RESUMO
Background and aims: Irritable Bowel Syndrome (IBS)-like symptoms are frequent following bariatric surgery. This study aims to evaluate the frequency of IBS symptoms severity before and after bariatric surgery and their association with short-chain fermentable carbohydrates (FODMAPs) consumption. Patients and methods: IBS symptoms severity in a cohort of obese patients was evaluated prospectively before, 6 and 12 months after bariatric surgery by validated questionnaires and tools (Irritable Bowel Syndrome Severity Scoring System (IBS SSS), Bristol Stool Scale (BSS), Quality of Life Short- Form-12 (SF-12), Hospital Anxiety and Depression scale (HAD)). FODMAPs consumption and its association with IBS symptom severity was evaluated by using a food frequency questionnaire focused on high-FODMAPs food consumption. Results: Fifty-one patients were included (41 female; mean age 41 years (SD: 12)), 84% received a sleeve gastrectomy, and 16% a Roux-en-Y gastric bypass. Symptoms compatible with IBS were observed in 43% of patients before surgery, in 58% of patients at 6 months and 33% at 12 months (NS, p-value=0,197 and 0,414). In a multivariate model, a significant association was found between the IBS SSS score and lactose consumption at 6 months (ß = + 58, 1; p = 0.03), and with polyols consumption at 12 months (ß = + 112,6; p = 0.01). Conclusions: Mild to moderate IBS symptoms are frequent in obese patients before bariatric surgery. A significant association between lactose and polyols consumption and IBS SSS score was observed after bariatric surgery, suggesting a potential link between the severity of IBS symptoms and some specific FODMAPs consumption.
Assuntos
Cirurgia Bariátrica , Síndrome do Intestino Irritável , Humanos , Feminino , Adulto , Síndrome do Intestino Irritável/epidemiologia , Síndrome do Intestino Irritável/etiologia , Dissacarídeos , Lactose , Estudos Prospectivos , Qualidade de Vida , Monossacarídeos , Cirurgia Bariátrica/efeitos adversos , Obesidade/epidemiologia , Obesidade/cirurgiaRESUMO
This study investigates the association of CRP (C-reactive protein) single-nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25-75) disease duration of 1 (0.6-1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25-75) disease duration of 8.9 (3.5-17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19-0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P-value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg dl(-1) when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.
Assuntos
Artrite Reumatoide/etnologia , Artrite Reumatoide/genética , Negro ou Afro-Americano/genética , Proteína C-Reativa/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico por imagem , Estudos Transversais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etiologia , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RadiografiaRESUMO
BACKGROUND: C-reactive protein (CRP) promotes tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression in vitro, and an elevated plasma CRP concentration is associated with an increased risk of vein graft (VG) thrombosis after coronary artery bypass surgery. However, little is known about the effects of CRP on VG TF and PAI-1 expression in vivo, or on VG thrombosis. OBJECTIVES: We studied transgenic (Tg) mice expressing human CRP in a VG model to explore in vivo cause-and-effect relationships between CRP and TF, PAI-1, and VG thrombosis. METHODS: Vein segments from wild-type (WT) and CRP-Tg donors were transplanted into carotid arteries of WT and CRP-Tg recipients. VGs were analyzed 1-4 weeks later. RESULTS: Human CRP accumulated in VGs during the first 4 weeks after surgery, but appeared to originate exclusively from systemic sources, rather than local production. Human CRP significantly increased TF gene expression, protein concentration and activity in VGs. Human CRP also increased PAI-1 concentrations in VGs, although only in vascular endothelial cells. Human CRP stimulated macrophage migration, invasion into VGs, and TF expression. Fibrin deposition was significantly greater in VGs of CRP-Tg mice than in WT controls. CONCLUSIONS: CRP accumulates in VGs early after surgery, originating from systemic sources rather than local synthesis. Human CRP promotes TF and PAI-1 expression in VGs, although with different expression patterns. Human CRP stimulates macrophage invasion and fibrin deposition within VGs. These results suggest that CRP induces pathologic changes in VGs that contribute to early VG occlusion.
