RESUMEN
BACKGROUND: Metabolic syndrome occurs more often among people living in poorer social conditions. The health status of the largest minority ethnic group in Hungary lags in many aspects behind that of the general population. METHODS: To estimate the prevalence of metabolic syndrome a screening was initiated in the city of Gyor among subjects aged 20-70 years who declared themselves as Gypsy. Subjects with known diabetes and cardiovascular disease were excluded. The diagnosis of metabolic syndrome was based on the ATP-III criteria. RESULTS: Among the 77 individuals screened (35 men, 42 women, age 46.9 ± 10.6 years, x ± SD) diabetes mellitus was found in 14 cases (18.2 %), and pre-diabetes (impaired fasting blood glucose (IFG) or impaired glucose tolerance (IGT) could be diagnosed in further 14 cases (18.2 %). Individual components of the metabolic syndrome occurred as follows: hypertension in 47 subjects (61.0 %), abnormal waist circumference in 40 individuals (51.9 %), abnormal HDL-cholesterol in 39 cases (50.6 %), abnormal triglycerides in 35 individuals (45.5 %) and abnormal fasting blood glucose in 15 subjects (19.5 %). Within the cohort metabolic syndrome could be diagnosed in 39 individuals (50.6 %) without a significant gender difference (males 20/35 = 57.1 %; women: 19/42 = 45.2 %, p>0.05). CONCLUSION: The occurrence of metabolic syndrome and that of glucose intolerance is high among adult Gypsy people in Hungary. In order to recognise cardio-metabolic risks and to prevent their cardiovascular consequences, continuous health promotion and adequate medical care should be provided for the Gypsy population in Hungary (Tab. 5, Ref. 32).
Asunto(s)
Síndrome Metabólico/etnología , Grupos Minoritarios , Romaní/estadística & datos numéricos , Adulto , Anciano , Femenino , Humanos , Hungría/epidemiología , Masculino , Síndrome Metabólico/diagnóstico , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVES: Hungary has high cardiovascular mortality. Recent studies have revealed a high prevalence of several cardiovascular risk factors, including obesity, diabetes and hypertension. The objective of this study was to assess the prevalence of the metabolic syndrome in Hungary. STUDY DESIGN: Cross-sectional study. METHODS: Within the framework of the Hungarian General Practitioners' Morbidity Sentinel Stations Programme, a random sample of 2006 individuals aged 20-69 years was selected in 2006. Physical examinations, blood sampling and data collection were performed by general practitioners. Information on environmental factors was gathered using a questionnaire. The population prevalence was estimated based on the sample frequencies. RESULTS: The overall response rate was 91%. The age-adjusted prevalence of the metabolic syndrome using the 2009 Harmonized definition was 38% [95% confidence interval (CI) 35-42%] in males and 30% (95% CI 28-33%) in females aged 20-69 years. There were no significant regional differences in the frequency figures. CONCLUSIONS: The high prevalence of the metabolic syndrome is a serious public health problem in Hungary, and remains a major determinant of the high burden of cardiovascular disease.
Asunto(s)
Síndrome Metabólico/epidemiología , Adulto , Anciano , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Femenino , Humanos , Hungría/epidemiología , Masculino , Persona de Mediana Edad , PrevalenciaRESUMEN
UNLABELLED: The prevalence rate and clinical significance of the metabolic syndrome in type 1 diabetic patients are not well established. The aim of this study was to estimate the prevalence rate of the metabolic syndrome in adult patients with type 1 diabetes. Patients with type 1 diabetes (n=533; age: 35.6+/-11.6 years; duration of diabetes: 18.0+/-11.1 years; x+/-SD) were consecutively enrolled from 11 diabetes outpatient departments. Data on medical history, actual treatment, anthropometric and laboratory parameters as well as actual blood pressure were registered while eating habits and physical activity were evaluated by standardized questionnaires. The prevalence rate of the metabolic syndrome according to the ATP-III criteria was 31.1% (29.7% in men, 32.7% in women; p>0.05). Using the IDF criteria a higher overall prevalence rate of the metabolic syndrome (36.2%; [32,8% in men, 39.4% in women; p>0.05]) was observed. Comparing type 1 diabetic patients to the general population, the prevalence rate of the metabolic syndrome proved to be significantly higher in each age-group of patients with type 1 diabetes. According to the stepwise logistic regression analysis the metabolic syndrome in type 1 diabetic patients was associated in a decreasing ranking order of significance with waist circumference, serum triglycerides, female gender, antihypertensive medication, HDL-cholesterol, diastolic blood pressure and serum creatinine. CONCLUSIONS: The metabolic syndrome can frequently be detected and is predominantly associated with higher waist circumference in adult patients with type 1 diabetes in Hungary.
