RESUMO
BACKGROUND: Plasmodium falciparum-infected erythrocytes bind to specific endothelial cell receptors via members of the PfEMP1 family exported onto the erythrocyte surface. These interactions are mediated by different types of cysteine-rich interdomain region (CIDR) domains found in the N-terminal region of all PfEMP1. CIDRα1 domains bind endothelial protein C receptor (EPCR), CIDRα2-6 domains bind CD36, whereas the receptor specificity of CIDRß/γ/δ domains is unknown. METHODS: In this study, we investigated the level of immunoglobulin (Ig)G targeting the different types of PfEMP1 CIDR during the first year of life. We used plasma collected longitudinally from children of pregnant women who had been followed closely through pregnancy. RESULTS: Antibodies to CIDRα1 domains were more frequent in cord blood compared with antibodies to CIDRα2-6 domains. Higher IgG levels to EPCR-binding CIDRα1 variants positively correlated with the timing of first infections. Antibodies to all PfEMP1 types declined at similar rates to the point of disappearance over the first 6 months of life. At 12 months, children had acquired antibody to all types of CIDR domains, mostly in children with documented P falciparum infections. CONCLUSIONS: These observations agree with the notion that the timing and phenotype of first P falciparum infections in life are influenced by the immune status of the mother.
Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Proteínas de Protozoários/imunologia , Adulto , Anticorpos Antiprotozoários/imunologia , Benin , Eritrócitos/parasitologia , Feminino , Seguimentos , Humanos , Imunidade Materno-Adquirida , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , Idade Materna , Gravidez , Complicações Parasitárias na Gravidez/sangue , Complicações Parasitárias na Gravidez/parasitologia , Domínios Proteicos/imunologiaRESUMO
APOE É4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE É4+ (10 352 cases and 9207 controls) and APOE É4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE É4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE É4+: 1250 cases and 536 controls; APOE É4-: 718 cases and 1699 controls). Among APOE É4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE É4+ subjects (CR1 and CLU) or APOE É4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE É4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
Assuntos
Doença de Alzheimer/genética , Polimorfismo de Nucleotídeo Único , Apolipoproteína E4/genética , Cromossomos Humanos Par 17 , Estudo de Associação Genômica Ampla , Humanos , Proteínas tau/genéticaRESUMO
In epidemiological cohorts, there is an increased interest for the implementation of biobanks. The potential role of biological determinants of diseases needs to be investigated before the onset of the event of interest in order to limit the problems encountered when examining biological determinants in classical case-control studies. Biobank is now a very sophisticated system that consists of a programmed storage of biological material and related data. Our aim in this paper is to document how biobank constitution is useful for studying biological determinants of aging and to give some indications on methodological issues that can be helpful to optimize the constitution and use of biobanks in aging cohorts. Optimization of sampling through two-phase designs (nested case control or case-cohort studies) allows better efficiency. These elements are, for most of them, not specific to aging populations but are useful more generally for the epidemiology of chronic diseases. Our purpose will be illustrated with some examples and results obtained in an ongoing aging cohort, the Three-City Study.