Assuntos
Proteína C-Reativa/metabolismo , Fibrina/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Tromboplastina/metabolismo , Veias/transplante , Animais , Movimento Celular , Cloretos/química , Ponte de Artéria Coronária , Compostos Férricos/química , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Recombinantes/metabolismo , Transgenes , Trombose Venosa/sangueRESUMO
An important obstacle to achieve optimal glycaemic control in diabetics on intensive insulin therapy is the frequent occurrence of insulin induced hypoglycaemic events. In healthy subjects and in diabetics without autonomic neuropathy hypoglycaemia activates the sympathetic nervous system, resulting in epinephrine and glucagon release. Both hormones increase hepatic glucose production and this counterregulatory response is of key importance of glucose homeostasis. Recent research shed light on the fact that antecedent hypoglycaemic episodes play pivotal role in hypoglycaemia associated autonomic failure (HAAF). In this condition the sympatho-adrenal response to decreased blood glucose level is blunted. The existence of HAAF clearly indicates that the nervous system contributes to glucose homeostasis in a substantial manner. This review outlines the mechanisms of both peripheral and central neuronal glucose sensing and of neural pathways involved in the counterregulatory response.
Assuntos
Glicemia/metabolismo , Hipoglicemia/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Vias Autônomas/metabolismo , Homeostase , Humanos , Veia Porta/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
AIMS/HYPOTHESIS: Although C-reactive protein (CRP) has been implicated as a risk factor in diabetes, its pathogenic importance in diabetic kidney disease (DKD) remains unclear. The present study investigated the potential role of CRP in DKD. METHODS: Diabetes was induced by streptozotocin in human CRP transgenic and wild-type mice for assessment of kidney injury at 24 weeks by real-time PCR, immunohistochemistry and western blot analysis. In vitro, the pathogenic effect of CRP was investigated using human kidney tubular epithelial cells cultured with high glucose and/or CRP. RESULTS: We found that CRP transgenic mice developed much more severe diabetic kidney injury than wild-type mice, as indicated by a significant increase in urinary albumin excretion and kidney injury molecule-1 abundance, enhanced infiltration of macrophages and T cells, and upregulation of pro-inflammatory cytokines (IL-1ß, TNFα) and extracellular matrix (collagen I, III and IV). Enhanced renal inflammation and fibrosis in CRP transgenic mice was associated with upregulation of CRP receptor, CD32a, and over-activation of the TGF-ß/SMAD and nuclear factor κB signalling pathways. In vitro, CRP significantly upregulated pro-inflammatory cytokines (IL-1ß, TNFα, monocyte chemoattractant protein-1 [MCP-1]) and pro-fibrotic growth factors (TGF-ß1, connective tissue growth factor [CTGF]) via CD32a/64. CRP was induced by high glucose, which synergistically promoted high glucose-mediated renal inflammation and fibrosis. CONCLUSIONS/INTERPRETATION: CRP is not only a biomarker, but also a mediator in DKD. Enhanced activation of TGF-ß/SMAD and nuclear factor κB signalling pathways may be the mechanisms by which CRP promotes renal inflammation and fibrosis under diabetic conditions.
Assuntos
Proteína C-Reativa/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Animais , Western Blotting , Proteína C-Reativa/genética , Linhagem Celular , Quimiocina CCL2/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Diabetes Mellitus Tipo 1/genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Allelopathy is an untapped resource for weed control in crops that could give good possibilities for environmentally sound, integrated crop production. Allelopathy is defined as the direct or indirect harmful or beneficial effects of one plant on another through the production of chemical compounds, called allelochemicals, which escape into the environment. Allelochemicals can be produced by weeds and affect crops, and the reverse is also true. Allelopathic interactions include weed-weed, weed-crop, and crop-crop. Allelopathy offers potential for selective biological weed control for instance weed-suppressing crops and the use of plant residues in cropping systems, allelopathic rotational crops, or companion plants with allelopathic potential. Bromus species occur in many habitats in temperate regions of the world, including America, Eurasia, Australia, and Africa. The genus Lolium is one of the most important forage grasses. The weed species usually grow in the same production zones as wheat and are considered weeds since they parasitize wheat fields. Some of the weed species in these two genus have been reported to have allelopathic effect. One of the methods that has been successful in studying allelopathic activity are bioassays. Laboratory experiments were conducted to determine allelopathic effect of watery shoot extracts of four weed species of the Poaceae family, namely Bromus rigidus, Bromus diandrus, Lolium multiflorum and Lolium temulentum on germination and growth of winter wheat (Triticum aestivum L.), spring barley (Hordeum vulgare L.), corn (Zea mays L), perennial ryegrass (Lolium perenne L.), bean (Phaseolus sp.) and sunflower (Helianthus annuus L.) and on each other. The experiment was carried out during the period March 2010 to October 2010. Twenty five seeds were put into one Petri-dish on filter paper, adding 15ml of extract to each in four repeats. The germination took place in a Binder-type thermostat in the dark. The timing of germination was checked in every two days and the rate of growth was estimated after a week, by counting the number of germinated seeds and measuring the length of the radicle and plumule. The measured data was statistically analyzed and the effect of the extracts on germination percentage and seedling length was evaluated.
