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

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

doi:10.1155/2020/6541761

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.

Highlights

The current body of knowledge in the pemphigus foliaceus (PF) field points to an evident multistep model of disease pathogenesis characterized by blister formation and acantholysis which most likely associated with downstream events following the binding of desmoglein-1- (Dsg1-) specific IgG pathogenic autoantibodies (-Antibodies Dsg1 (Abs)) [1, 2]
The diagnosis of PF was confirmed by the clinical presentation, histopathology, direct immunofluorescence (IgG and C3 deposits most often located on the whole epidermis and less frequently predominant in the upper layers of the epidermis), indirect immunofluorescence (IgG Abs directed against the epithelial cell surface), and ELISA test for circulatory anti-Dsg1 Abs that was positive for all patients [22, 23]
A study in a Chinese cohort in different intraepidermal bullouse diseases showed a relocalization of tlr4 expression sites with increased expression in pemphigus and BP lesions [32]. These findings argue for the implication of other particular polymorphisms that should enhance TLR4 signaling in PF’s keratinocytes

Summary

Introduction

The current body of knowledge in the pemphigus foliaceus (PF) field points to an evident multistep model of disease pathogenesis characterized by blister formation and acantholysis which most likely associated with downstream events following the binding of desmoglein-1- (Dsg1-) specific IgG pathogenic autoantibodies (-Abs) [1, 2]. The disease occurs in a genetically susceptible individual who is exposed to a triggering environmental antigen that leads, by molecular mimicry, to anti-Dsg Abs triggers [3]. Little is known regarding the environmental trigger. Infectious agents are plausible environmental triggers for autoimmunity in genetically susceptible individuals. Ongoing studies to identify the triggering environmental antigen in PF will be critically important to make significant progress in the disease’s therapy [6]

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