RESUMO
Pemphigus foliaceus (PF) is an autoimmune skin blistering disease characterized by antidesmoglein-1 IgG production, with an endemic form (EPF) in Brazil. Genetic and epigenetic factors have been associated with EPF, but its etiology is still not fully understood. To evaluate the genetic association of histone (de)acetylation-related genes with EPF susceptibility, we evaluated 785 polymorphisms from 144 genes, for 227 EPF patients and 194 controls. Carriers of HDAC4_rs4852054*A were more susceptible (OR = 1.79, p = 0.0038), whereas those with GSE1_rs13339618*A (OR = 0.57, p = 0.0011) and homozygotes for PHF21A_rs4756055*A (OR = 0.39, p = 0.0006) were less susceptible to EPF. These variants were not associated with sporadic PF (SPF) in German samples of 75 SPF patients and 150 controls, possibly reflecting differences in SPF and EPF pathophysiology. We further evaluated the expression of histone (de)acetylation-related genes in CD4+ T lymphocytes, using RNAseq. In these cells, we found a higher expression of KAT2B, PHF20, and ZEB2 and lower expression of KAT14 and JAD1 in patients with active EPF without treatment compared to controls from endemic regions. The encoded proteins cause epigenetic modifications related to immune cell differentiation and cell death, possibly affecting the immune response in patients with PF.
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Pemphigus foliaceus is an autoimmune disease that is sporadic around the world but endemic in Brazil, where it is known as fogo selvagem (FS). Characterized by autoantibodies against the desmosomal cadherin desmoglein 1, FS causes painful erosions, and crusts that may be widespread. The recognition of antigens, including exposed sugar moieties, activates the complement system. Complement receptor 1 (CR1, CD35), which is responsible for the Knops blood group on erythrocytes (York and McCoy antigens), is also expressed by antigen-presenting cells. This regulates the complement system by removing opsonized antigens, blocking the final steps of the complement cascade. Membrane-bound CR1 also fosters antigen presentation to B cells, whereas soluble CR1 has anti-inflammatory properties. CR1 gene polymorphisms have been associated with susceptibility to complex diseases. In order to investigate the association of CR1 polymorphisms with FS susceptibility, we developed a multiplex sequence-specific assay to haplotype eleven polymorphisms in up to 367 FS patients and 242 controls from an endemic area and 289 from a non-endemic area. We also measured soluble CR1 (sCR1) in the serum of 53 FS patients and 27 controls and mRNA levels in the peripheral blood mononuclear cells of 63 genotyped controls. The haplotypes CR1*3B2B (with the York antigen-encoded by p.1408Met) and CR1*3A2A (with p.1208Arg) were associated with protection against FS (OR = 0.57, P = 0.027, and OR = 0.46, P = 0.014, respectively). In contrast, the CR1*1 haplotype (with the McCoy antigen - encoded by p.1590Glu) was associated with FS susceptibility (OR = 4.97, P < 0.001). Heterozygote rs12034383*A/G individuals presented higher mRNA expression than homozygotes with the G allele (P = 0.04). The lowest sCR1 levels occurred in patients with active disease before treatment (P = 0.036). Patients in remission had higher levels of sCR1 than did healthy controls (P = 0.013). Among those under treatment, patients with localized lesions also presented higher sCR1 levels than those with generalized lesions (P = 0.0073). In conclusion, the Knops blood group seems to modulate susceptibility to the disease. Furthermore, corticosteroid treatment might increase sCR1 serum levels, and higher levels may play an anti-inflammatory role in patients with FS, limiting the distribution of lesions. Based on these results, we suggest CR1 as a potential new therapeutic target for the treatment of FS.