Assuntos
Bromus/química , Produtos Agrícolas/efeitos dos fármacos , Lolium/química , Feromônios/farmacologia , Extratos Vegetais/farmacologia , Plantas Daninhas/química , Produtos Agrícolas/crescimento & desenvolvimento , Germinação/efeitos dos fármacos , Feromônios/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Brotos de Planta/químicaRESUMO
During the past years ragweed has been coming to the forefront of interest in Hungary and in other European countries as well because its serious health risk. Results of the 5th National Weed Survey has proven that ragweed is the most important weed species on Hungarian field lands, its coverage shows a rising tendency in cereals moreover it not only occurs in cultivated plants. Allelopathic effects of aqueous extracts derived from different parts of ragweed plants (air dried leafy stems, seeds) on the germination and growth of other cultivated plants [maize (Zea mays L.), winter wheat (Triticum aestivum L.), rye (Secale cereale L.), oat (Avena sativa L.)] were studied. The extracts made for the trials were prepared with distilled water. Petri dishes were used for the germination experiments and distilled water was used as a control treatment. The seven days long experiment was carried out within a Binder-type thermostat under dark conditions. The germination percentage was checked in every two days and the growth of sprouts was evaluated after a week counting the germinated seeds and measuring the length of the radicle and plumule. The measured data were statistically analysed and the effect of extracts on germinating and length of sprouts were assessed.
Assuntos
Ambrosia/química , Produtos Agrícolas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Daninhas/química , Avena/efeitos dos fármacos , Avena/crescimento & desenvolvimento , Produtos Agrícolas/crescimento & desenvolvimento , Germinação/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Brotos de Planta/química , Secale/efeitos dos fármacos , Secale/crescimento & desenvolvimento , Sementes/química , Triticum/efeitos dos fármacos , Triticum/crescimento & desenvolvimento , Zea mays/efeitos dos fármacos , Zea mays/crescimento & desenvolvimentoRESUMO
Defects in the primary cilium/basal body complex of renal tubular cells cause polycystic kidney disease (PKD). To uncover pathways associated with disease progression, we determined the kidney transcriptome of 10-day-old severely and mildly affected cpk mice, a model of recessive PKD. In the severe phenotype, the most highly expressed genes were those associated with the innate immune response including many macrophage markers, particularly those associated with a profibrotic alternative activation pathway. Additionally, gene expression of macrophage activators was dominated by the complement system factors including the central complement component 3. Additional studies confirmed increased complement component 3 protein levels in both cystic and non-cystic epithelia in the kidneys of cpk compared to wild-type mice. We also found elevated complement component 3 activation in two other mouse-recessive models and human-recessive PKD. Our results suggest that abnormal complement component 3 activation is a key element of progression in PKD.