Asunto(s)
Enfermedades Cardiovasculares/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Síndrome Metabólico/complicaciones , Adolescente , Adulto , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Humanos , Masculino , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Factores de RiesgoRESUMEN
A low educational level and a poor socioeconomic status could be associated with increased risk for chronic diseases. The aim of the study was to evaluate the relationship between the educational level and cardiometabolic risk in adult patients with type 1 diabetes (n = 437; age: 38.0 +/- 10.4 years, duration of diabetes: 19.2 +/- 11.1 years; x +/- SD). Educational levels were classified as low [primary school, n = 56 (12.8%)], middle [high school, n = 251 (57.4%)] or high [university, n = 130 (29.7%)]. The prevalence rate of the metabolic syndrome proved to be higher in patients with low versus high educational levels (ATP-III criteria: 42.9 vs. 21.5%, P = 0.0006). Antihypertensive treatment and cardiovascular diseases were more prevalent in patients with low versus high educational level (46.4 vs. 26.2%, P = 0.01; 12.5 vs. 2.3%, P = 0.02; respectively). Overall glycemic control was worse in patients with low versus high educational level (HbA(lc): 8.8 +/- 1.6 vs. 7.9 +/- 1.4%; P = 0.0006). Patients with low versus high educational level differed significantly regarding smoking habits (smokers: 28.6 vs. 11.6%; P = 0.01) and regular physical activity (5.4 vs. 33.1%; P = 0.0001). Higher prevalence rate of certain cardiometabolic risk factors was associated with low educational level in middle-aged type 1 diabetic patients with relatively long duration of diabetes; therefore, these patients should have priority when preventing cardiovascular complications.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/epidemiología , Escolaridad , Factores Socioeconómicos , Adulto , Edad de Inicio , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Hungría/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
The metabolic syndrome is characterised by hyperinsulinaemia (insulin resistance) leading to an increased risk of atherosclerotic cardiovascular diseases. Carotid intima-media thickness (IMT) can be easily measured to detect early atherosclerosis. In order to evaluate the clinical characteristics of the metabolic syndrome a screening procedure was performed and carotid IMT was determined by high-resolution B-mode ultrasonography in a cohort of middle-aged (40-60 years) subjects who proved to be hyperinsulinaemic [fasting plasma insulin >15 microU/ml and/or post-prandial (120 min) insulin > 45 microU/ml; n = 91; men/women: 35/56; homeostasis model assessment (HOMA)-index: 6.42 +/- 3.65; x +/- SD]. Subjects known to have diabetes were not involved. Subjects were divided into subgroups according to the stages of glucose intolerance (normal glucose tolerance, n = 46; impaired glucose tolerance, n = 26; diabetes mellitus, n = 19). As controls, age- and sex-matched non-diabetic and non-hyperinsulinaemic subjects (n = 20; HOMA-index: 2.09 +/- 0.85) were investigated. The values of IMT of the internal carotid arteries were higher in hyperinsulinaemic subjects than in controls (0.93 +/- 0.39 mm vs 0.57 +/- 0.13 mm,p < 0.001), whereas the lumen diameter proved to be smaller than in control subjects (5.04 +/- 0.75 mm vs 5.45 +/- 0.71 mm; p < 0.05). In hyperinsulinaemic subjects only a trend of increasing IMT values and that of decreasing lumen diameter of the internal carotid arteries were observed when subgroups classified according to the stages of glucose intolerance were compared. No significant changes in IMT or lumen diameter of the common carotid arteries were observed. Early and asymptomatic signs of atherosclerosis could be detected in middle-aged subjects who proved to be hyperinsulinaemic in a screening procedure. The prevention of clinically manifest cardiovascular diseases in these subjects could be of great importance.
