphigus over a century: Part II.

Publications

Endemic pemphigus over a century: Part II.

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