Assuntos
Complemento C3/genética , Imunidade Inata/genética , Rim/imunologia , Doenças Renais Policísticas/genética , Ativação Transcricional , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Ativação de Macrófagos/genética , Masculino , Camundongos , Camundongos MutantesRESUMO
OBJECTIVE: C-reactive protein (CRP) has been associated with risk of cardiovascular disease. It is not clear whether CRP is causally involved in the development of atherosclerosis. Mouse CRP is not expressed at high levels under normal conditions and increases in concentration only several-fold during an acute phase response. Because the dynamic range of human CRP is much larger, apolipoprotein E*3-Leiden (E3L) transgenic mice carrying the human CRP gene offer a unique model to study the role(s) of CRP in atherosclerosis development. METHODS AND RESULTS: Atherosclerosis development was studied in 15 male and 15 female E3L/CRP mice; E3L transgenic littermates were used as controls. The mice were fed a hypercholesterolemic diet to induce atherosclerosis development. Cholesterol exposure did not differ between E3L/CRP and E3L mice. Plasma CRP levels were on average 10.2+/-6.5 mg/L in male E3L/CRP mice, 0.2+/-0.1 mg/L in female E3L/CRP mice, and undetectable in E3L mice. Quantification of atherosclerosis showed that lesion area in E3L/CRP mice was not different from that in E3L mice. CONCLUSIONS: This study demonstrates that mildly elevated levels of CRP in plasma do not contribute to the development of early atherosclerosis in hypercholesterolemic E3L/CRP mice.
Assuntos
Apolipoproteínas E/genética , Aterosclerose/imunologia , Aterosclerose/metabolismo , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Animais , Apolipoproteína E3 , Apolipoproteínas E/metabolismo , Aterosclerose/epidemiologia , Aterosclerose/patologia , Biomarcadores/metabolismo , Peso Corporal , Proteína C-Reativa/imunologia , Colesterol/sangue , Diagnóstico Precoce , Ingestão de Alimentos , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Humanos , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/imunologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Masculino , Camundongos , Camundongos Transgênicos , Monócitos/patologia , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
To investigate whether functional polymorphisms exist in the C-reactive protein (CRP) gene, i.e., ones that contribute directly to differences in baseline CRP among individuals, we sequenced a 1,156-nucleotide-long stretch of the CRP gene promoter in 287 ostensibly healthy people. We identified two single-nucleotide polymorphisms (SNPs), a bi-allelic one at nucleotide -409 (G-->A), and a tri-allelic one at -390 (C-->T-->A), both resident within the hexameric core of transcription factor binding E-box elements. Electrophoretic mobility shift assays confirmed that the SNP within the sequence (-412)CACGTG(-407) (E-box 1) modulates transcription factor binding, and that the one within (-394)CACTTG(-389) (E-box 2) supports transcription factor binding only when the -390 T allele is present. The commonest of four E-box 1/E-box 2 haplotypes (-409G/-390T) identified in the population supported highest promoter activity in luciferase reporter assays, and the rarest one (-409A/-390T) supported the least. Importantly, serum CRP in people with these haplotypes reproduced this rank order, i.e., people with the -409G/-390T haplotype had the highest baseline serum CRP (mean +/- SEM 10.9 +/- 2.25 microg/ml) and people with the -409A/-390T haplotype had the lowest (5.01 +/- 1.56 microg/ml). Furthermore, haplotype-associated differences in baseline CRP were not due to differences in age, sex, or race, and were still apparent in people with no history of smoking. At least two other SNPs in the CRP promoter lie within E-box elements (-198 C-->T, E-box 4, and -861 T-->C, E-box 3), indicating that not only is the quality of E-box sites in CRP a major determinant of baseline CRP level, but also that the number of E-boxes may be important. These data confirm that the CRP promoter does encode functional polymorphisms, which should be considered when baseline CRP is being used as an indicator of clinical outcome. Ultimately, development of genetic tests to screen for CRP expression variants could allow categorization of healthy people into groups at high versus low future risk of inflammatory disease.
