RESUMO
Several genes have been associated with breast cancer (BC) susceptibility. The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and interferon lambda receptor 1 (IFNLR1) genes encode receptors that mediate the action of inflammatory cytokines. Previous studies have demonstrated the association of the variants rs1800693 (TNFRSF1A) and rs4649203 (IFNLR1) with some inflammatory diseases. The present study aimed to verify a possible association of these variants with BC, its clinical pathologic features, as well as epidemiological data in a Brazilian population. A total of 243 patients and 294 individuals without history of BC were genotyped for these polymorphisms through TaqMan® SNP genotyping assays by qPCR. For the TNFRSF1A gene, no significant results were found. For IFNLR1, the AA genotype (p = 0.008) and the A allele (p = 0.02) were significantly associated with a lower risk of developing BC. When analyzing the age, it was observed that each increase of one year contributes to the development of BC (p < 0.001). Also, the smoking habit (p < 0.001) and body mass index (p = 0.018) increase the risk of disease development. Analyzing progesterone receptor factor an association was found with the AA genotype of the IFNLR1 (p = 0.02). The findings suggest that polymorphism in the immune-related IFNLR1 gene contribute to BC susceptibility in a Brazilian population. These findings can contribute to the further understanding of the role this gene and pathways in BC development.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores de Interferon/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: The interferon pathways have been commonly implicated in autoimmune disease development but the identity of the genes involved has not yet been fully clarified. Variation in genes involved in interferon pathways is expected to have a role in the etiology of these diseases. METHODS: The potential association of a polymorphism in the IL28RA gene, involved in these pathways, with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and disease-related phenotypes was investigated in 603 Brazilian individuals (354 well-characterized SLE and RA patients, and 249 controls). IL28RA (rs4649203) variant was genotyped by TaqMan assay. Statistical analysis was performed including both diseases and a comprehensive list of patient clinical manifestations. RESULTS: The rs4649203-G (minor) allele was associated with SLE and RA occurrence and was shown to be a risk factor for serositis and anemia among SLE patients as well as a protective factor for rheumatoid vasculitis and rheumatoid nodules in RA patients, suggesting an association with a milder form of the disease. CONCLUSIONS: The IL28RA gene may contribute to SLE and RA susceptibility and to specific clinical manifestations of the diseases.
Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interferon/genética , Adolescente , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Several mutations have been described leading to impaired immunity in the IL-12/IFN-γ axis and, they confer susceptibility to mycobacterial infections. One of the more serious clinical phenotypes is secondary to mutations at IFN-γ receptor 1 gene, characterized by an early onset and more severe disease. CLINICAL REPORT: We present a 3-month-old female patient with systemic M. tuberculosis complex who has a homozygous mutation, it affects the splicing site at IFNGR1 c.201-1G> T. At time of this report, she is with antimycobacterial treatment in the protocol of pluripotent hematopoietic cell transplantation (TCHP). CONCLUSION: It has been reported that antiphimic treatment should be maintained until the immune system is restored by the TCHP. If patients receive THCP before the age of 1 year old, they have a better prognosis. Diminish the levels of IFN-γ in plasma before the procedure is associated to better results.
Antecedentes: Se han descrito diversas mutaciones que llevan a inmunidad alterada en el eje interleucina 12/interferón gamma (IL-12/IFN-γ) y confieren susceptibilidad a infecciones por micobacterias. Uno de los fenotipos clínicos más graves es secundario a mutaciones en el gen del receptor 1 de IFN-γ, caracterizado por su inicio a temprana edad y mayor gravedad. Caso clínico: Paciente femenina de 3 meses de edad, con afección sistémica por complejo M. tuberculosis, en quien se identificó una mutación homocigota que afecta el sitio de splicing a nivel de IFNGR1 c.201-1G>T. Al momento de este reporte es manejada con antifímicos en un protocolo de trasplante de células hematopoyéticas pluripotenciales. Conclusión: Se ha informado que el tratamiento antifímico debe mantenerse hasta que se restaure el sistema inmunológico mediante trasplante de células hematopoyéticas pluripotenciales, cuyo mejor pronóstico se asocia con edad del receptor menor a un año y reducción de los niveles plasmáticos de IFN-γ.