Asunto(s)
Arteria Carótida Común/patología , Arteria Carótida Común/fisiopatología , Hiperinsulinismo/fisiopatología , Túnica Íntima/patología , Túnica Íntima/fisiopatología , Adulto , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Presión Sanguínea/fisiología , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/fisiopatología , Arteria Carótida Común/metabolismo , Estudios de Cohortes , Creatinina/sangre , Ayuno/sangre , Femenino , Humanos , Hungría/epidemiología , Hiperinsulinismo/sangre , Insulina/sangre , Resistencia a la Insulina/fisiología , Lípidos/sangre , Masculino , Persona de Mediana Edad , Estadística como Asunto , Túnica Íntima/metabolismoAsunto(s)
Escolaridad , Hiperinsulinismo/epidemiología , Síndrome Metabólico/fisiología , Índice de Masa Corporal , Análisis por Conglomerados , Femenino , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/epidemiología , Humanos , Hiperinsulinismo/sangre , Incidencia , Persona de Mediana EdadRESUMEN
Because retention of mutant alpha(1)-antitrypsin (alpha(1)-AT) Z in the endoplasmic reticulum (ER) is associated with liver disease in alpha(1)-AT-deficient individuals, the mechanism by which this aggregated glycoprotein is degraded has received considerable attention. In previous studies using stable transfected human fibroblast cell lines and a cell-free microsomal translocation system, we found evidence for involvement of the proteasome in degradation of alpha(1)-ATZ (Qu, D., Teckman, J. H., Omura, S., and Perlmutter, D. H. (1996) J. Biol. Chem. 271, 22791-22795). In more recent studies, Cabral et al. (Cabral, C. M., Choudhury, P., Liu, Y., and Sifers, R. N. (2000) J. Biol. Chem. 275, 25015-25022) found that degradation of alpha(1)-ATZ in a stable transfected murine hepatoma cell line was inhibited by tyrosine phosphatase inhibitors, but not by the proteasomal inhibitor lactacystin and concluded that the proteasome was only involved in ER degradation of alpha(1)-ATZ in nonhepatocytic cell types or in cell types with levels of alpha(1)-AT expression that are substantial lower than that which occurs in hepatocytes. To examine this important issue in further detail, in this study we established rat and murine hepatoma cell lines with constitutive and inducible expression of alpha(1)-ATZ. In each of these cell lines degradation of alpha(1)-ATZ was inhibited by lactacystin, MG132, epoxomicin, and clasto-lactacystin beta-lactone. Using the inducible expression system to regulate the relative level of alpha(1)-ATZ expression, we found that lactacystin had a similar inhibitory effect on degradation of alpha(1)-ATZ at high and low levels of alpha(1)-AT expression. Although there is substantial evidence that other mechanisms contribute to ER degradation of alpha(1)-ATZ, the data reported here indicate that the proteasome plays an important role in many cell types including hepatocytes.