Assuntos
Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Soro/química , Fatores de Transcrição/metabolismo , Adulto , Negro ou Afro-Americano/genética , Alelos , Proteína C-Reativa/química , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Regulação da Expressão Gênica/genética , Frequência do Gene , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , População Branca/genéticaRESUMO
OBJECTIVES: To determine if a polymorphic GTn repeat in the intron of the C-reactive protein (CRP) gene associates with occurrence of vascular arterial events in systemic lupus erythematosus (SLE). METHODS: We performed a nested case-control study on the LUMINA cohort of 546 Hispanic, African-American and Caucasian SLE patients. Twenty-five patients who developed vascular arterial events (i.e. myocardial infarction, angina, coronary artery bypass graft surgery, stroke, claudication, gangrene or significant tissue loss and/or arterial peripheral thrombosis) after enrolment were selected as cases and 32 ethnically matched patients with no previous vascular arterial events served as controls. Their CRP gene GTn polymorphism and plasma CRP was determined. RESULTS: Patients with vascular events had more severe SLE and were more likely to have plasma CRP in the highest quintile of measured values. The overall distribution of GTn alleles for patients with vascular events had a greater number of the GT20 variant compared with controls [26.0% of alleles (13/50) vs 15.6% (10/64)]. This greater number of GT20 in patients with vascular events was observed for African-Americans [29.2% (7/24) vs 21.0% (8/38)] and Hispanics [33.0% (4/12) vs 0% (0/16)] but not for Caucasians [14.3% (2/14) vs 20.0% (2/10)]. For African-Americans and Hispanics combined (45 patients), the frequency of GT20 in those with vascular events (30.6%, 11/36) was significantly higher than in those without them (14.8%, 8/54) (P<0.05, one-tailed test for difference in proportions). When patients were categorized according to the number of GT20 alleles they carried (thus GT20/GT20, GT20/GTx or GTx/GTx, where x is any allele other than GT20), for both African-Americans and Hispanics the likelihood of vascular arterial events increased in proportion with the GT20 dose, and all GT20-homozygous patients developed vascular arterial events. CONCLUSIONS: The CRP GT20 variant is more likely to occur in African-American and Hispanic SLE patients than in Caucasian ones, and SLE patients carrying the GT20 allele are more likely to develop vascular arterial events.
Assuntos
Proteína C-Reativa/genética , Doenças Cardiovasculares/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Adulto , Negro ou Afro-Americano , Proteína C-Reativa/análise , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Hispânico ou Latino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , População BrancaRESUMO
The effect of complement on transgene expression was evaluated in vivo and in vitro using mice lacking complement components. Complement component 3 (C3) deficient mice (C3-/-) and appropriate wild-type controls were intravenously injected with a replication incompetent, luciferase-expressing normal Ad5 (Ad5Luc1), or fibritin-fiber Ad5 (Ad5FFLuc1). Repeated, noninvasive bioluminescence imaging was conducted over 35 days. Our data show for the first time that C3 facilitates both short- and long-term hepatic expression of luciferase following systemic delivery. C3-/- mice showed significantly less (P < 0.05) luciferase expression in their liver than treatment-matched wild-type mice when 2.3 x 10(9) (Ad5Luc1) and 4.0 x 10(9) (Ad5Luc1 or Ad5FFLuc1) viral particles (v.p.) were infused. The maximal difference in luciferase activity between C3-/- and wild-type mice was 99-fold difference at 3 days for the 2.3 x 10(9) v.p. dose (Ad5Luc1), 35-fold at 13 days for the 4.0 x 10(9) v.p. dose (Ad5Luc1), and 22-fold at 13 days for the 4.0 x 10(9) v.p. dose (Ad5FFLuc1). Preincubation of Ad5Luc1 with wild-type, C1q-/-, or factor B (FB) deficient mouse sera for 5 min significantly (P < 0.05) increased transduction of mouse liver cells, as compared to preincubation with C3-/- sera or PBS. These results suggest the classical or alternate complement pathway enhances Ad5-mediated liver transduction.
Assuntos
Adenoviridae/genética , Complemento C3/fisiologia , Vetores Genéticos/administração & dosagem , Fígado/imunologia , Transdução Genética/métodos , Animais , Complemento C3/genética , Expressão Gênica , Vetores Genéticos/genética , Injeções Intravenosas , Fígado/enzimologia , Luciferases/genética , Medições Luminescentes , Camundongos , Camundongos Knockout , Fatores de Tempo , TransgenesRESUMO
Elevation of baseline C-reactive protein (CRP) is associated with increased risk of cardiac disease. This increase might reflect low-grade inflammation, but differences in CRP serum levels might also have a genetic component. To test this possibility, we investigated whether a polymorphic GT-repeat in the intron of the CRP gene contributes to variation in baseline CRP. We found that the polymorphism was associated with differences in baseline CRP in both normal individuals and in patients with the inflammatory disease systemic lupus erythematosus, viz. donors carrying two GT(16) alleles, two GT(21)alleles, or GT(16/21) heterozygotes had two-fold lower serum CRP than those with other genotypes. The frequency of GT(16) and GT(21) was two-fold higher in Caucasians than in African-Americans, but there was no difference in allele distribution between patients and controls. It is not yet known how this genetic polymorphism mediates its effect on CRP expression, and it probably is not a systemic lupus erythematosus susceptibility factor. Rather, the CRP intron polymorphism likely modifies the disease phenotype. On the other hand, the fact that baseline CRP does have a genetic component suggests that in coronary disease, stratification of risk assessment based on CRP levels might be enhanced by consideration of this polymorphism.