Assuntos
Envelhecimento , Bases de Dados Factuais , Demência/epidemiologia , Métodos Epidemiológicos , Bancos de Tecidos , Doenças Vasculares/epidemiologia , Distribuição por Idade , Pesquisa Biomédica/métodos , Estudos de Coortes , Comorbidade , Mineração de Dados/métodos , Demência/diagnóstico , Feminino , França/epidemiologia , Humanos , Masculino , Prevalência , Medição de Risco/métodos , Doenças Vasculares/diagnósticoRESUMO
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Assuntos
Doença de Alzheimer/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Predisposição Genética para Doença/genética , Hereditariedade/genética , Fatores Etários , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Feminino , França/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Several lines of evidence indicate that a decrease in the CSF concentration of amyloid beta(42) (Abeta(42)) is a potential biomarker for incident Alzheimer disease. In contrast, studies on plasma Abeta(1-40) and Abeta(1-42) peptide levels have yielded contradictory results. Here, we explored the links between incident dementia and plasma Abeta(1-40) and Abeta(1-42) peptide concentrations in the prospective, population-based Three-City (3C) Study. We also assessed the association between plasma concentrations of truncated Abeta (Abeta(n-40) and Abeta(n-42)) and the risk of dementia. METHODS: During a subsequent 4-year follow-up period, 257 individuals presented incident dementia from 8,414 participants, and a subcohort of 1,185 individuals without dementia was drawn as a control cohort. Plasma levels of Abeta(1-40), Abeta(1-42), Abeta(n-40), and Abeta(n-42) were measured using an xMAP-based assay technology. The association between plasma Abeta peptide levels and the risk of dementia was assessed using Cox proportional hazard models. RESULTS: Of the various Abeta variables analyzed, the Abeta(1-42)/Abeta(1-40) and Abeta(n-42)/Abeta(n-40) ratios presented the strongest association with the risk of dementia: people with a high Abeta(1-42)/Abeta(1-40) or Abeta(n-42)/Abeta(n-40) ratio had a lower risk of developing dementia. These associations were restricted to individuals diagnosed at 2 years of follow-up and the Abeta(n-42)/Abeta(n-40) ratio was mainly associated with the risk of mixed/vascular dementia. CONCLUSION: Plasma Abeta peptide concentrations and Abeta(1-42)/Abeta(1-40) and Abeta(n-42)/Abeta(n-40) ratios may be useful markers to indicate individuals susceptible to short-term risk of dementia.
Assuntos
Peptídeos beta-Amiloides/sangue , Demência/sangue , Fragmentos de Peptídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Demência/diagnóstico , Feminino , França , Humanos , Masculino , Estudos Prospectivos , Kit de Reagentes para DiagnósticoRESUMO
In tropical countries, malaria and hypertension are common diseases of pregnancy. They have physiopathologic similarities such as placental ischemia, endothelial dysfunction, and production of proinflammatory cytokines. Recent findings suggested their possible link. The authors conducted a case-control study to explore the relation between malaria and hypertension at Guediawaye, a hypoendemic malarial setting in Senegal. Cases were pregnant women admitted to the delivery unit for hypertension. Controls were pregnant women admitted for normal delivery, without any history of hypertension or proteinuria during the present pregnancy. Malarial infection was determined by placental tissue examination. From January to December 2002, 77 cases of gestational hypertension, 113 cases of preeclampsia, 59 cases of eclampsia, and 241 controls were enrolled. Placental malarial infection (PMI) was present in 14 cases (6.3%) and in 15 controls (6.2%). The prevalence of PMI was 4.6% for eclampsia, 4.0% for preeclampsia, and 11.6% for gestational hypertension. In multivariate analysis, PMI appeared to be an independent risk factor for gestational hypertension (adjusted odds ratio = 2.7, 95% confidence interval: 1.0, 7.6). The authors found an association between PMI and nonproteinuric hypertension in women living in a malaria-hypoendemic area. The exact significance of such relation should be clarified in further studies in different settings of malarial endemicity.
