Mostrando recursos 1 - 16 de 16

  1. Early skin immunological disturbance after Plasmodium-infected mosquito bites

    Silva, Henrique Borges da; Caetano, Susana S; Monteiro, Isadora; Gómez-Conde, Iván; Hanson, Kirsten; Penha-Gonçalves, Carlos; Olivieri, David N; Mota, Maria M; Marinho, Cláudio R.; D’Imperio Lima, Maria R.; Tadokoro, Carlos E
    Although the role of regulatory T cells (Tregs) during malaria infection has been studied extensively, such studies have focused exclusively on the role of Treg during the blood stage of infection; little is known about the detailed mechanisms of Tregs and sporozoite deposition in the dermis by mosquito bites. In this paper we show that sporozoites introduced into the skin by mosquito bites increase the mobility of skin Tregs and dendritic cells (DCs). We also show differences in MHC class II and/or CD86 expression on skin-resident dendritic cell subtypes and macrophages. From the observed decrease of the number of APCs...

  2. The Liver Plays a Major Role in Clearance and Destruction of Blood Trypomastigotes in Trypanosoma cruzi Chronically Infected Mice

    Sardinha, L. R.; Mosca, T.; Elias, R. M.; do Nascimento, R. S.; Goncalves, L. A.; Bucci, D. Z.; Marinho, C. R. F.; Penha-Goncalves, C.; Lima, M. R. D.; Alvarez, J. M.
    Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5x10(6) trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of liver-cleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased:...

  3. Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children

    Sambo, Maria Rosário; Trovoada, Maria Jesus; Benchimol, Carla; Quinhentos, Vatúsia; Gonçalves, Lígia; Velosa, Rute; Marques, Maria Isabel; Sepúlveda, Nuno; Clark, Taane G.; Mustafa, Stefan; Wagner, Oswald; Coutinho, António; Penha-Gonçalves, Carlos; Rodrigues, Mauricio Martins
    BACKGROUND: Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes. METHODOLOGY/PRINCIPAL FINDINGS: We report that the clinical outcome of P. falciparum infection in a cohort of...

  4. Non-HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients

    Fourati, Hajer; Bouzid, Dorra; Abida, Olfa; Kharrat, Najla; Mnif, Fatma; Haddouk, Samy; Fesel, Constantin; Costa, João; Ayed, Mourad Ben; Abid, Mohamed; Rebai, Ahmed; Penha-Gonçalves, Carlos; Masmoudi, Hatem
    Autoimmune Polyglandular Syndrome Type II (APSII) is characterized by the co-occurrence of clinical insufficiency of at least two endocrine glands. Although, HLA determinants of APSII predisposition have been identified, little attention has been paid to non-HLA genes. Here, we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co-occurrence of Autoimmune Thyroid Disease (AITD) and Type 1 Diabetes (T1D) and lower frequency of Addison's disease (AD). We tested the high a priori possibility that well-established non-HLA autoimmunity loci were involved in APSII and confirmed five association...

  5. Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

    Côrte-Real, J; Duarte, N.; Tavares, L; Penha-Gonçalves, C

  6. Regulatory T cells Contribute to Diabetes Protection in Lipopolysaccharide-Treated Non-Obese Diabetic Mice

    Caramalho, I; Rodrigues-Duarte, L; Perez, A; Zelenay, S; Penha-Gonçalves, C; Demengeot, J.
    It is well established that viral, parasitic or bacterial infections can prevent type 1 diabetes (T1D) occurrence in non-obese diabetic (NOD) mice. On the other hand, defects in CD4(+) Regulatory T cell (Treg) numbers and/or function contribute to T1D aetiology in NOD mice and in humans. In this work, we formally tested whether the protective role of the bacterial product lipopolysaccharide (LPS) on diabetes incidence results from enhanced Treg activity. We first report that weekly administration of LPS to young prediabetic NOD mice, presenting or not insulitis at the time of treatment, afforded full protection from diabetes. Taking advantage from...

