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Toll-like-Receptor Gene Polymorphisms in Tunisian Endemic Pemphigus Foliaceus.

ABSTRACT: 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.

SUBMITTER: Abida O

PROVIDER: S-EPMC7661111 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Toll-like-Receptor Gene Polymorphisms in Tunisian Endemic Pemphigus Foliaceus.

Abida O O Bahloul E E Elloumi N N Toumi A A Tahri Safa S Ben Jmaa M M Fakhfakh R R Mahfoudh N N Turki H H Masmoudi H H

BioMed research international 20201105

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 ...[more]

PMID: 33204706

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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:IntroductionPrimarily driven by autoreactive B cells, pemphigus foliaceus (PF) is an uncommon autoimmune blistering skin disease of sporadic occurrence worldwide. However, PF reaches a prevalence of 3% in the endemic areas of Brazil, the highest ever registered for any autoimmune disease, which indicates environmental factors influencing the immune response in susceptible individuals. We aimed to provide insights into the immune repertoire of patients with PF living in the endemic region of the disease, compared to healthy individuals from the endemic region and a non-endemic area.MethodsWe characterized the B-cell repertoire in i) nontreated patients (n=5); ii) patients under immunosuppressive treatment (n=5); iii) patients in remission without treatment (n=6); and two control groups iv) from the endemic (n=6) and v) non-endemic areas in Brazil (n=4). We used total RNA extracted from peripheral blood mononuclear cells and performed a comprehensive characterization of the variable region of immunoglobulin heavy chain (IGH) in IgG and IgM using next-generation sequencing.ResultsCompared to individuals from a different area, we observed remarkably lower clonotype diversity in the B-cell immune repertoire of patients and controls from the endemic area (p < 0.02), suggesting that the immune repertoire in the endemic area is under geographically specific and intense environmental pressure. Moreover, we observed longer CDR3 sequences in patients, and we identified differential disease-specific usage of IGHV segments, including increased IGHV3-30 and decreased IGHV3-23 in patients with active disease (p < 0.04). Finally, our robust network analysis discovered clusters of CDR3 sequences uniquely observed in patients with PF.DiscussionOur results indicate that environmental factors, in addition to disease state, impact the characteristics of the repertoire. Our findings can be applied to further investigation of the environmental factors that trigger pemphigus and expand the knowledge for identifying new targeted and more effective therapies.

Project description:Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that occurs sporadically across the globe and is endemic in Brazil. Keratinocyte adhesion loss (acantholysis) is associated with high levels of anti-desmoglein 1 IgG autoantibodies, but the role of cell death is poorly understood in PF. Current evidence disqualifies apoptosis as the major cell death mechanism and no other process has yet been investigated. To approach the role of variation in genes responsible for cell death pathways in pemphigus susceptibility, we systematically investigated the frequencies of 1,167 polymorphisms from genes encoding products of all 12 well-established cell death cascades (intrinsic and extrinsic apoptosis, necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic, NETotic, lysosome-dependent, autophagy-dependent, and immunogenic). By multivariate logistic regression, we compared allelic and genotypic frequencies of 227 PF patients and 194 controls obtained by microarray hybridization. We found 10 variants associated with PF (p < 0.005), belonging to six cell death pathways: apoptosis (TNF, TRAF2, CD36, and PAK2), immunogenic cell death (EIF2AK3, CD47, and SIRPA), necroptosis (TNF and TRAF2), necrosis (RAPGEF3), parthanatos (HK1), and pyroptosis (PRKN). Five polymorphisms were associated with susceptibility: TNF rs1800630*A (OR = 1.9, p = 0.0003), CD36 rs4112274*T (OR = 2.14, p = 0.0015), CD47 rs12695175*G (OR = 1.77, p = 0.0043), SIRPA rs6075340*A/A (OR = 2.75, p = 0.0009), and HK1 rs7072268*T (OR = 1.48, p = 0.0045). Other five variants were associated with protection: TRAF2 rs10781522*G (OR = 0.64, p = 0.0014), PAK2 rs9325377*A/A (OR = 0.48, p = 0.0023), EIF2AK3 rs10167879*T (OR = 0.48, p = 0.0007), RAPGEF3 rs10747521*A/A (OR = 0.42, p = 0.0040), and PRKN rs9355950*C (OR = 0.57, p = 0.0004). Through functional annotation, we found that all associated alleles, with the exception of PRKN rs9355950*C, were previously associated with differential gene expression levels in healthy individuals (mostly in skin and peripheral blood). Further functional validation of these genetic associations may contribute to the understanding of PF etiology and to the development of new drugs and therapeutic regimens for the disease.

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

Toll-like-Receptor Gene Polymorphisms in Tunisian Endemic Pemphigus Foliaceus.

Publications

Toll-like-Receptor Gene Polymorphisms in Tunisian Endemic Pemphigus Foliaceus.

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