Assuntos
Doenças Endêmicas , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/parasitologia , Malária/epidemiologia , Doenças Placentárias/epidemiologia , Doenças Placentárias/parasitologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão Induzida pela Gravidez/patologia , Análise por Pareamento , Pessoa de Meia-Idade , Análise Multivariada , Doenças Placentárias/patologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/parasitologia , Gravidez , Fatores de Risco , Senegal/epidemiologiaRESUMO
The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE epsilon 4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE epsilon 4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the A beta(40) peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Interleucinas/genética , Interleucinas/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Apolipoproteína E4/genética , Encéfalo/metabolismo , Células COS , Estudos de Casos e Controles , Linhagem Celular Transformada , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/metabolismo , Angiopatia Amiloide Cerebral/patologia , Chlorocebus aethiops , Feminino , Seguimentos , Carga Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Interleucina-33 , Cooperação Internacional , Masculino , Neuroblastoma , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fragmentos de Peptídeos/metabolismo , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Transfecção/métodosRESUMO
BACKGROUND: Pregnancy-associated malaria (PAM) is precipitated by the accumulation of parasites in the placental intervillous spaces and causes maternal anemia and low birth weight. In PAM, placental parasites adhere to chondroitin sulfate A (CSA) through a unique set of variant surface antigens (VSAPAM). Several studies have shown that 1 var gene, var2csa, is transcribed at high levels and expressed in CSA-binding Plasmodium falciparum parasites. METHODS: Plasma levels of anti-VAR2CSA immunoglobulin G (IgG) in Senegalese women were measured during pregnancy by enzyme-linked immunosorbent assay, using 3 recombinant proteins representing 3 domains of the var2csa gene product. RESULTS: The 3 recombinant proteins were specifically recognized by plasma from pregnant women but not by control plasma. A parity-dependent recognition pattern was observed with 2 of the 3 VAR2CSA antigens. A kinetic study demonstrated that a single P. falciparum infection was able to trigger a VAR2CSA-specific antibody response. Among women with infected placentas, women with high anti-VAR2CSA IgG levels at enrollment were more likely to present with a past infection than with an acute/chronic infection. CONCLUSIONS: Anti-VAR2CSA IgGs are involved in clinical protection against pregnancy-associated malaria and strengthens the hope for making a VAR2CSA-based vaccine.
Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Imunoglobulina G/sangue , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Adolescente , Adulto , Animais , Antígenos de Protozoários/química , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Placenta/parasitologia , Plasmodium falciparum/metabolismo , Gravidez , Estrutura Terciária de Proteína , Proteínas Recombinantes , SenegalRESUMO
OBJECTIVE: To examine the association of plasma cholesterol levels, lipid-lowering agent (LLA) intake, and APOE genotype with dementia prevalence. METHODS: The Three-City Study is a population-based cohort of 9,294 subjects selected from the electoral rolls of three French cities (Bordeaux, Dijon, Montpellier). Baseline examination included extensive assessment of exposure to vascular risk factors (including cholesterol levels and LLA use [statin or fibrate]) and clinical diagnosis of dementia. RESULTS: Two percent of participants were demented at baseline. Overall 32.4% of participants had hyperlipidemia, and 15.6% were prescribed statins and 13.7% fibrates. After adjusting for age, gender, education level, and study center, the odds ratio (OR) for dementia was observed to be lower among LLA users (OR = 0.61, 95% CI = 0.41 to 0.91) compared with subjects taking no LLAs. There was no differential effect between statin and fibrate users. The odds for dementia were increased in subjects with hyperlipidemia (OR = 1.43, 95% CI = 1.03 to 1.99). Further adjustment for potential confounders did not modify these associations. In addition, the association between LLA intake and dementia was not modified by APOE genotype, whereas hyperlipidemia was significantly associated with increased dementia prevalence only in non-epsilon4 carriers and non-Alzheimer disease cases. Finally, in participants taking LLAs, the odds for dementia were decreased only in those having normal lipid levels. CONCLUSIONS: This observational study provides further evidence that lipid-lowering agents are associated with decreased risk of dementia, whereas hyperlipidemia is associated with increased odds for non-Alzheimer-disease-type dementia. These effects appear to be independent of all major potential confounders.
Assuntos
Apolipoproteínas E/genética , Colesterol/sangue , Demência/genética , Hiperlipidemias/genética , Hipolipemiantes/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4 , Causalidade , Ácido Clofíbrico/uso terapêutico , Estudos de Coortes , Estudos Transversais , Demência/sangue , Demência/epidemiologia , Feminino , França/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos , Genótipo , Inquéritos Epidemiológicos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/epidemiologia , Masculino , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
In utero transmission of HIV-1 has been demonstrated and may account for around 10-20% of all materno-fetal HIV-1 transmission. The possible routes for such transmission are transannexial or transplacental. In both cases, the microenvironment (cytokines and chemokines) at the placental interface could be an important regulatory factor in viral transmission. We therefore performed explant cultures of placental villi, and isolated purified trophoblasts, from term placentae obtained from HIV-1-seropositive and HIV-1-seronegative women in order to assess and compare the cytokine and chemokine secretion profiles using ELISA and semiquantitative RT-PCR. No major differences could be seen in the secretions of cytokines and chemokines at the level of whole placental tissue in HIV-1-positive and HIV-1-negative women. However, variations were observed in the expression of inflammatory cytokines and chemokines from trophoblastic cells, depending on the status of HIV-1 infection of the mothers but not the babies, all of which remained uninfected. The significance of these data is discussed.