  7. Association of the RAVER2 gene with increased susceptibility for ulcerative colitis

    Bouzid, D.; Fourati, H.; Amouri, A.; Marques, I.; Abida, O.; Haddouk, S.; Ben Ayed, M.; Tahri, N.; Penha-Gonçalves, C; Masmoudi, H.
    Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE) and autoimmune polyglandular syndromes (APS) are autoimmune diseases (ADs) that may share common susceptibility pathways. We examined ribonucleo-protein, polypyrimidine tract-binding protein (PTB)-binding 2 (RAVER2) loci for these diseases in a cohort of 39 CD cases, 67 UC cases, 93 SLE cases, 60 APS cases and 162 healthy control subjects of Tunisian origin. We genotyped 3 SNPs of RAVER2 (rs2780814, rs1333739 and rs2780889) and evaluated it genetic association with each ADs, using X2-test. For each association, odds ratio (OR) and 95% CI were calculated. We show that rs2780814 is significantly associated...

  8. The {CREM} gene is involved in genetic predisposition to inflammatory bowel disease in the Tunisian population

    Bouzid, Dorra; Fourati, Hajer; Amouri, Ali; Marques, Isabel; Abida, Olfa; Haddouk, Samy; Ben Ayed, Mourad; Tahri, Nabil; Penha-Gonçalves, Carlos; Masmoudi, Hatem
    The identification of susceptibility genes for inflammatory bowel disease (IBD) is key to understanding pathogenic mechanisms. Recently, the results of genetic association studies have highlighted many loci that are shared among several autoimmune diseases. We aimed to study the genetic epidemiology of polymorphisms in specific genes previously associated with other autoimmune diseases, namely the CREM, STAT4, STAT5a, Stat5b, and IRF5 genes. Twelve polymorphisms in the CREM, STAT4, STAT5a, Stat5b, and IRF5 genes were genotyped in a cohort of 107 IBD patients (39 Crohn's disease [CD] and 68 ulcerative colitis [UC]) and 162 controls from southern Tunisia. One CREM single nucleotide...

  9. IFNAR1 Controls Progression to Cerebral Malaria in Children and CD8+ T Cell Brain Pathology in Plasmodium berghei-Infected Mice

    Ball, E. A.; Sambo, M. R.; Martins, M.; Trovoada, M. J.; Benchimol, C.; Costa, J.; Antunes Goncalves, L.; Coutinho, A.; Penha-Goncalves, C.
    Malaria in pregnancy is exquisitely aggressive, causing a range of adverse maternal and fetal outcomes prominently linked to Plasmodium-infected erythrocyte cytoadherence to fetal trophoblast. To elucidate the physiopathology of infected erythrocytes (IE) sequestration in the placenta we devised an experimental system for intravital placental examination of P. berghei-infected mice. BALB/c females were mated to C57Bl/6 CFP+ male mice and infected with GFP+ P. berghei IE, and at gestational day 18, placentas were exposed for time-lapse imaging acquisition under two-photon microscopy. Real-time images and quantitative measurements revealed that trophoblast conformational changes transiently restrain blood flow in the mouse placental labyrinth. The...

  10. Intravital placenta imaging reveals microcirculatory dynamics impact on sequestration and phagocytosis of Plasmodium-infected erythrocytes

    Moraes, Luciana Vieira de; Tadokoro, Carlos Eduardo; Gómez-Conde, Ivan; Olivieri, David N.; Penha-Gonçalves, Carlos
    Malaria in pregnancy is exquisitely aggressive, causing a range of adverse maternal and fetal outcomes prominently linked to Plasmodium-infected erythrocyte cytoadherence to fetal trophoblast. To elucidate the physiopathology of infected erythrocytes (IE) sequestration in the placenta we devised an experimental system for intravital placental examination of P. berghei-infected mice. BALB/c females were mated to C57Bl/6 CFP+ male mice and infected with GFP+ P. berghei IE, and at gestational day 18, placentas were exposed for time-lapse imaging acquisition under two-photon microscopy. Real-time images and quantitative measurements revealed that trophoblast conformational changes transiently restrain blood flow in the mouse placental labyrinth. The...