Asunto(s)
Acetilcisteína/análogos & derivados , Carcinoma Hepatocelular/metabolismo , Cisteína Endopeptidasas/fisiología , Retículo Endoplásmico/metabolismo , Hepatocitos/metabolismo , Complejos Multienzimáticos/fisiología , Mutación , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Acetilcisteína/farmacología , Animales , Antibióticos Antineoplásicos/farmacología , Línea Celular , Células Cultivadas , Cisteína Endopeptidasas/metabolismo , Electroforesis en Gel de Poliacrilamida , Fibroblastos/metabolismo , Células HeLa , Humanos , Lactonas/metabolismo , Leupeptinas/farmacología , Hígado/citología , Ratones , Complejos Multienzimáticos/antagonistas & inhibidores , Complejos Multienzimáticos/metabolismo , Oligopéptidos/farmacología , Pruebas de Precipitina , Complejo de la Endopetidasa Proteasomal , Unión Proteica , Ratas , Factores de Tiempo , Transfección , Células Tumorales CultivadasRESUMEN
In order to evaluate the clinical characteristics of metabolic syndrome, a screening procedure was performed and in a cohort of middle-aged (40-60 years) hyperinsulinaemic (fasting plasma insulin > 15 microU/ml) and/or postprandial [120 min after 75 g glucose load] insulin > 45 microU/ml) subjects (n = 91; men/women: 38/53; age mean +/- SD 47.6 +/- 4.3 years; body mass index: 34.6 +/- 4.9 kg/m2; waist-hip ratio: 0.92 +/- 0.07; actual blood pressure 146 +/- 16/87 +/- 9 mmHg; fasting insulin: 24.2 +/- 11.3 microU/ml; postprandial insulin 125.5 +/- 103.8 microU/ml; serum LDL-cholesterol: 3.73 +/- 1.09 mmol/l; HDL-cholesterol: 1.12 +/- 0.30 mmol/l; triglycerides: 2.97 +/- 2.38 mmol/l; uric acid 279 +/- 79 mumol/l) plasma fasting homocysteine, vitamin B12 and folic acid levels were simultaneously determined. The values were separately evaluated according to the stages of glucose tolerance (normal glucose tolerance [n = 47]; impaired glucose tolerance [n = 24] and diabetes mellitus [n = 20]). Laboratory normal values were determined in 47 healthy subjects (control group, age: 45.0 +/- 7.8 years, men/women: 19/28). There was no significant difference between hyperinsulinaemic and control subjects regarding plasma homocysteine (9.28 +/- 3.81 mumol/l vs. 9.63 +/- 2.70 mumol/l), folic acid (8.5 +/- 5.9 ng/ml vs. 7.5 +/- 2.1 ng/ml) and vitamin B12 levels (423 +/- 141 pg/ml vs. 356 +/- 121 pg/ml). Plasma homocysteine levels were significantly (p < 0.001) higher in hyperinsulinaemic men than women (11.34 +/- 4.72 mumol/l [n = 38] vs. 7.86 +/- 2.13 mumol/l [n = 53]). There was no significant difference between subgroups classified according to the stages of glucose tolerance in hyperinsulinaemic groups. Plasma homocysteine values exceeding the upper limit of normal range (> 12.45 mumol/l) were detected at a similar prevalence rate in control (4/47 = 8.5%) and in hyperinsulinaemic subjects (10/91 = 10.9%). A weak but statistically significant correlation was found between plasma homocysteine values and age of subjects (r = 0.222; p < 0.05) whereas a stronger correlation was documented between plasma homocysteine and serum creatinine values (r = 0.658; p < 0.001) in hyperinsulinaemic groups (n = 91). Plasma homocysteine values independently from the stages of glucose tolerance are not elevated in hyperinsulinaemic subjects. Hyperhomocysteinaemia is not a characteristic feature of hyperinsulinism suggesting that plasma homocysteine levels are of no considerable importance in the complex pathomechanism of atherosclerosis at early stages of metabolic syndrome.
Asunto(s)
Homocisteína/sangre , Hiperinsulinismo/sangre , Adulto , Glucemia/metabolismo , Estudios de Cohortes , Femenino , Ácido Fólico/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factores Sexuales , Vitamina B 12/sangreAsunto(s)
Homocisteína/sangre , Hiperinsulinismo/sangre , Adulto , Femenino , Intolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Genetic deficiencies of the complement protein C3 occur naturally in humans and animal models and have been induced in mice by targeted deletion of the C3 gene. The study of these deficiencies has provided evidence for C3 functions in immune responses. C3 deficient mice were generated by replacing the 5'-flanking region of the C3 gene with the neomycin-resistance (neo) gene. Serum from these mice had no detectable C3 protein or complement activity. Challenge with Streptococcus pneumoniae revealed approximately 2000-fold increase in bacteremia as compared to littermate controls. C3 mRNA was absent in the liver, but it was detected in the lung, kidney, fat tissue, heart and spleen. Metabolic labeling of the lung tissue and peritoneal macrophages showed synthesis of pro-C3, but no post-synthetic intracellular processing of the protein and no secretion of mature C3. cDNA analysis at the cap site indicated that extrahepatic transcription of the targeted gene was initiated in the neo cassette, close to the C3/neo junction and predicted a primary translation product lacking the leader peptide. The data indicate that these mice provide a good animal model for the study of complete C3 deficiencies and a potential probe for tissue-specific C3 gene regulatory elements.
