RESUMO
AIM AND BACKGROUND: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. METHODS: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. RESULTS: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R2=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005). CONCLUSIONS: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout.
Assuntos
Doenças Cardiovasculares/metabolismo , Gota/metabolismo , Telomerase/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Progressão da Doença , Feminino , Gota/epidemiologia , Humanos , Células Matadoras Naturais/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismoRESUMO
Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor ß (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.
Assuntos
Antígenos CD59/genética , Rejeição de Enxerto/diagnóstico , Transplante de Pulmão , Polimorfismo Genético/genética , Complicações Pós-Operatórias , Regiões Promotoras Genéticas/genética , Doadores de Tecidos , Adolescente , Adulto , Ativação do Complemento , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/metabolismo , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the internal organs. Except for anticentromere, antitopoisomerase I and antipolymerase III antibodies, there are no reliable circulating markers predicting susceptibility and internal organ complications. This study has exploited a proteome-wide profiling method with the aim to identify new markers to identify SSc phenotype. METHOD: 40 SSc patients were included for proteomic identification. Patients were stratified as having diffuse cutaneous SSc (dcSSc) (n=19) or limited cutaneous SSc (lcSSc) (n=21) according to the extent of skin involvement. As controls 19 healthy donors were included. Blood was drawn and plasma was stored before analysing with the SELDI-TOF-MS. For replication in serum, the cohort was extended with 60 SSc patients. RESULTS: Proteomic analysis revealed a list of 25 masspeaks that were differentially expressed between SSc patients and healthy controls. One of the peaks was suggestive for S100A8, a masspeak we previously found in supernatant of plasmacytoid dendritic cells from SSc patients. Increased expression of S100A8/A9 in SSc patients was confirmed in replication cohort compared with controls. Intriguingly, S100A8/A9 was highest in patients with limited cutaneous SSc having lung fibrosis. CONCLUSIONS: S100A8/A9 was robustly found to be elevated in the circulation of SSc patients, suggesting its use as a biomarker for SSc lung disease and the need to further explore the role of TLR in SSc.
Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Proteômica , Escleroderma Sistêmico/metabolismo , Receptores Toll-Like/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Calgranulina A/imunologia , Calgranulina B/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/imunologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Receptores Toll-Like/imunologiaRESUMO
OBJECTIVE: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). METHODS: We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. RESULTS: In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001). CONCLUSION: Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.
Assuntos
Interleucina-6/metabolismo , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Receptor 2 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo , Estudos de Coortes , Comorbidade , Células Dendríticas/metabolismo , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Masculino , Monócitos/metabolismo , Fenótipo , Prognóstico , Artéria Pulmonar/fisiopatologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/metabolismoRESUMO
Objectives: Immunomodulatory agents are safe and effective as treatment for various immune-mediated inflammatory diseases (IMIDs), but are associated with a slightly increased infection risk. It is uncertain whether, in the event of an infection, continuation or temporary interruption of immunomodulatory agents leads to better outcomes. Owing to this uncertainty, it is of importance to explore the perspectives of health-care providers (HCPs) and patients on this topic. In this study, we set out to identify and provide an overview of reasons for both treatment strategies. Methods: Semi-structured interviews were conducted with HCPs involved in the pharmacological treatment of IMIDs and with IMID patients using one or more immunomodulatory agent. Purposive sampling was used to enrich data variation. Interviews were conducted until data saturation was reached and subsequently analysed using qualitative content analysis. Results: In total, 13 HCPs and 19 IMID patients were interviewed. A wide range of reasons for both treatment strategies were identified, categorized into 10 overarching themes, including IMID characteristics, infection characteristics and the patient-HCP relationship. Conclusion: In this interview study, we identified various reasons for continuation or temporary interruption of immunomodulatory agents during infections for both IMID patients and HCPs. We found overlapping themes, such as IMID characteristics; however, the content and interpretation of these themes might differ between HCPs and patients. Both HCPs and patients mentioned that the decision for a treatment strategy is often about weighing benefits against risks (e.g. infection severity vs disease flare).