Assuntos
Pênfigo/sangue , Pênfigo/etiologia , Polimorfismo Genético , Receptores de Complemento 3b/sangue , Receptores de Complemento 3b/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Loci Gênicos , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Pênfigo/diagnóstico , Filogenia , RNA Mensageiro/genética , Adulto JovemRESUMO
Pemphigus foliaceus (PF) is an autoimmune skin disease characterized by autoantibodies directed mainly against desmoglein-1. The purpose of this study was to determine whether differential susceptibility to endemic PF in Brazil (fogo selvagem) is associated with polymorphisms at the cytogenetic location 1p13.2. Four single nucleotide polymorphisms that together tag 28 SNPs on a segment of approximately 312,000 bp encompassing the protein-coding genes MAGI3, PHTF1, RSBN1, PTPN22, BCL2L15, AP4B1, DCLRE1B, the pseudogenes MTND5P20, RPS2P14 (AL133517.1) and the long non-coding RNA genes AL137856.1, and AP4B1-AS1 were used as markers for association analysis in a case-control study. Allele, genotype and haplotype frequencies of rs33996649, rs2476601, rs3789604 and rs3195954 were compared between patient and control samples. No significant association was found. Lack of association with rs2476601 of the PTPN22 gene agrees with previous results for pemphigus vulgaris and the Tunisian form of endemic pemphigus foliaceus. The other three SNPs had never been analysed before in any form of pemphigus. We conclude that variants in structural and regulatory sites of region 1p13.2 are not susceptibility factors for fogo selvagem. We suggest careful investigation of this genomic region in diseases that had been previously associated with PTPN22, since there are several other genes relevant for immune-mediated diseases located in 1p13.2.
Assuntos
Cromossomos Humanos Par 1/genética , Pênfigo/genética , Brasil/epidemiologia , Predisposição Genética para Doença , Humanos , Pênfigo/epidemiologia , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , RNA Longo não Codificante/genéticaRESUMO
The aim of this study was to evaluate the ethanolic extract of green propolis (EEP) in the protection of common bean plants against two main bacterial cultures, bacterial blight (Xanthomonas axonopodis pv. phaseoli) and wildfire (Pseudomonas syringae pv. tabaci). Experiments on antimicrobial activity were performed, inducing phytoalexins, defense-related enzymes, and disease severity, under concentrations of 0, 0.5, 1.0, 2.5, and 5.0%. The EEP presented antimicrobial activity on both phytobacteria, causing a decrease in their development. It has also promoted a linear accumulation of phaseolin in bean hypocotyls according to the EEP concentration used. There was a reduction in the lesion area, which was caused by bacterial blight on bean leaves treated with EEP, and local and systemic effect were observed. Polyphenoloxidase was activated with 5% EEP, reaching the maximum activation time 62.5 h after application. An increase was observed in the activity of phenylalanine ammonia-lyase in plants treated with EEP, with local and systemic effect. Results indicated the potential of EEP in the control of these diseases.(AU)
Este trabalho teve como objetivo avaliar o extrato etanólico de própolis verde (EEP) na proteção de plantas de feijoeiro contra as duas principais bacterioses da cultura, crestamento bacteriano (Xanthomonas axonopodis pv. phaseoli) e fogo selvagem (Pseudomonas syringae pv. tabaci). Foram realizados experimentos sobre atividade antimicrobiana indutora de fitoalexinas, de enzimas relacionadas à defesa, e na severidade da doença, usando as concentrações de 0, 0,5, 1,0, 2,5 e 5,0%. O EEP apresentou atividade antimicrobiana sobre ambas fitobactérias, causando uma redução em seu desenvolvimento. O EEP também promoveu um acúmulo linear de faseolina em hipocótilos de feijoeiro conforme a concentração usada. Houve uma redução na área lesionada pelo crestamento bacteriano em folhas de feijoeiro tratadas com EEP, com efeito local e sistêmico. A enzima polifenoloxidase foi ativada pelo EEP a 5%, com ponto máximo de ativação 62,5 horas após aplicação. Houve um aumento na atividade de fenilalanina amônia-liase em plantas tratadas com EEP, com efeito local e sistêmico. Os resultados indicam o potencial do EEP no controle dessas doenças.(AU)
Assuntos
Phaseolus , Própole/análise , Etanol/análise , Anti-InfecciososRESUMO
ABSTRACT: The aim of this study was to evaluate the ethanolic extract of green propolis (EEP) in the protection of common bean plants against two main bacterial cultures, bacterial blight (Xanthomonas axonopodis pv. phaseoli) and wildfire (Pseudomonas syringae pv. tabaci). Experiments on antimicrobial activity were performed, inducing phytoalexins, defense-related enzymes, and disease severity, under concentrations of 0, 0.5, 1.0, 2.5, and 5.0%. The EEP presented antimicrobial activity on both phytobacteria, causing a decrease in their development. It has also promoted a linear accumulation of phaseolin in bean hypocotyls according to the EEP concentration used. There was a reduction in the lesion area, which was caused by bacterial blight on bean leaves treated with EEP, and local and systemic effect were observed. Polyphenoloxidase was activated with 5% EEP, reaching the maximum activation time 62.5 h after application. An increase was observed in the activity of phenylalanine ammonia-lyase in plants treated with EEP, with local and systemic effect. Results indicated the potential of EEP in the control of these diseases.