Assuntos
Citocinas/biossíntese , Infecções por HIV/imunologia , HIV-1 , Placenta/imunologia , Complicações Infecciosas na Gravidez/imunologia , Trofoblastos/imunologia , Feminino , Infecções por HIV/transmissão , Soronegatividade para HIV , Humanos , Transmissão Vertical de Doenças Infecciosas , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologiaRESUMO
Otherwise clinically immune women in areas endemic for malaria are highly susceptible to Plasmodium falciparum malaria during their first pregnancy. Pregnancy-associated malaria (PAM) is characterized by placental accumulation of infected erythrocytes that adhere to chondroitin sulfate A (CSA). Susceptibility to PAM decreases with increasing parity, apparently due to acquisition of antibodies directed against the variant surface antigens (VSAs) that mediate the adhesion to CSA (VSA(CSA)). This study found that levels of VSA(CSA)-specific antibodies depend on endemicity, that anti-VSA(CSA) IgG is acquired during gestation week 20, and that plasma levels of the antibodies decline during the postpartum period. There is evidence that VSA(CSA)-specific antibodies are linked to placental infection and that high antibody levels contribute to the control of placental infection by inhibiting parasite adhesion to CSA. Data suggest that VSA(CSA) is a target for vaccination against PAM.
Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Eritrócitos/parasitologia , Malária Falciparum/imunologia , Doenças Placentárias/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Animais , Antimaláricos/uso terapêutico , Adesão Celular , Cloroquina/uso terapêutico , Sulfatos de Condroitina/metabolismo , Eritrócitos/fisiologia , Feminino , Humanos , Malária Falciparum/parasitologia , Parasitemia/imunologia , Parasitemia/parasitologia , Parasitemia/prevenção & controle , Doenças Placentárias/parasitologia , Doenças Placentárias/prevenção & controle , Gravidez , Complicações Parasitárias na Gravidez/parasitologiaRESUMO
During pregnancy, a local and systemic Th2 bias of maternal immunity favors Th1-dependent infections such as malaria. This study measured cytokines secreted in cultures of chorionic villi, placental blood cells (PBC), and serum in term placentas from 88 malaria-infected and -noninfected Cameroon women. Interleukin (IL)--2 and --4 were consistently low; IL-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)--beta 2 were highest in villi cultures. Tumor necrosis factor (TNF)--alpha, interferon (IFN)--gamma, and IL-10 were highest in PBC cultures. Malaria placental infection increased Th1-type cytokines, whereas Th2-type cytokines and TGF-beta 2 were unchanged. Addition of lipopolysaccharide or infected erythrocytes to cultures increased TNF-alpha, IL-1 beta, IL-6, and IL-10 secretions but not those of IFN-gamma and IL-4. Overall, Plasmodium falciparum induced a placental immune response involving both Th1- and Th2-type cell activation. Although the Th1 pathway was favored, IL-10 secretion was also increased, and this increase should be effective in protecting the placenta by controlling the negative effects of Th1 cytokines on pregnancy.