Asunto(s)
Complemento C3/deficiencia , Complemento C3/genética , Regiones Promotoras Genéticas/genética , ARN Mensajero/metabolismo , Animales , Secuencia de Bases , Northern Blotting , Cloranfenicol O-Acetiltransferasa/biosíntesis , Cloranfenicol O-Acetiltransferasa/genética , Complemento C3/biosíntesis , Complemento C3/inmunología , ADN/genética , Exones , Femenino , Eliminación de Gen , Expresión Génica , Marcación de Gen , Inmunidad Innata , Hibridación in Situ , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Especificidad de Órganos , Infecciones Neumocócicas/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Streptococcus pneumoniaeRESUMEN
Factor H, a secretory glycoprotein composed of 20 short consensus repeat modules, is an inhibitor of the complement system. Previous studies of inherited factor H deficiency revealed single amino acid substitutions at conserved cysteine residues, on one allele arginine for cysteine 518 (C518R) and on the other tyrosine for cysteine 941 (C941Y) (Ault, B. H., Schmidt, B. Z., Fowler, N. L., Kashtan, C. E., Ahmed, A. E., Vogt, B. A., and Colten, H. R. (1997) J. Biol. Chem. 272, 25168-25175). To ascertain if the phenotype, impaired secretion of factor H, is due to the C518R substitution or the C941Y substitution and to ascertain the mechanism by which secretion is impaired, we studied COS-1 and HepG2 cells transfected with wild type and several mutant factor H molecules. The results showed markedly impaired secretion of both C518R and C941Y factor H as well as that of factor H molecules bearing alanine or arginine substitutions at the Cys518-Cys546 disulfide bond (C518A, C546A, C546R, C518A-C546A). In each case, mutant factor H was retained in the endoplasmic reticulum and degraded relatively slowly as compared with most other mutant secretory and membrane proteins that are retained in the endoplasmic reticulum. These data indicate that impaired secretion of the naturally occurring C518R and C941Y mutant factor H proteins is due to disruption of framework-specific disulfide bonds in factor H short consensus repeat modules.
Asunto(s)
Factor H de Complemento/deficiencia , Disulfuros/metabolismo , Animales , Secuencia de Bases , Células COS , Línea Celular , Factor H de Complemento/genética , Factor H de Complemento/metabolismo , Cartilla de ADN , Humanos , Cinética , Mutagénesis Sitio-Dirigida , TransfecciónRESUMEN
Recently we have reported on several observations which indicate that allergen-induced complement activation contributes to the development of the symptoms of ragweed allergy. In the present paper a new finding that supports this assumption is summarized. In 48 ragweed-allergic patients individual skin reactivity to ragweed allergen extract (RWA) was assessed using dilution skin prick testing. Sera of these patients were incubated with 20, 100, and 400 U/ml RWA and generation of two complement activation products, alternative pathway C3-convertase (C3bBbP) and terminal pathway activation complex (C5b-9) was measured by ELISA methods. A strong positive correlation (Spearman correlation coefficient r = 0.495, P = 0.0004, and r = 0.454, P = 0.0012, respectively) was found between individual skin reactivity to RWA and C3bBbP generation induced by 20 and 100 A allergological units/ml (U/ml) RWA. This finding further supports the role of complement activation products in the aggravation of the basic IgE-mediated immunopathology of ragweed allergy.