  11. Allelic penetrance approach as a tool to model twolocus

    Sepúlveda, Nuno; Paulino, Carlos Daniel; Carneiro, Jorge; Penha-Gonçalves, Carlos
    Many binary phenotypes do not follow a classical Mendelian inheritance pattern. Interaction between genetic and environmental factors is thought to contribute to the incomplete penetrance phenomena often observed in these complex binary traits. Several two-locus models for penetrance have been proposed to aid the genetic dissection of binary traits. Such models assume linear genetic effects of both loci in different mathematical scales of penetrance, resembling the analytical framework of quantitative traits. However, changes in phenotypic scale are difficult to envisage in binary traits and limited genetic interpretation is extractable from current modeling of penetrance. To overcome this limitation, we derived an allelic penetrance approach that partitioned incomplete penetrance into the alleles controlling the phenotype...

  12. The multigenic structure of the MHC locus contributes to positive selection efficiency: A role for MHC class II gene-genespecific

    Monteiro, Miguel Caetano; Couceiro, Sofia; Penha-Gonçalves, Carlos
    The study of T cell positive selection in the thymus has long been focused on the specificity of the MHC-TCR interactions, making use of genetically manipulated mice that display TCR specificities or selecting peptides of limited diversity. However, little is known on the role of the MHC molecules irrespective of the peptide specificity and the implications of MHC multigenic structure in thymic positive selection have not been addressed. Here, we investigated the effect of MHC class II genetic configuration on the positive selection efficiency of naturally generated pre-selection repertoires in the mouse thymus. Analysis of positively selected thymocyte populations in MHC-congenic and -transgenic mice revealed that expression of...

  13. Mapping of quantitative trait loci using the skew-normal distribution

    Fernandes, Elisabete; Pacheco, António; Penha-Gonçalves, Carlos
    In standard interval mapping (IM) of quantitative trait loci (QTL), the QTL effect is described by a normal mixture model. When this assumption of normality is violated, the most commonly adopted strategy is to use the previous model after data transformation. However, an appropriate transformation may not exist or may be difficult to find. Also this approach can raise interpretation issues. An interesting alternative is to consider a skew-normal mixture model in standard IM, and the resulting method is here denoted as skew-normal IM. This flexible model that includes the usual symmetric normal distribution as a special case is important, allowing continuous variation from normality...

  14. Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

    Côrte-Real, J; Rodo, Joana; Almeida, P; Coutinho, António; Demengeot, Jocelyne; Penha-Gonçalves, Carlos
    Natural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice...

  15. Bayesian analysis of allelic penetrance models for complex binary traits

    Sepúlveda, Nuno; Paulino, Carlos Daniel; Penha-Gonçalves, Carlos
    Complex binary traits result from an intricate network of genetic and environmental factors. To aid their genetic dissection, several generalized linear models have been described to detect interaction between genes. However, it is recognized that these models have limited genetic interpretation. To overcome this problem, the allelic penetrance approach was proposed to model the action of a dominant or a recessive allele at a single locus, and to describe two-locus independent, inhibition, and cumulative actions. Classically, a recessive inheritance requires the expression of both recessive alleles in homozygotes to obtain the phenotype (type I recessiveness). In previous work, recessiveness was defined alternatively as a situation where a recessive...

  16. Modelos de interacção genética de dois genes em fenótipos

    Sepúlveda, Nuno; Paulino, C.D.; Penha-Gonçalves, Carlos
    Em trabalhos anteriores foram propostos diversos modelos estatísticos para a penetrância de forma a inferir a interacção de dois genes dial´elicos na construção de fenótipos binários complexos: modelos de acção independente, modelos de inibição e modelos de número mínimo de alelos. Estes modelos baseiam-se numa decomposição da penetrância através da abordagem por penetrâncias alélicas, que permitiu a inclusão dos conceitos mendelianos de dominância e recessividade alélica na sua modelação. Pretende-se aqui dar a conhecer os avanços mais recentes na parte da modelação da interacção genética, apresentando uma nova decomposição da penetrância e uma nova formulação matemática da dominância e da recessividade. Aplicam-se ainda ferramentas bayesianas...

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