RESUMO
There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of ≤ 1 was a significant risk factor for SSc (OR=1.55 (1.13-2.14), P=0.007) relative to CN ≥ 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.
Assuntos
Deleção de Genes , Receptores de IgG/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Autoanticorpos/sangue , Sequência de Bases , Estudos de Casos e Controles , Centrômero/imunologia , Variações do Número de Cópias de DNA , Sondas de DNA/genética , DNA Topoisomerases Tipo I/imunologia , Europa (Continente) , Proteínas Ligadas por GPI/genética , Dosagem de Genes , Estudos de Associação Genética , Humanos , Fatores de Risco , Esclerodermia Difusa/genética , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/genética , Esclerodermia Limitada/imunologia , População Branca/genéticaRESUMO
Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.
Assuntos
Doenças Autoimunes/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Escleroderma Sistêmico/genética , Adulto , Doenças Autoimunes/imunologia , Loci Gênicos , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/imunologiaRESUMO
The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Escleroderma Sistêmico/genética , População Branca/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/patologia , População Branca/etnologiaRESUMO
OBJECTIVE: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. METHODS: 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc. RESULTS: The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). CONCLUSION: The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.
Assuntos
Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Escleroderma Sistêmico/genética , Autoanticorpos/sangue , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Escleroderma Sistêmico/imunologiaRESUMO
OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Membrana/genética , Esclerodermia Difusa/genética , População Branca/genética , Autoanticorpos/análise , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Esclerodermia Difusa/imunologiaRESUMO
OBJECTIVES: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. METHODS: An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay. RESULTS: Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes. CONCLUSIONS: Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.
Assuntos
Receptores de Interleucina/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Mice of the C.B-17 strain homozygous for the scid mutation (SCID mice) were infected with lactate dehydrogenase-elevating virus (LDV), and plasma samples obtained at intervals up to 42 days postinfection were analyzed for total immunoglobulins, anti-LDV antibodies, virus-specific immune complexes, and viremia levels. The mice responded to LDV infection with transient increases in total blood IgM, production of IgM-antigen complexes and IgM anti-LDV, as well as increased blood IgG2a. However, SCID mice failed to make a specific IgG2a anti-LDV immune response, and their blood LDV levels were elevated about 100-fold relative to those of control mice. The results suggest a role for IgG antibodies in the regulation of viremia and demonstrate a viral pathway of B-cell differentiation in SCID mice.
Assuntos
Linfócitos B/imunologia , L-Lactato Desidrogenase/metabolismo , Vírus Elevador do Lactato Desidrogenase/imunologia , Ativação Linfocitária/imunologia , Viremia/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Western Blotting , Expressão Gênica , Genes de Imunoglobulinas/imunologia , Imunoglobulinas/análise , Interferon gama/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Mutantes , Baço/metabolismo , Viremia/enzimologiaRESUMO
Immunodeficient SCID (C.B-17 scid/scid) mice with persistent lactate dehydrogenase-elevating virus (LDV) infection failed to produce IgG anti-LDV antibodies, and during chronic infection transmitted virus infection to 95% of their offspring. In contrast, normal mice infected 15 or more days prior to giving birth produced IgG anti-LDV antibodies and transmitted LDV infection to only 0-46% of their fetuses. Transplacental transmission of LDV infection was dependent on the timing of maternal infection. Adoptive transfer of immune competence to LDV-infected SCID mice resulted in fetal protection from maternally transmitted virus infection. Fetal protection correlated with the presence of maternal IgG anti-LDV but not with fetal levels of IgG anti-LDV, and the levels of viremia in nonimmune SCID mice did not affect transplacental virus transmission. These results demonstrate the importance of maternal immunity in protecting the fetus from infection, and validate the use of this mouse model for investigation of immune mechanisms of transplacental virus transmission.