Asunto(s)
Activación de Complemento , Hipersensibilidad Inmediata/inmunología , Polen/inmunología , Pruebas Cutáneas , C3 Convertasa de la Vía Alternativa del Complemento , Complemento C3b/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Humanos , Hipersensibilidad Inmediata/patología , Inmunoglobulina E/sangre , Fragmentos de Péptidos/inmunología , Poaceae/inmunologíaRESUMEN
We have previously reported a correlation between the extent of ragweed allergen (RWA)-induced in vitro serum complement activation and the symptom scores registered daily during the ragweed (RW)-blooming season in RW-allergic patients. The present study was performed in 22 15-17-year-old RW-allergic adolescents. Serum samples were incubated with 100 micrograms/ml RWA, and the generation of different complement activation products was measured by ELISA or RIA. Symptom scores were registered for 4 weeks during the RW-blooming season. The patients were divided according to the extent (low or high) of the generation of complement activation products, and symptom scores registered in the two groups were compared by two-way ANOVA. Significantly higher symptom scores were obtained in the high than in the low complement activation group (P values: 0.049 for C1rC1sC1inh, 0.022 for C3bBbP, 0.015 for C5b-9, 0.0001 for C3a, and 0.0008 for C5a). Similar results were obtained at the measurement performed in the sera obtained from the same patients half a year before the season (P values: 0.022 for C3bBbP, and 0.005 for C5b-9). These findings indicate that complement activation induced by the allergen may enhance the clinical symptoms of RW allergy.
Asunto(s)
Alérgenos/inmunología , Alérgenos/farmacología , Activación de Complemento/efectos de los fármacos , Hipersensibilidad/sangre , Hipersensibilidad/inmunología , Polen/inmunología , Adolescente , Análisis de Varianza , Complemento C3a/análisis , Complemento C3b/análisis , Complemento C5a/análisis , Complejo de Ataque a Membrana del Sistema Complemento/análisis , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Estaciones del Año , Factores de TiempoRESUMEN
To investigate the role of complement protein factor B (Bf) and alternative pathway activity in vivo, and to test the hypothesized potential genetic lethal effect of Bf deficiency, the murine Bf gene was interrupted by exchange of exon 3 through exon 7 (including the factor D cleaving site) with the neor gene. Mice heterozygous for the targeted Bf allele were interbred, yielding Bf-deficient offspring after the F1 generation at a frequency suggesting that Bf deficiency alone has no major effect on fertility or fetal development. However, in the context of one or more genes derived from the 129 mouse strain, offspring homozygous for Bf deficiency were generated at less than expected numbers (P = 0.012). Bf-deficient mice showed no gross phenotypic difference from wild-type littermates. Sera from Bf-deficient mice lacked detectable alternative complement pathway activity; purified mouse Bf overcame the deficit. Classical pathway-dependent total hemolytic activity was lower in Bf-deficient than wild-type mice, possibly reflecting loss of the alternative pathway amplification loop. Lymphoid organ structure and IgG1 antibody response to a T-dependent antigen appeared normal in Bf-deficient mice. Sensitivity to lethal endotoxic shock was not significantly altered in Bf-deficient mice. Thus, deficiency of Bf and alternative complement activation pathway led to a less dramatic phenotype than expected. Nevertheless, these mice provide an excellent model for the assessment of the role of Bf and the alternative pathway in host defense and other functions in vivo.
Asunto(s)
Activación de Complemento/fisiología , Factor B del Complemento/genética , Eliminación de Gen , Animales , Factor B del Complemento/inmunología , Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Embarazo , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: To study the mechanism of the complement-mediated antibody-dependent enhancement (C'-ADE) of HIV infection which may play a significant role in the progression of HIV-disease. METHODS: In vitro complement activating and complement-mediated HIV-infection enhancing abilities of three human anti-gp41 monoclonal antibodies (MAb) were tested. C'-ADE was estimated using HIV-1IIIB and CR2 (CD21)-carrying MT-4 target cells. Normal human serum (NHS), purified C1q, C1q-deficient (C1qD) and C2-deficient (C2D) human sera were applied as complement sources. RESULTS: All MAb mediated increased C1q binding to solid-phase gp41. All MAb had a marked dose-dependent and strictly complement-mediated HIV-infection enhancing effect. Mixtures of the MAb with purified C1q also significantly increased HIV-1 infection. C1qD serum had a markedly lower enhancing effect than NHS, which could be raised to normal level by addition of purified C1q. Pretreatment of the target cells with anti-CR2 antibodies only partially inhibited the enhancing effect of the MAb plus normal human serum. CONCLUSION: These novel findings indicate that besides the well-known facilitation of entry of HIV-1 by the interaction between virus-bound C3 fragments and CR2 present on the target cells, fixation of C1q to intact virions also results in an enhanced productive HIV-1 infection in the MT-4 cell cultures.