RESUMO: Este trabalho teve como objetivo avaliar o extrato etanólico de própolis verde (EEP) na proteção de plantas de feijoeiro contra as duas principais bacterioses da cultura, crestamento bacteriano (Xanthomonas axonopodis pv. phaseoli) e fogo selvagem (Pseudomonas syringae pv. tabaci). Foram realizados experimentos sobre atividade antimicrobiana indutora de fitoalexinas, de enzimas relacionadas à defesa, e na severidade da doença, usando as concentrações de 0, 0,5, 1,0, 2,5 e 5,0%. O EEP apresentou atividade antimicrobiana sobre ambas fitobactérias, causando uma redução em seu desenvolvimento. O EEP também promoveu um acúmulo linear de faseolina em hipocótilos de feijoeiro conforme a concentração usada. Houve uma redução na área lesionada pelo crestamento bacteriano em folhas de feijoeiro tratadas com EEP, com efeito local e sistêmico. A enzima polifenoloxidase foi ativada pelo EEP a 5%, com ponto máximo de ativação 62,5 horas após aplicação. Houve um aumento na atividade de fenilalanina amônia-liase em plantas tratadas com EEP, com efeito local e sistêmico. Os resultados indicam o potencial do EEP no controle dessas doenças.
RESUMO
INTRODUCTION: The endemic form (fogo selvagem-FS) of pemphigus foliaceus is an autoimmune disease characterized by the presence of IgG autoantibodies against desmoglein-1. Despite the array of findings, the role of chemokines and cytokines that dictate the immune response and disease outcome is still poorly investigated. MATERIALS AND METHODS: Serum from 64 patients diagnosed with FS was used to draw and establish the levels of these molecules on this disease and establish the levels of these molecules with the severity of FS, and influence of treatment. RESULTS: In comparison to healthy subjects, FS patients, newly diagnosed and still without therapeutic intervention, had higher levels of IL-22 and CXCL-8, and reduced levels of IFN-γ, IL-2, IL-15, and CCL-11. Furthermore, treatment using immunosuppressant drugs augmented the production of IFN-γ, IL-2, CCL-5, and CCL-11 besides reducing the levels of IL-22 and CXCL-10. Immunosuppressive therapy seemed to have long-lasting effects on the production of higher amounts of IFN-γ, IL-2, and CCL-5, besides keeping lowered the levels of IL-22 in remission FS patients. CONCLUSION: Taken together, our findings suggest a putative role of IL-22 in the pathogenesis of FS. Finally, data presented here may contribute for better understanding the immune aspects that control disease outcome.