Assuntos
Proteína C-Reativa/análise , Proteína C-Reativa/genética , Íntrons , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Adulto , Fatores Etários , Alelos , Asiático/genética , Sequência de Bases , População Negra/genética , Feminino , Dosagem de Genes , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Indígenas Norte-Americanos/genética , Lúpus Eritematoso Sistêmico/sangue , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Sequências Repetitivas de Ácido Nucleico , População Branca/genéticaRESUMO
The exact mechanisms leading to CNS inflammation and myelin destruction in multiple sclerosis and in its animal model, experimental allergic encephalomyelitis (EAE) remain equivocal. In both multiple sclerosis and EAE, complement activation is thought to play a pivotal role by recruiting inflammatory cells, increasing myelin phagocytosis by macrophages, and exerting direct cytotoxic effects through the deposition of the membrane attack complex on oligodendrocytes. Despite this assumption, attempts to evaluate complement's contribution to autoimmune demyelination in vivo have been limited by the lack of nontoxic and/or nonimmunogenic complement inhibitors. In this report, we used mice deficient in either C3 or factor B to clarify the role of the complement system in an Ab-independent model of EAE. Both types of complement-deficient mice presented with a markedly reduced disease severity. Although induction of EAE led to inflammatory changes in the meninges and perivascular spaces of both wild-type and complement-deficient animals, in both C3(-/-) and factor B(-/-) mice there was little infiltration of the parenchyma by macrophages and T cells. In addition, compared with their wild-type littermates, the CNS of both C3(-/-) and factor B(-/-) mice induced for EAE are protected from demyelination. These results suggest that complement might be a target for the therapeutic treatment of inflammatory demyelinating diseases of the CNS.
Assuntos
Complemento C3/deficiência , Complemento C3/genética , Fator B do Complemento/deficiência , Fator B do Complemento/genética , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/genética , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Animais , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Imuno-Histoquímica , Incidência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medula Espinal/patologia , Medula Espinal/ultraestruturaRESUMO
C-reactive protein (CRP) is an acute-phase protein with a well-known association with infection and other inflammatory conditions. We have shown that expression of human CRP by CRP transgenic (CRPtg) mice is protective against lethal infection by Streptococcus pneumoniae, an effect likely mediated by CRP's ability to bind to this gram-positive pathogen. In the present study we tested whether CRPtg mice are resistant to infection with Salmonella enterica serovar Typhimurium, a gram-negative pathogen that causes the murine equivalent of typhoid fever. CRPtg mice experimentally infected with a virulent Typhimurium strain lived longer and had significantly lower mortality than their non-tg littermates. The greater resistance of CRPtg mice could be attributed to significantly increased early (0 to 4 h) blood clearance of salmonellae and significantly decreased numbers of bacteria in the liver and spleen on day 7 postinfection. In addition, 14 days after infection with an avirulent Salmonella strain, the serum titer of anti-Salmonella immunoglobulin G antibodies was higher in CRPtg than non-tg mice. This study provides unequivocal evidence that CRP plays an important role in vivo in host defense against salmonellae during the early stages of infection. In addition, as the beneficial effect of CRP includes enhancement of the host's humoral immune response, CRP may also contribute indirectly to host defense during later stages of infection.