Assuntos
Malária Falciparum/imunologia , Placenta/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Células Cultivadas , Vilosidades Coriônicas/imunologia , Citocinas/biossíntese , Feminino , Humanos , GravidezRESUMO
In Plasmodium falciparum-parasitized pregnant women, erythrocytes infected by mature stages of the parasite sequester into placental intervillous spaces. The presence of parasites in the placenta causes maternal anaemia and low birth weight of the infant. In-vitro studies suggest placental sequestration may involve the cytoadherence of infected erythrocytes to chondroitin sulphate A (CSA) and/or intercellular adhesion molecule 1 (ICAM-1) expressed by human placental syncytiotrophoblast. We identified P. falciparum receptors expressed on the surface of human syncytiotrophoblast using immunofluorescence of placental biopsies from Cameroon, a malaria-endemic area. In all placentas, a strongly positive staining was observed on the syncytiotrophoblast for CSA, but not for ICAM-1, vascular endothelium cell adhesion molecule-1, E-selectin, nor CD36. The cytoadherence ability of parasites from pregnant women and nonpregnant subjects was assessed on in-vitro cultured syncytiotrophoblast. Parasites from pregnant women bound to the trophoblast via CSA but not ICAM-1. Parasites from nonpregnant hosts either did not bind to the trophoblast culture or bound using ICAM-1. Our data support the idea that placental sequestration may result from cytoadherence to placental trophoblast and that pregnant women are parasitized by parasites that differ from parasites derived from nonpregnant host by their cytoadherence ability.
Assuntos
Placenta/imunologia , Placenta/parasitologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Complicações Parasitárias na Gravidez/parasitologia , Animais , Antígenos CD36/metabolismo , Adesão Celular/imunologia , Sulfatos de Condroitina/imunologia , Selectina E/metabolismo , Eritrócitos/imunologia , Eritrócitos/parasitologia , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Molécula 1 de Adesão Intercelular/imunologia , Parasitemia/imunologia , Parasitemia/parasitologia , Plasmodium falciparum/patogenicidade , Gravidez , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Two populations of schoolchildren from Gabon and Cameroon were tested in 1995 for their immunological reactivity to synthetic peptides (LSA-Rep, LSA-J and LSA-CTL) from Plasmodium falciparum liver stage antigen-1 (LSA-1). The prevalence and levels of both cellular (lymphocyte proliferation, tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma), and interleukin-10 (IL-10)) and humoral (immunoglobulin G) responses were determined. Protection from clinical malaria, determined after a prospective 1 year study in both sites, was associated with elevated proliferative responses to LSA-Rep and LSA-CTL in the Gabonese children, as well as with higher antibody levels to both schizont extract and LSA-Rep. The prevalence of peptide-stimulated TNF-alpha secretion was higher in the Cameroonian group, but higher levels of antibodies to LSA-Rep and LSA-J were found in the Gabonese children. The immunological differences observed between children in the 2 study sites are discussed in the context of both epidemiological and individual host factors.
Assuntos
Antígenos de Protozoários/imunologia , Hepatopatias Parasitárias/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Animais , Formação de Anticorpos , Camarões , Criança , Estudos de Coortes , Citocinas/imunologia , Feminino , Gabão , Humanos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , MasculinoRESUMO
We performed ex vivo experiments with Plasmodium falciparum-infected human placentas from primi- and multigravida women from Cameroon. All women, independent of their gravida status, had anti-chondroitin sulfate A (CSA) adhesion antibodies which cross-reacted with heterologous strains, such as FCR3 and Palo-Alto(FUP)1, which were selected for CSA binding. These antibodies, directed against the surface of infected erythrocytes obtained by flushing with CSA (IRBC(CSA)), were restricted to the immunoglobulin G3 isotypes. Massive desequestration of parasites was achieved with soluble CSA but not with anti-ICAM-1 and anti-CD36 monoclonal antibodies. All of the CSA-flushed parasites were analyzed immediately by using in vitro assays of binding to Saimiri brain endothelial cells (SBEC) expressing various adhesion receptors. Parasites derived from all six placentas displayed the CSA adhesion phenotype. However, only partial inhibition of adhesion was observed in the presence of soluble CSA or when Sc1D SBEC were treated with chondroitinase ABC. These results suggest that an additional adhesive molecule of IRBC(CSA) which binds to an unidentified receptor is present in the placenta. This new phenotype was lost once the parasites adapted to in vitro culture. We observed additional differences in the CSA adhesion phenotype between placental parasites and in vitro-cultured parasites panned on endothelial cells carrying CSA. The minimum size of fractionated CSA required for a significant inhibition of placental IRBC(CSA) adhesion to Sc1D cells was 1 to 2 kDa, which contrasts with the 4-kDa size necessary to reach equivalent levels of inhibition with panned IRBC(CSA) of this phenotype. All placental IRBC(CSA) cytoadhered to Sc17 SBEC, which express only the CSA receptor. Panning of IRBC(CSA) on these cells resulted in a significant quantitative increase of IRBC cytoadhering to the CSA of Sc1D cells but did not change their capacity for adhesion to CSA on normal placenta cryosections. Our results indicate that the CSA binding phenotype is heterogeneous and that several distinct genes may encode P. falciparum-CSA ligands with distinct binding properties.