RESUMO
Introdução: Durante a primeira metade do século XX, o pênfigo foliáceo endêmico (fogo selvagem) teve importante impacto social, econômico e político no Brasil. Após mais de um século desde seus primeiros relatos essa doença ainda guarda interrogações sobre o envolvimento de fatores ambientais desencadeantes e sua característica autoimune e endêmica. O objetivo do trabalho é revisar trabalhos publicados por mais de um século, destacando os aspectos epidemiológicos da doença (das diferentes formas endêmicas pelo mundo) e avanços no estudo da sua etiologia. Material e Métodos: Utilizaram-se de trabalhos no PubMed, LILACS, CAPES, Google Acadêmico, Anais Brasileiros de Dermatologia. Resultados: O fogo selvagem sofreu grande redução do número de casos, principalmente a partir da década de 80 do século XX. O número de estudos sobre a doença vem diminuindo a cada década, várias informações sobre seus aspectos etiológicos e epidemiológicos permanecem há mais de um século sem comprovação precisa. Conclusões: Concluímos que o reduzido número de trabalhos atuais sobre o fogo selvagem se deve a redução considerável da sua incidência após mudanças ecológicas, avanços tecnológicos e melhoria das condições de vida da população das áreas endêmicas. As autoridades deveriam torná-la de notificação compulsória, facilitando a identificação de novos casos e de possíveis áreas endêmicas nos dias atuais. Mais estudos na área contribuiriam também ao estudo das doenças autoimunes em geral e dos fatores relacionados com o aumento da incidência de pênfigo vulgar em áreas endêmicas para fogo selvagem.
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OBJECTIVES: Fogo Selvagem (FS) in Limao Verde (LV), Brazil shows clinical and histological features of pemphigus foliaceus (PF) and shares pathogenic IgG4 anti-desmoglein 1 (Dsg1) autoantibodies. Previously, our group reported that mothers with active FS deliver babies with normal skin and low/negative titers of IgG4 autoantibodies by indirect immunofluorescence. It was postulated that maternal pathogenic IgG4 autoantibodies do not cross the placenta due to differential receptor mediated transplacental passage of IgG subclasses. It was also thought that placental Dsg1 may immunoadsorb pathogenic autoantibodies from the mother; hence pathogenic IgG4 autoantibodies do not reach the baby. In this study we use a Dsg1-specific ELISA to test anti-Dsg1 autoantibodies of the IgM, IgG and the IgG subclasses in the sera of 68 pairs of normal mothers and their neonates living in a highly endemic area of FS. Determination of these baseline anti-Dsg1 autoantibodies will allow us to follow and predict in this and other cohorts the appearance of preclinical serological markers of FS. METHODS: The sera of mothers and neonates living in the endemic region were tested by ELISA for IgM, IgG and IgG subclasses using recombinant Dsg1 and anti-IgG subclass-specific monoclonal antibodies. RESULTS: The index values of anti-Dsg1 IgG1, IgG2 and IgG3 are similar in mothers and neonates (all p>0.18), while the index values of IgM, total IgG and IgG4 are higher in mothers (all p<0.001). CONCLUSIONS: Narrowing the IgM, IgG and IgG subclasses of mothers and neonates to autoantibodies against Dsg1, we found, as expected, that IgM remains only in maternal circulation. In three mothers and two neonates we detected IgG4 anti-Dsg1 autoantibodies above the normal range. The remaining IgG subclasses show low values. The results of the neonatal sera will serve as a baseline for ongoing seroepidemiological studies of children and adults in the endemic regions of FS.
RESUMO
Pemphigus foliaceus is an organ-specific autoimmune disease characterized by autoantibodies against the extracellular region of desmoglein 1, a protein that mediates intercellular adhesion in desmosomes. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key negative regulator of the T cell immune response, playing an important role in T cell homeostasis and maintenance of peripheral tolerance. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases and the functional CT60 single nucleotide polymorphism (rs3087243, also named 6230G > A) has been proposed to be a casual variant in several of these diseases. The aim of this study was to ascertain whether this polymorphism is associated with inter-individual variation in susceptibility to pemphigus foliaceus. The population sample in this case-control association study comprised 248 patient and 367 controls. We did not found a significant association of pemphigus foliaceus with the CT60 variants. We conclude that the CTLA4CT60 polymorphism is not an important factor for pemphigus foliaceus pathogenesis in the population analyzed.