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Anticorpos Antivirais/imunologia , Doenças Fetais/imunologia , Vírus Elevador do Lactato Desidrogenase/imunologia , Viroses/transmissão , Animais , Anticorpos Antivirais/biossíntese , Feminino , Feto/imunologia , Imunização Passiva , Imunoterapia Adotiva , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/microbiologia , Viremia/imunologia , Viroses/imunologiaRESUMO
The mechanisms which regulate the replication of lactate dehydrogenase-elevating virus (LDV), a persistent murine model virus which infects macrophages, are unclear. For this study, the effects of murine recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on LDV replication were examined. LDV permissiveness was reduced in macrophages obtained from uninfected mice treated with IFN-gamma prior to cell harvest and in vitro LDV infection. Virus inhibition by IFN-gamma was also observed when neonatal LDV-infected mice were injected with this cytokine prior to macrophage harvest and analysis of LDV replication-positive cells. Persistently LDV-infected mice demonstrated an increase in viremia levels following treatment with TNF-alpha. Neither IFN-gamma nor TNF-alpha had any direct in vitro effect on LDV replication in cultured macrophages, suggesting that the actions of these cytokines required secondary or accessory in vivo events. These results provide evidence for cytokine-mediated regulation of LDV infection and support a role for the immune system in the LDV-host relationship.
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Interferon gama/farmacologia , Vírus Elevador do Lactato Desidrogenase/fisiologia , Macrófagos/microbiologia , Fator de Necrose Tumoral alfa/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Infecções por Arterivirus/microbiologia , Células Cultivadas , Injeções Intraperitoneais , Injeções Intravenosas , Vírus Elevador do Lactato Desidrogenase/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Fator de Necrose Tumoral alfa/administração & dosagem , Viremia/microbiologiaRESUMO
The murine lactate dehydrogenase-elevating virus (LDV) was used to study the effects of prostaglandin-acting agents on mucosal resistance to virus infection. Mice treated with non-steroidal anti-inflammatory drugs (NSAIDs) prior to oral exposure to LDV demonstrated a reduction in the mucosal barrier to LDV infection. Histological studies indicated that these NSAID effects were not a result of gross or microscopic tissue damage. The effects of two NSAIDs, indomethacin and diclofenac, were inhibited by co-treatment of mice with misoprostol, a synthetic PGE1 analog. The ability of misoprostol to modulate NSAID effects was not due to direct antiviral activity or to actions on LDV-permissive macrophages. These results show that the mammalian mucosal barrier to virus infection is prostaglandin-sensitive, and provide a model for the study of resistance to viral infection.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/farmacologia , Alprostadil/análogos & derivados , Alprostadil/farmacologia , Animais , Aspirina/farmacologia , Diclofenaco/farmacologia , Feminino , Indometacina/farmacologia , Vírus Elevador do Lactato Desidrogenase/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Misoprostol , Viroses/tratamento farmacológicoRESUMO
Mucosal resistance to infection with lactate dehydrogenase-elevating virus (LDV) has been previously demonstrated, and the LDV system presents an important murine model for the study of mucosal barriers to viral infection. In the present study, duodenal molecules were isolated from normal mice which had potent virucidal activity, when tested against LDV as well as canine herpes, canine hepatitis, Semliki forest, and visna viruses. The virucidal activity was demonstrated to be non-immune in nature, and was present in apparently non-enzymatic protein molecules, having a molecular mass of between 10-100 kDa by membrane filtration and 10-17 kDa by gel filtration. The anti-LDV activity of these molecules was suppressed by anti-duodenum antibodies in vitro, and in vivo studies suggested a possible protective role for the anti-viral molecules. We conclude that the normal mouse duodenum contains potent virucidal molecules, which are of interest to the study of biological and molecular mechanisms of viral resistance.