Assuntos
Sulfatos de Condroitina/metabolismo , Eritrócitos/parasitologia , Malária Falciparum/parasitologia , Placenta/parasitologia , Plasmodium falciparum/isolamento & purificação , Complicações Parasitárias na Gravidez/parasitologia , Animais , Anticorpos/análise , Bovinos , Adesão Celular , Sulfatos de Condroitina/imunologia , Eritrócitos/fisiologia , Feminino , Humanos , Malária Falciparum/sangue , Plasmodium falciparum/metabolismo , Gravidez , Complicações Parasitárias na Gravidez/sangueRESUMO
In areas where Plasmodium falciparum is endemic, pregnant women are at increased risk for malaria, and this risk is greatest during the first pregnancy. The placenta sequesters parasites that are able to cytoadhere to chondroitin sulfate A (CSA), a molecule expressed by the placental syncytiotrophoblast, while parasites from a nonpregnant host do not bind to CSA. Cytoadherence is mediated by the expression of variants of the P. falciparum-erythrocyte membrane protein 1 family. Each member of this molecule family induces antibodies that specifically agglutinate infected erythrocytes and inhibit their cytoadherence ability. We investigated whether the higher susceptibility of primigravidae was related to the lack of immune response towards CSA-binding parasites. In a cross-sectional study, primigravidae delivering with a noninfected placenta were less likely to have antibodies agglutinating CSA-binding parasites than multigravidae (P < 0.01). In contrast, parasites from nonpregnant hosts were as likely to be recognized by the sera from women of various parities. In a longitudinal study, at 6 months of pregnancy, antibodies against CSA-binding parasites were present in 31.8% of primigravidae and in 76.9% of secundigravidae (P = 0.02). The antibodies against CSA-binding parasites inhibited the cytoadherence of a CSA-adherent parasite strain to the human placental trophoblast. Our data support the idea that the higher susceptibility of primiparae is related to a lack of a specific immune response to placental parasites.
Assuntos
Anticorpos Antiprotozoários/imunologia , Sulfatos de Condroitina/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Adesividade , Adolescente , Adulto , Aglutinação , Animais , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Gravidez , Complicações Parasitárias na Gravidez/prevenção & controle , Trofoblastos/parasitologiaRESUMO
The frequency and level of cellular and humoral responses to seven synthetic peptides from asexual blood stages of Plasmodium falciparum were measured in two cohorts of children living in areas highly endemic for malaria in Gabon and Cameroon. A prospective longitudinal study was conducted for one year in these sites to examine the relationship between specific in vitro immune responses and susceptibility to clinical malaria. Clinical protection was related to high proliferative responses (merozoite surface antigen-1 [MSA-1] and MSA-2 peptides) as well as to elevated antibody levels (schizont extract, MSA-2, and rhoptry-associated protein-1 [RAP-1] peptides) in the village of Dienga, Gabon. Higher response rates of interferon-gamma but lower response rates of tumor necrosis factor-alpha to four and six peptides, respectively, were observed in Dienga than in Pouma that were independent of the older age of the Gabonese children. Age accounted only for the higher prevalence rate in Dienga of the antibody responders to the peptide from Pf155/ring-infected erythrocyte surface antigen (RESA). Our results support the inclusion of epitopes from MSA-1, MSA-2, RAP-1, and Pf155/RESA antigens in a subunit vaccine against malaria, but show that a longitudinal clinical, parasitologic, and immunologic study conducted according to identical criteria in two separate areas may lead to contrasting observations, demonstrating the geographic limitation of the interpretation of such results.