RESUMO
Pemphigus foliaceus is an organ-specific autoimmune disease characterized by autoantibodies against the extracellular region of desmoglein 1, a protein that mediates intercellular adhesion in desmosomes. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key negative regulator of the T cell immune response, playing an important role in T cell homeostasis and maintenance of peripheral tolerance. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases and the functional CT60 single nucleotide polymorphism (rs3087243, also named 6230G > A) has been proposed to be a casual variant in several of these diseases. The aim of this study was to ascertain whether this polymorphism is associated with inter-individual variation in susceptibility to pemphigus foliaceus. The population sample in this case-control association study comprised 248 patient and 367 controls. We did not found a significant association of pemphigus foliaceus with the CT60 variants. We conclude that the CTLA4 CT60 polymorphism is not an important factor for pemphigus foliaceus pathogenesis in the population analyzed.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Doenças Autoimunes , Pênfigo/genética , Brasil , Suscetibilidade a Doenças , Genótipo , Polimorfismo Genético , Polimorfismo de Fragmento de RestriçãoRESUMO
O pênfigo foliáceo ou fogo selvagem (FS) é uma doença órgão-específica auto-imune, de pele, caracterizada por aparecimento de vesículas na epiderme e mediada por auto-anticorpos. Casos familiares são frequentes e nem todos os indivíduos que vivem em regiões endêmicas desenvolvem FS, o que sugere que fatores próprios do hospedeiro possam ter o papel de determinar quais indivíduos expostos são afetados. Um estudo inicial com mestiços brasileiros demonstrou que a predisposição à doença era associada com HLA-DRB1*01. Duas outras populações brasileiras foram estudadas, os índios Xavantes e os Terenas. Um risco aumentado foi encontrado associado com HLA-DRB1*0404 e 1402 entre Xavante. O estudo com Terena confirmou esses achados e descreveu um novo alelo associado: 19 dos 20 pacientes Terena foram positivos para DRB1*0404 ou 1406 (p<0.005, RR=14). Todos esses alelos envolvidos na predisposção à doença, nas três diferentes populações, compartilham a mesma sequência de aminoácidos nas posições 67-74 da molécula codificada pela terceira região hipervariável do gene HLA-DRB1: LLEQRRAA. Esse achado sugere que a herança dessa sequência está envolvida na susceptibilidade a FS. Quando pacientes e controles foram tomados em conjunto, os resultados obtidos demonstraram claramente que a hipótese de se testar para o epítopo descrito é claramente significante e preditiva de susceptibilidade para FS (p,0.00001, RR=6.4.
Endemic pemphigus foliaceus or fogo selvagem (FS) is an organ-specific autoimmune skin disease characterized by epidermal vesicles and mediated by autoantibodies. Family cases are frequent and not everyone living in endemic region develops FS, suggesting that host factors play a role in determining whether exposed individuals will be affected. An initial study with Brazilian mestizos showed that predisposition to the disease was associated with HLA-DRB1*01. Two other Brazilian populations were studiet, the Xavante and the Terena Indians. An increased risk was found associated with HLA-DRB1*0404 and 1402 among Xavante. The study with Terena confirmed those findings and described a new associated allele: 19 out of 20 Terena patients were either positive for DRB10404, 1402 or 1406 (p,0.005, RR=14). All these alleles involved in predisposition to the disease in the three different populations shared the same aminoacid sequence at positions 67-74 on the molecule coded by the third hypervariable region of the HLA-DRB1 gene: LLEQRRAA. This finding suggested that the inheritance of this sequence is involved in the susceptibility to FS. When patients and controls data from different studies were pooled and analysed disregarding the etnicbackground and the HLA alleles involved, the results obtained clearly supported the hypothesis that matching for the described epitope is highly significant and predictive of FS predisposition (p,0.00001.RR=6.4).