CARLOS ALBERTO MOREIRA FILHO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Pediatria, Faculdade de Medicina - Docente
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina - Líder
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conferenceObject TRISOMY 21-DRIVEN GENE EXPRESSION DYSREGULATION IN HUMAN THYMUS: CONVERGING GENOMIC AND EPIGENOMIC MECHANISMS(2016) MOREIRA-FILHO, Carlos Alberto; BANDO, Silvia Yumi; BERTONHA, Fernanda Bernardi; SILVA, Filipi Nascimento; COSTA, Luciano da Fontoura; FEREIRA, Leandro Rodrigues; CARNEIRO-SAMPAIO, MagdaconferenceObject Sexual Dimorphism and AIRE-AIRE Interactors-miRNA Coexpression Networks in the Infant Human Thymus(2019) BANDO, Silvia Y.; BERTONHA, Fernanda B.; OLIVEIRA, Lucila H. B.; MOREIRA-FILHO, Carlos Alberto; CARNEIRO-SAMPAIO, MagdaconferenceObject Complete Transcriptional Network Driven-View of Thymic Hypofunction in Down Syndrome(2014) MOREIRA-FILHO, Carlos Alberto; BANDO, Silvia Yumi; BERTONHA, Fernanda Bernardi; FEREIRA, Leandro Rodrigues; SILVA, Filipi Nascimento; COSTA, Luciano da Fontoura; GRASSI, Marcilia Sierro; CARNEIRO-SAMPAIO, Magdaarticle 16 Citação(ões) na Scopus Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants(2016) MOREIRA-FILHO, Carlos Alberto; BANDO, Silvia Yumi; BERTONHA, Fernanda Bernardi; SILVA, Filipi Nascimento; COSTA, Luciano da Fontoura; FERREIRA, Leandro Rodrigues; FURLANETTO, Glaucio; CHACUR, Paulo; ZERBINI, Maria Claudia Nogueira; CARNEIRO-SAMPAIO, MagdaTrisomy 21-driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and miRNA-target analyses. We used whole thymic tissue - obtained at heart surgery from Down syndrome (DS) and karyotipically normal subjects (CT) - and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires (communities) and the interactions between all the system's constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS networks corresponded to community changes. Distinct communities of highly interconnected genes were topologically identified in these networks. The role of miRNAs in modulating the expression of highly connected genes in CT and DS was revealed through miRNA-target analysis. Trisomy 21 gene dysregulation in thymus may be depicted as the breakdown and altered reorganization of transcriptional modules. Leading networks acting in normal or disease states were identified. CT networks would depict the ""canonical"" way of thymus functioning. Conversely, DS networks represent a ""non-canonical"" way, i. e., thymic tissue adaptation under trisomy 21 genomic dysregulation. This adaptation is probably driven by epigenetic mechanisms acting at chromatin level and through the miRNA control of transcriptional programs involving the networks' high-hierarchy genes.conferenceObject MODULAR TRANSCRIPTIONAL REPERTOIRE AND microRNA-TARGET ANALYSES IN THYMIC TISSUE OF DOWN SYNDROME INFANTS(2015) MOREIRA-FILHO, Carlos Alberto; BANDO, Silvia Yumi; BERTONHA, Fernanda Bernardi; SILVA, Filipi Nascimento; COSTA, Luciano da Fontoura; FEREIRA, Leandro Rodrigues; CARNEIRO-SAMPAIO, Magda- Decreased AIRE Expression and Global Thymic Hypofunction in Down Syndrome(2011) LIMA, Flavia A.; MOREIRA-FILHO, Carlos A.; RAMOS, Patricia L.; BRENTANI, Helena; LIMA, Leandro de A.; ARRAIS, Magaly; BENTO-DE-SOUZA, Luiz C.; BENTO-DE-SOUZA, Luciana; DUARTE, Maria I.; COUTINHO, Antonio; CARNEIRO-SAMPAIO, MagdaThe Down syndrome (DS) immune phenotype is characterized by thymus hypotrophy, higher propensity to organ-specific autoimmune disorders, and higher susceptibility to infections, among other features. Considering that AIRE (autoimmune regulator) is located on 21q22.3, we analyzed protein and gene expression in surgically removed thymuses from 14 DS patients with congenital heart defects, who were compared with 42 age-matched controls with heart anomaly as an isolated malformation. Immunohistochemistry revealed 70.48 +/- 49.59 AIRE-positive cells/mm(2) in DS versus 154.70 +/- 61.16 AIRE-positive cells/mm(2) in controls (p < 0.0001), and quantitative PCR as well as DNA microarray data confirmed those results. The number of FOXP3-positive cells/mm(2) was equivalent in both groups. Thymus transcriptome analysis showed 407 genes significantly hypoexpressed in DS, most of which were related, according to network transcriptional analysis (FunNet), to cell division and to immunity. Immune response-related genes included those involved in 1) Ag processing and presentation (HLA-DQB1, HLA-DRB3, CD1A, CD1B, CD1C, ERAP) and 2) thymic T cell differentiation (IL2RG, RAG2, CD3D, CD3E, PRDX2, CDK6) and selection (SH2D1A, CD74). It is noteworthy that relevant AIRE-partner genes, such as TOP2A, LAMNB1, and NUP93, were found hypoexpressed in DNA microarrays and quantitative real-time PCR analyses. These findings on global thymic hypofunction in DS revealed molecular mechanisms underlying DS immune phenotype and strongly suggest that DS immune abnormalities are present since early development, rather than being a consequence of precocious aging, as widely hypothesized. Thus, DS should be considered as a non-monogenic primary immunodeficiency. The Journal of Immunology, 2011, 187: 3422-3430.