Assuntos
Proteína C-Reativa/imunologia , Salmonelose Animal/imunologia , Salmonella typhimurium/imunologia , Animais , Anticorpos Antibacterianos/sangue , Bacteriemia/microbiologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Humanos , Fígado/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Salmonelose Animal/microbiologia , Salmonelose Animal/mortalidade , Salmonella typhimurium/isolamento & purificação , Baço/microbiologia , TransgenesRESUMO
The acute-phase response (APR) is regulated by TNF-alpha, IL-1beta, and IL-6 acting alone, in combination, or in concert with hormones. The anaphylotoxin C5a, generated during complement activation, induces in vitro the synthesis of these cytokines by leukocytes and of acute-phase proteins by HepG2 cells. However, there is no clear evidence for a role of C5a or any other complement activation product in regulation of the APR in vivo. In this study, using human C-reactive protein (CRP) transgenic mice deficient in C3 or C5, we investigated whether complement activation contributes to induction of the acute-phase proteins CRP and serum amyloid P-component (SAP). Absence of C3 or C5 resulted in decreased LPS-induced up-regulation of the CRP transgene and the mouse SAP gene. Also, LPS induced both the IL-1beta and IL-6 genes in normocomplementemic mice, but in complement-deficient mice it significantly induced only IL-6. Like LPS injection, activation of complement by cobra venom factor led to significant elevation of serum CRP and SAP in normocomplementemic mice but not in complement-deficient mice. Injection of recombinant human C5a into human CRP transgenic mice induced the IL-1beta gene and caused significant elevation of both serum CRP and SAP. However, in human CRP transgenic IL-6-deficient mice, recombinant human C5a did not induce the CRP nor the SAP gene. Based on these data, we conclude that during the APR, C5a generated as a consequence of complement activation acts in concert with IL-6 and/or IL-1beta to promote up-regulation of the CRP and SAP genes.
Assuntos
Reação de Fase Aguda/imunologia , Proteína C-Reativa/biossíntese , Proteínas do Sistema Complemento/fisiologia , Componente Amiloide P Sérico/biossíntese , Reação de Fase Aguda/genética , Animais , Proteína C-Reativa/genética , Ativação do Complemento , Complemento C5a/administração & dosagem , Proteínas Inativadoras do Complemento/administração & dosagem , Proteínas do Sistema Complemento/deficiência , Relação Dose-Resposta Imunológica , Venenos Elapídicos/administração & dosagem , Regulação da Expressão Gênica/imunologia , Humanos , Injeções Intraperitoneais , Interleucina-1/fisiologia , Interleucina-6/fisiologia , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Camundongos Transgênicos , Componente Amiloide P Sérico/genética , Transgenes/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.
Assuntos
Reação de Arthus/imunologia , Proteínas do Sistema Complemento/fisiologia , Tiofenos/farmacologia , Animais , Reação de Arthus/patologia , Reação de Arthus/prevenção & controle , Ativação do Complemento/efeitos dos fármacos , Proteínas Inativadoras do Complemento 1/farmacologia , Fator D do Complemento/antagonistas & inibidores , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Relação Dose-Resposta Imunológica , Cobaias , Humanos , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacologia , Especificidade da EspécieRESUMO
Pneumococcal surface protein A (PspA) is a surface-exposed protein virulence factor for Streptococcus pneumoniae. In this study, no significant depletion of serum complement was observed for the serum of mice infected with pneumococci that express PspA. In contrast, in mice infected with an isogenic strain of pneumococci lacking PspA, significant activation of serum complement was detected within 30 min after infection. Also, the PspA-deficient strain but not the PspA-expressing strain was cleared from the blood within 6 h. The contribution of PspA to pneumococcal virulence was further investigated by using mice deficient for C5, C3, or factor B. In mice deficient for C3 or factor B, PspA-negative pneumococci became fully virulent. In contrast, in C5-deficient mice as in wild-type mice, PspA-deficient pneumococci were avirulent. These in vivo data suggest that, in nonimmune mice infected with pneumococci, PspA interferes with complement-dependent host defense mechanisms mediated by factor B. Immunoblots of pneumococci opsonized in vitro suggested that more C3b was deposited on PspA-negative than on PspA-positive pneumococci. This was observed with and without anticapsular antibody. Furthermore, processing of the alpha chain of C3b was reduced in the presence of PspA. We propose that PspA exerts its virulence function by interfering with deposition of C3b onto pneumococci and/or by inhibiting formation of a fully functional alternative pathway C3 convertase. By blocking recruitment of the alternative pathway, PspA reduces the amount of C3b deposited onto pneumococci, thereby reducing the effectiveness of complement receptor-mediated pathways of clearance.