Assuntos
Receptores de Interferon/deficiência , Tuberculose/imunologia , Feminino , Humanos , Lactente , México , Linhagem , Receptores de Interferon/genética , Receptor de Interferon gamaRESUMO
In addition to previously studied immunological variables, the relative expression of IFNGR2, IFNAR1, CD18, and CD275 (all encoded in chromosome 21) on circulating leucocytes and multifunctional T cells (evaluated by an intracellular cytokine/proliferation assay) were compared between children with Down syndrome (DS) and healthy controls (HC). As previously reported, numbers of lymphocytes, CD4(+) T cells, Treg cells, B cells, and levels of serum IgM were decreased, and levels of IgG and IgA were increased in children with DS. Moreover, the relative expression of CD18 on T and B cells (previously and not previously reported, respectively) were elevated in DS children (p⩽0.01). Age and numbers of B and Treg cells moderately correlated with retrospectively identified infection related hospitalizations (rho: 0.300-0.460, p⩽0.003). Age and the numbers of Treg cells also correlated with prospectively identified infection related hospitalizations. Future studies are necessary to clarify the role of these parameters in the immunity of DS patients.
Assuntos
Linfócitos B/imunologia , Cromossomos Humanos Par 21/genética , Síndrome de Down/imunologia , Hospitalização/estatística & dados numéricos , Infecções/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Antígenos CD18/metabolismo , Proliferação de Células , Criança , Pré-Escolar , Citocinas/metabolismo , Síndrome de Down/complicações , Síndrome de Down/epidemiologia , Feminino , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Lactente , Infecções/complicações , Infecções/epidemiologia , Ativação Linfocitária , Masculino , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismoRESUMO
It is well understood that helminth infections modulate the immune responses of their hosts but the mechanisms involved in this modulation are not fully known. Macrophages and dendritic cells appear to be consistently affected during this type of infection and are common target cells for helminth-derived molecules. In this report, we show that macrophages obtained from chronically Taenia crassiceps-infected mice displayed an impaired response to recombinant murine IFN-γ, but not to recombinant murine IL-4, as measured based on the phosphorylation of STAT1 and STAT6, respectively. These macrophages expressed high levels of SOCS3. However, the inhibition of phosphatase activity by orthovanadate restored the IFN-γ response of these macrophages by increasing STAT1 phosphorylation without affecting SOCS3 expression. Therefore, we aimed to identify the phosphatases associated with IFN-γ signaling inhibition and found that macrophages from T. crassiceps-infected mice displayed enhanced SHP-1 expression. Interestingly, the exposure of naïve macrophages to T. crassiceps excreted/secreted products similarly interfered with IFN-γ-induced STAT1 phosphorylation. Moreover, macrophages exposed to T. crassiceps excreted/secreted products expressed high levels of SOCS3 as well as SHP-1. Strikingly, human peripheral blood mononuclear cells that were exposed to T. crassiceps excreted/secreted products in vitro also displayed impaired STAT1 phosphorylation in response to IFN-γ; again, phosphatase inhibition abrogated the T. crassiceps excreted/secreted product-altered IFN-γ signaling. These data demonstrate a new mechanism by which helminth infection and the products derived during this infection target intracellular pathways to block the response to inflammatory cytokines such as IFN-γ in both murine and human cells.
