ABSTRACT
Pemphigus consists of a group of chronic blistering skin diseases mediated by autoantibodies (autoAbs). The dogma that pemphigus is caused by keratinocyte dissociation (acantholysis) as a distinctive and direct consequence of the presence of autoAb targeting two main proteins of the desmosome-desmoglein (DSG) 1 and/or DSG3-has been put to the test. Several outside-in signaling events elicited by pemphigus autoAb in keratinocytes have been described, among which stands out p38 mitogen-activated protein kinase (p38 MAPK) engagement and its apoptotic effect on keratinocytes. The role of apoptosis in the disease is, however, debatable, to an extent that it may not be a determinant event for the occurrence of acantholysis. Also, it has been verified that compromised DSG trans-interaction does not lead to keratinocyte dissociation when p38 MAPK is inhibited. These examples of conflicting results have been followed by recent work revealing an important role for endoplasmic reticulum (ER) stress in pemphigus' pathogenesis. ER stress is known to activate the p38 MAPK pathway, and vice versa. However, this relationship has not yet been studied in the context of activated signaling pathways in pemphigus. Therefore, by reviewing and hypothetically connecting the role(s) of ER stress and p38 MAPK pathway in pemphigus, we highlight the importance of elucidating the crosstalk between all activated signaling pathways, which may in turn contribute for a better understanding of the role of apoptosis in the disease and a better management of this life-threatening condition.
ABSTRACT
Genetic variations mapping to 3' untranslated regions (3'UTRs) may overlap with microRNA (miRNA) binding sites, therefore potentially interfering with translation inhibition or messenger RNA (mRNA) degradation. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) located within the 3'UTRs of six candidate genes and predicted to interfere with miRNA ligation could account for disease-relevant differential mRNA levels. Focusing on pemphigus foliaceus (PF) - an autoimmune blistering skin condition with unique endemic patterns - we investigated whether nine 3'UTR SNPs from the CD1D, CTLA4, KLRD1, KLRG1, NKG7, and TNFSF13B genes differentially expressed in PF were disease-associated. The heterozygous genotype of the KLRG1 rs1805672 polymorphism was associated with increased predisposition to PF (A/G vs. A/A: P=0.038; OR=1.60), and a trend for augmented susceptibility was observed for carriers of the G allele (P=0.094; OR=1.44). In silico analyses suggested that rs1805672 G allele could disrupt binding of miR-584-5p, and indicated rs1805672 as an expression Quantitative Trait Locus (eQTL), with an effect on KLRG1 gene expression. Dual-luciferase assay showed that miR-584-5p mediated approximately 50% downregulation of the reporter gene's activity through the 3'UTR of KLRG1 harboring rs1805672 A allele (vs. miRNA-negative condition, P=0.006). This silencing relationship was lost after site-directed mutation to G allele (vs. miRNA-negative condition, P=0.391; vs. rs1805672 A allele, P=0.005). Collectively, these results suggest that a disease-associated SNP located within the 3'UTR of KLRG1 directly interferes with miR-584-5p binding, allowing for KLRG1 mRNA differential accumulation, which in turn may contribute to pathogenesis of autoimmune diseases, such as pemphigus.
Subject(s)
3' Untranslated Regions , Genetic Predisposition to Disease , Lectins, C-Type/genetics , MicroRNAs/genetics , Pemphigus/genetics , Polymorphism, Single Nucleotide , Trans-Activators/genetics , Alleles , Antigens, CD1d/genetics , Antigens, CD1d/metabolism , B-Cell Activating Factor/genetics , B-Cell Activating Factor/metabolism , Base Sequence , Binding Sites , CTLA-4 Antigen/genetics , CTLA-4 Antigen/metabolism , Case-Control Studies , DNA Mutational Analysis , Gene Expression Regulation , Gene Frequency , Haplotypes , Humans , Lectins, C-Type/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/metabolism , Mutation , NK Cell Lectin-Like Receptor Subfamily D/genetics , NK Cell Lectin-Like Receptor Subfamily D/metabolism , Pemphigus/diagnosis , Pemphigus/metabolism , Pemphigus/pathology , Receptors, Immunologic , Trans-Activators/metabolismABSTRACT
Histórico: Os corticosteróides tópicos produzem alteraçöes atróficas na pele, inclusive diminuiçäo da espessura da epiderme e da substância essencial dérmica. Observamos que o lactato de amônio a 12 por cento produziu aumento da espessura da epiderme e aumento na qualidade de glicosaminoglicanos dérmicos. Objetivo: Determinar se o lactato de amônio a 12 por cento poderia minimizar a atrofia cutânea produzida por um corticosteróide tópico potente. Métodos: Ambos, o propionato de clobetasol e o lactato de amônio a 12 por cento, foram aplicados repetidas vezes sob patches oclusivos, bem como em patches abertos nos antebraços de voluntários durante 3 a 4 semanas. As amostras para biópsia foram avaliadas por análise de imagem quanto à espessura da epiderme e quanto à quantidade de glicosaminoglicanos dérmicos. Resultados: O lactato de amônio a 12 por cento atenuou significativamente a atrofia da epiderme e da derme sem nenhuma influência sobre a biodisponibilidade ou sobre as propriedades antiinflamatórias do corticosteróide. Conclusäo: O lactato de amônio a 12 por cento pode ser útil na atenuaçäo dos efeitos adversos do corticosteróide na pele