Assuntos
Antígenos de Protozoários/imunologia , Malária Falciparum/imunologia , Peptídeos/imunologia , Plasmodium falciparum/imunologia , Adolescente , Sequência de Aminoácidos , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/química , Camarões , Criança , Estudos de Coortes , Citocinas/biossíntese , Suscetibilidade a Doenças , Gabão , Humanos , Estudos Longitudinais , Ativação Linfocitária , Dados de Sequência Molecular , Peptídeos/química , Plasmodium falciparum/crescimento & desenvolvimento , Estudos Prospectivos , Linfócitos T/imunologiaRESUMO
BACKGROUND: Individuals may be homozygous (SS) or heterozygous (AS) sickle cell gene carriers or have normal adult haemoglobin (AA). Haemoglobin S could have a protective role against malaria but evidence is sparse and the operating mechanisms are poorly known. METHODS: We followed two cohorts of children. The first was enrolled at birth (156 newborn babies) and the second at 24-36 months old (84 children). Both cohorts were followed for 30 months; monthly for parasitological data and half yearly for immunological data. RESULTS: In the first cohort, 22%, and in the second 13% of children were AS. Whatever their age parasite prevalence rates were similar in AA and AS individuals. Mean parasite densities increased less rapidly with age in AS than in AA children, and were significantly lower in AS than in AA children >48 months old. The AA children tended to be more often admitted to hospital than AS children (22% versus 11%, NS). Both anti-Plasmodium falciparum and anti-Pfl55/RESA antibody rates increased more rapidly in AA than in AS children. Conversely, the prevalence rate of cellular responders to the Pfl55/RESA antigen was similar in AA and AS children during the first 2 years of life, then it was higher in AS than in AA children. CONCLUSIONS: Sickle cell trait related antimalarial protection varies with age. The role of the modifications of the specific immune response to P. falciparum in explaining the protection of AS children against malaria is discussed.
Assuntos
Eritrócitos/parasitologia , Imunidade Celular , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Traço Falciforme/imunologia , Animais , Anticorpos Antiprotozoários/análise , Camarões/epidemiologia , Pré-Escolar , Eritrócitos/imunologia , Eritrócitos/metabolismo , Feminino , Seguimentos , Genótipo , Hemoglobina A/genética , Hemoglobina Falciforme/genética , Humanos , Lactente , Recém-Nascido , Malária Falciparum/complicações , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Masculino , Plasmodium falciparum/isolamento & purificação , Prevalência , Proteínas de Protozoários/imunologia , Estudos Retrospectivos , Traço Falciforme/sangue , Traço Falciforme/complicaçõesRESUMO
The placenta of pregnant women is frequently parasitized by erythrocytes infected by mature stages of Plasmodium falciparum (IE), a phenomenon associated with low birth weight of the offspring. The cytoadherence phenotype of the parasites from pregnant women suggests that placental sequestration may result from cytoadherence to the syncytiotrophoblast. However, as anatomopathological studies report that cytoadherence in the placenta is a rare event, we investigated whether placental parasites may sequester by forming rosettes with uninfected erythrocytes, another possible sequestration mechanism. Parasites from placental blood as well as parasites from the peripheral blood of pregnant and non pregnant subjects were assessed for their ability to rosette. In non pregnant subjects, the rosetting capacity of parasites was as reported in literature while, except in one case, parasites from pregnant women did not rosette. We conclude that the lack of rosetting is a new feature of IEs from pregnant women and that rosetting cannot be involved in the placental sequestration of IEs.