Assuntos
Interferon gama/metabolismo , Taenia/metabolismo , Teníase/parasitologia , Adulto , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interferon gama/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/parasitologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Álcool Feniletílico/análogos & derivados , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Fosforilação , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Teníase/metabolismo , Receptor de Interferon gamaRESUMO
Helicobacter pylori (Hp) has a worldwide distribution showing its higher prevalence of infection in developing countries. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) are proteins that recognize pathogen-associated molecular patterns (PAMPs) and initiate an innate immune response by promoting growth and differentiation of specialized hematopoietic cells for host defense. Gastric infections led by Hp induce a Th-1 cellular immune response, regulated mainly by the expression of IFN-γ. In this retrospective case-control study, we evaluated the TLR1 1805T/G, TLR2 2029C/T, TLR4 896A/G, CD209 -336A/G and IFNGR1 -56C/T polymorphisms and their relationship with susceptibility to Hp infection. TLR1 1805T/G showed statistical differences when the control (Hp-) and infected (Hp+) groups (P = 0.041*) were compared; the TLR1 1805G allele had a protective effect towards infection (OR = 0.1; 95% CI = 0.01-0.88, P = 0.033*). Similarly, the IFNGR1 -56C/T polymorphism showed statistical differences between Hp+ and Hp- (P = 0.018*), and the IFNGR1 -56TT genotype exhibited significant risk to Hp infection (OR = 2.9, 95% CI = 1.27-6.54, P = 0.018*). In conclusion, the pro-inflammatory TLR1 1805T and IFNGR1 -56T alleles are related with susceptibility to Hp infection in Ecuadorian individuals. The presence of these polymorphisms in individuals with chronic infection increases the risk of cellular damage and diminishes the cellular immune response efficiency towards colonizing agents.
Assuntos
Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Imunidade Inata/imunologia , Polimorfismo de Nucleotídeo Único/imunologia , Receptores de Superfície Celular/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Equador , Frequência do Gene , Genótipo , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genética , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Estudos Retrospectivos , Receptor 1 Toll-Like/genética , Receptor 1 Toll-Like/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Adulto Jovem , Receptor de Interferon gamaRESUMO
Cancer is a multifactorial disease with a high mortality rate in Brazil and worldwide. Gastric cancer (GC) is considered the fourth type of malignancy more frequent in the population worldwide and the second leading cause of death. This work aimed to evaluate single nucleotide polymorphisms (SNPs) of IFNGR1, GSTT1, and GSTP1 genes samples in gastric cancer. We analyzed 60 samples of gastric cancer, 26 diffuse and 34 intestinal types, totaling 120 alleles for each SNP. The results were obtained by PCR and allele-specific PCR. Statistical analyzes performed using BioEstat 5.0 software, applying the Fisher's exact test and chi-square. Only the SNP gene GSTP1 (rs1695) were significantly associated with gastric cancer in the samples analyzed (χ(2) = 8.73, P < 0.05). Our results suggest that the GSTP1 gene SNP (rs1695) can be considered a risk factor associated with gastric carcinogenesis.
Assuntos
Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interferon/genética , Neoplasias Gástricas/genética , Brasil , Humanos , Neoplasias Gástricas/etiologia , Receptor de Interferon gamaRESUMO
BACKGROUND: Recently, attenuation of anti-inflammatory and increase of pro-inflammatory mediators was demonstrated in individuals with Down syndrome (DS) in comparison with euploid patients during periodontal disease (PD), suggesting a shift to a more aggressive inflammation in DS. AIM: To determine the influence of DS in the modulation of interferons (IFNs) signaling pathway in PD. MATERIALS AND METHODS: Clinical periodontal assessment was performed and gingival tissue samples obtained from a total of 51 subjects, including 19 DS individuals with PD, 20 euploid individuals with PD and 12 euploid individuals without PD. Expression levels of interferon-gamma (IFNG) and interferon-alpha (IFNA), and their receptors IFNGR1, IFNGR2, IFNAR1 and IFNAR2, the signaling intermediates Janus kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) were determined using real time quantitative polymerase chain reaction (qPCR). RESULTS: Clinical signs of periodontal disease were markedly more severe in DS and euploid patients with PD in comparison to euploid and periodontally healthy patients. There was no difference on mRNA levels of IFNA, IFNG, INFGR2, IFNAR1 and IFNAR2 between DS and euploid individuals, even though some of these genes are located on chromosome 21. STAT1 and IRF1 mRNA levels were significantly lower in DS patients in comparison with euploid individuals with PD. In euploid individuals, PD was associated with an increased expression of IFNGR1, IFNGR2, IFNAR1, STAT1 and IRF1. CONCLUSIONS: Reduced expression of STAT1 and IRF1 genes indicate an impaired activation of IFNs signaling in individuals with DS and PD. Expression of IFNA, IFNG and IFN receptors was not altered in DS patients, indicating that indirect mechanisms are involved in the reduced activation of IFN signaling.