Asunto(s)
Complemento C1q/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp41 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Anticuerpos Monoclonales/inmunología , Complemento C1q/farmacología , Progresión de la Enfermedad , Infecciones por VIH/fisiopatología , Humanos , Células Tumorales CultivadasRESUMEN
Previous reports have defined the capacity of ragweed pollen extract (RWA) to activate human complement (C) in fluid phase through the classical pathway and have ascertained a strong correlation between the extent of complement activation and the severity of symptoms of allergic rhinoconjunctivitis during the ragweed blooming season. In the present study the complement-activating and specific IgE-binding capacities of various ragweed allergen preparations were compared. Elimination of physically adsorbed (flavonoid) pigments from the allergenic proteins had no significant effect on their complement-consuming capacity, although the process strongly diminished specific IgE binding. Removal of an IgE-binding trypsin inhibitor from RWA significantly enhanced RWA-induced complement activation, whereas it did not change IgE binding. These findings indicate that neither the physically adsorbed pigments nor the trypsin inhibitor are involved in complement activation by ragweed pollen allergens, and suggest that complement activation and specific IgE binding are distinct molecular properties of ragweed pollen allergen.
Asunto(s)
Alérgenos/inmunología , Activación de Complemento , Inmunoglobulina E/inmunología , Polen/inmunología , Complemento C3a/inmunología , Complemento C3b/inmunología , Humanos , Poaceae/inmunología , Inhibidores de Tripsina/farmacologíaRESUMEN
Ragweed allergen (RWA)-induced complement activation in sera of 40 RW allergic patients and of 40 non-allergic controls was investigated. After treatment of the sera with RWA, levels of C3a, C5a, C3bBbP, C1rC1sClinh, SC5b-9 and granulocyte-aggregating activity were determined. Concentration of RW-specific IgG was also measured. After RWA treatment dose-dependent complement activation was detected in sera of RW allergic and non-allergic persons. C3a generation was observed mostly in the sera of RW allergic individuals, while levels of C3bBbP and of RW-specific IgG were significantly higher in sera of allergics, and a strong correlation was found between these two parameters. In a prospective clinical study, a significant positive correlation was observed between the extent of RWA-induced alternative pathway (AP) activation and the severity of symptoms of allergic rhinoconjunctivitis that were developed in a 4-week period subsequent to blood sampling. These observations suggest that complement activation has a role in the development of the symptoms of RW allergy.
Asunto(s)
Activación de Complemento , Extractos Vegetales/inmunología , Rinitis Alérgica Estacional/etiología , Rinitis Alérgica Estacional/inmunología , Proteínas del Sistema Complemento/metabolismo , Humanos , Inmunoglobulina G/sangre , Rinitis Alérgica Estacional/diagnósticoRESUMEN
Previously we have investigated the interaction of human complement as well as one polyclonal and three human monoclonal antibody preparations with the human immunodeficiency virus type-1 (HIV-1) transmembrane recombinant glycoprotein (rgp41). A strong competition was found between the antibodies and deposited complement proteins for the same binding sites located within the immunodominant region of rgp41. The aim of the present experiments was to see if the same type of antibody-complement-HIV-1 interactions could be observed with the outer envelope glycoprotein (rgp120) of HIV-1. Three different glycosylated rgp120 preparations, as well as a synthetic peptide corresponding to the V3 loop of the MN strain, were adsorbed to enzyme-linked immunosorbent assay (ELISA) plates and incubated with mixtures of anti-rgp120 antibodies and normal human serum (NHS) as a complement source. Fixed complement proteins and antibodies were detected with specific, peroxidase-labelled antibodies against different complement proteins (C1q, C4b, C3b) and the gamma-chain of antibodies. In the absence of anti-rgp120, high amounts of C3 were deposited to each rgp120 preparation tested (including the V3 peptide) but significant differences in the amounts of bound C1q and C4b were observed. Using sera deficient in different complement proteins, we found that both the classical and the alternative pathways contributed to the C3 binding to rgp120. Addition of specific antibodies did not increase complement activation by rgp120 and only in the case of a monoclonal antibody to the V3-loop could we see complement-dependent inhibition of antibody binding.