Assuntos
Antivirais/farmacologia , Duodeno/química , Vírus Elevador do Lactato Desidrogenase/efeitos dos fármacos , Extratos de Tecidos/farmacologia , Animais , Feminino , Camundongos , Extratos de Tecidos/químicaRESUMO
OBJECTIVE: To investigate the possible role of the FAS -670A>G functional polymorphism in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. METHODS: A total of 2,900 SSc patients and 3,186 healthy controls were included in this study. We analyzed the genotype and allele frequencies of the FAS -670A>G polymorphism in 9 distinct ethnic cohorts, including 6 cohorts of European ancestry (a Spanish cohort of 228 SSc patients and 265 controls, a Dutch cohort of 203 SSc patients and 277 controls, a German cohort of 313 SSc patients and 247 controls, an Italian cohort of 323 SSc cases and 89 controls, a British cohort of 269 SSc patients, and a Swedish cohort of 182 patients) and 3 distinct ethnic cohorts from the US (a cohort of 1,047 white patients and 692 controls, a cohort of 159 Hispanic patients and 137 controls, and a cohort of 176 black SSc patients and 194 controls). Genotyping was performed using a TaqMan 5' allelic discrimination assay. RESULTS: In the British, Italian, and American white cohorts we observed an association of the FAS -670G allele with limited cutaneous SSc (lcSSc) (odds ratios [ORs] 1.25, 1.43, and 1.18, respectively). A meta-analysis comprising all 9 cohorts revealed an association of both the FAS -670G allele (OR 1.10) and the FAS -670GG genotype (OR 1.13) with the lcSSc phenotype. In a meta-analysis including only white subjects, both the FAS -670G allele and the FAS -670GG genotype remained associated with lcSSc (allele OR 1.12; genotype OR 1.16). In addition, a recessive model of the -670GG genotype exhibited a strong association with SSc, lcSSc, and anticentromere antibody-positive lcSSc (OR 1.23, OR 1.33, and OR 1.45, respectively). CONCLUSION: Our data show that the FAS -670A>G polymorphism plays a role in lcSSc susceptibility. A similar trend has been observed in other autoimmune diseases.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Esclerodermia Difusa/genética , Esclerodermia Limitada/genética , Receptor fas/genética , Adenosina/genética , Feminino , Genótipo , Guanosina/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Regiões Promotoras Genéticas , Esclerodermia Difusa/patologia , Esclerodermia Limitada/patologiaRESUMO
Previous work in our laboratory has shown that fetal protection from maternal transmission of the murine lactate dehydrogenase-elevating virus (LDV) infection is mediated by adoptive transfer of maternal anti-viral immunity. In the present report, we have characterized reconstitution of immunity in immunodeficient SCID mice following transplantation with BALB/c spleen cells, and studied the fate and distribution of maternally-derived antibodies after passage to neonatal SCID mice by nursing. Immune-reconstituted SCID mice maintained stable immunity for up to 7 months post-transplantation, during which time they produced nonneutralizing IgG anti-LDV antibodies and protected their offspring from maternally-derived LDV infection. Using IgG isotype and allotype assays, it was found that maternal IgG antibodies transferred from breast milk to nursing neonatal mice and appeared in their circulation. Weaning of SCID mice from immunocompetent mothers permitted the determination of blood immunoglobulin isotype half-lives (3.6-10.6 days) in the absence of endogenous antibody production. LDV infection was transferred to nursing mice by nonimmune LDV-infected mothers, but protection from nursing-acquired LDV infection was associated with maternal viral immunity, breast milk transfer of IgG anti-LDV to nursing mice, and reduced breast milk virus titers. These findings show a nursing pathway for LDV infection, and demonstrate the potential of immune protection from this infection pathway.
Assuntos
Imunoglobulina G/metabolismo , Lactação/imunologia , Animais , Animais Recém-Nascidos , Anticorpos Antivirais/sangue , Feminino , Imunização Passiva , Imunoglobulina G/sangue , Vírus Elevador do Lactato Desidrogenase , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Leite/imunologia , Gravidez , Baço/imunologia , Baço/transplante , Viroses/imunologia , Viroses/transmissãoRESUMO
Qa-1b and its human homolog, HLA-E, predominantly bind leader peptides derived from other class I molecules. Their presentation is TAP-dependent and proteasome-independent. We demonstrate that Dd targeted to the cytosol does not generate the Qa-1b peptide epitope even in the presence of lactacystin. Cells expressing herpes virus ICP-47 block the generation of this epitope, demonstrating that TAP functions in the transport of the peptide from cytosol to ER. This reveals a pathway for antigen presentation of leader peptides that involves translocation of a protein to the ER where its leader is cleaved followed by its release into the cytosol and transport back into the ER. Further, it ensures that Qa-1b expression mirrors the normal expression of class Ia molecules.