Assuntos
Síndrome de Down/genética , Regulação da Expressão Gênica , Interferon-alfa/metabolismo , Interferon gama/metabolismo , Periodontite/genética , Adulto , Síndrome de Down/complicações , Síndrome de Down/metabolismo , Feminino , Humanos , Fator Regulador 1 de Interferon/metabolismo , Janus Quinase 1/metabolismo , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta/análise , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Adulto Jovem , Receptor de Interferon gamaRESUMO
This study tested the hypothesis that the IFN-γ R1 287-YVSLI-91 intracellular motif regulates its endocytosis. IFN-γ exerts its biological activities by interacting with a specific cell-surface RC composed of two IFN-γ R1 and two IFN-γ R2 chains. Following IFN-γ binding and along with the initiation of signal transduction, the ligand and IFN-γ R1 are internalized. Two major types of consensus-sorting signals are described in receptors, which are rapidly internalized from the plasma membrane to intracellular compartments: tyrosine-based and dileucine-based internalization motifs. Transfection of HEK 293 cells and IFN-γ R1-deficient fibroblasts with WT and site-directed, mutagenesis-generated mutant IFN-γ R1 expression vectors helped us to identify region IFN-γ R1 287-YVSLI-291 as the critical domain required for IFN-γ-induced IFN-γ R1 internalization and Y287 and LI290-291 as part of a common structure essential for receptor endocytosis and function. This new endocytosis motif, YxxLI, shares characteristics of tyrosine-based and dileucine-based internalization motifs and is highly conserved in IFN-γ Rs across species. The IFN-γ R1 270-LI-271 dileucine motif, previously thought to be involved in this receptor endocytosis, showed to be unnecessary for receptor endocytosis.
Assuntos
Endocitose/imunologia , Leucina/química , Leucina/metabolismo , Receptores de Interferon/química , Receptores de Interferon/metabolismo , Motivos de Aminoácidos/imunologia , Sequência de Aminoácidos , Sequência Conservada/imunologia , Células HEK293 , Humanos , Dados de Sequência Molecular , Sinais Direcionadores de Proteínas/fisiologia , Receptores de Interferon/genética , Tirosina/química , Tirosina/metabolismo , Receptor de Interferon gamaRESUMO
Chronic inflammation induced by Helicobacter pylori is a key process in gastric carcinogenesis. We hypothesized that genetic polymorphisms in important mediators of H. pylori-induced inflammation may influence the risk of developing various grades of precancerous lesions. We studied the associations between single nucleotide polymorphisms (SNPs) in cyclooxygenase 1 and 2 (PTGS1 and PTGS2), inducible nitric oxide synthase (NOS2A), interferon gamma (IFNG) and its receptor (IFNGR1), and risk of gastric precancerous lesions in a Venezuelan population characterized by high rates of H. pylori infection. We found no association of precancerous lesions with SNPs in PTGS1 and in IFNG. A nonsynonymous SNP of NOS2A (Ser608Leu) and an SNP located in the promoter of IFNGR1 (C-56T) were associated with higher risk of atrophic gastritis [odds ratio (OR)=1.37, 95% confidence interval (CI)=1.01-1.86, and OR=1.49, 95% CI=1.01-2.19, respectively]. Two SNPs of PTGS2 were associated with risk of dysplasia (OR=1.60, 95% CI=1.01-2.54, and OR=0.66, 95% CI=0.43-0.99). We conclude that genetic variability in the genes we studied does not play a major role in the early stages of gastric carcinogenesis.