conferenceObject Congenital hypothyroidism associated with IPEX Congenital hypothyroidism associated with IPEX Congenital hypothyroidism associated with IPEX Congenital hypothyroidism and IPEX(2022) LIMA, Susana; NUNCIO, Fabio De; BARROS-CAMPOS, Nathalia; MOREIRA-FILHO, Carlos; CARNEIRO-SAMPAIO, Magda- Minipuberty and Sexual Dimorphism in the Infant Human Thymus(2018) MOREIRA-FILHO, Carlos Alberto; BANDO, Silvia Yumi; BERTONHA, Fernanda Bernardi; FERREIRA, Leandro Rodrigues; VINHAS, Christiana de Freitas; OLIVEIRA, Lucila Habib Bourguignon; ZERBINI, Maria Claudia Nogueira; FURLANETTO, Glaucio; CHACCUR, Paulo; CARNEIRO-SAMPAIO, MagdaAIRE expression in thymus is downregulated by estrogen after puberty, what probably renders women more susceptible to autoimmune disorders. Here we investigated the effects of minipuberty on male and female infant human thymic tissue in order to verify if this initial transient increase in sex hormones - along the first six months of life - could affect thymic transcriptional network regulation and AIRE expression. Gene co-expression network analysis for differentially expressed genes and miRNA-target analysis revealed sex differences in thymic tissue during minipuberty, but such differences were not detected in the thymic tissue of infants aged 7-18 months, i.e. the non-puberty group. AIRE expression was essentially the same in both sexes in minipuberty and in non-puberty groups, as assessed by genomic and immunohistochemical assays. However, A/RE-interactors networks showed several differences in all groups regarding gene-gene expression correlation. Therefore, minipuberty and genomic mechanisms interact in shaping thymic sexual dimorphism along the first six months of life.
- Intrauterine IPEX(2020) CARNEIRO-SAMPAIO, Magda; MOREIRA-FILHO, Carlos Alberto; BANDO, Silvia Yumi; DEMENGEOT, Jocelyne; COUTINHO, AntonioIPEX is one of the few Inborn Errors of Immunity that may manifest in the fetal period, and its intrauterine forms certainly represent the earliest human autoimmune diseases. Here, we review the clinical, histopathologic, and genetic findings from 21 individuals in 11 unrelated families, with nine different mutations, described as cases of intrauterine IPEX. Recurrent male fetal death (multigenerational in five families) due to hydrops in the midsemester of pregnancy was the commonest presentation (13/21). Noteworthy, in the affected families, there were only fetal- or perinatal-onset cases, with no affected individuals presenting milder forms with later-life manifestation. Most alive births were preterm (5/6). Skin desquamation and intrauterine growth restriction were observed in part of the cases. Fetal ultrasonography showed hyperechoic bowel or dilated bowel loops in the five cases with available imaging data. Histopathology showed multi-visceral infiltrates with T lymphocytes and other cells, including eosinophils, the pancreas being affected in most of the cases (11/21) and as early as at 18 weeks of gestational age. Regarding the nine FOXP3 mutations found in these cases, six determine protein truncation and three predictably impair protein function. Having found distinct presentations for the same FOXP3 mutation in different families, we resorted to the mouse system and showed that the scurfy mutation also shows divergent severity of phenotype and age of death in C57BL/6 and BALB/c backgrounds. We also reviewed age-of-onset data from other monogenic Tregopathies leading to IPEX-like phenotypes. In monogenic IPEX-like syndromes, the intrauterine onset was only observed in two kindreds with IL2RB mutations, with two stillbirths and two premature neonates who did not survive. In conclusion, intrauterine IPEX cases seem to constitute a particular IPEX subgroup, certainly with the most severe clinical presentation, although no strict mutation-phenotype correlations could be drawn for these cases.
- Disruption of the CREBBP gene and decreased expression of CREB, NF kappa B p65, c-JUN, c-FOS, BCL2 and c-MYC suggest immune dysregulation(2013) TORRES, Leuridan Cavalcante; KULIKOWSKI, Leslie Domenici; RAMOS, Patricia Locosque; SUGAYAMA, Sofia Mizuko Miura; MOREIRA-FILHO, Carlos Alberto; CARNEIRO-SAMPAIO, MagdaGenomic aberrations in the CREBBP (CREB-binding protein - CREBBP or CBP) gene such as point mutations, small insertions or exonic copy number changes are usually associated with Rubinstein-Taybi syndrome (RTs). In this study, the disruption of the CREBBP gene on chromosome 16p13.3, as revealed by CGH-array and FISH, suggests immune dysregulation in a patient with the Rubinstein Taybi syndrome (RTs) phenotype. Further investigation with Western blot techniques demonstrated decreased expression of CREB, NP kappa B, c-Jun, c-Fos, BCL2 and cMyc in peripheral blood mononuclear cells, thus indicating that the CREBBP gene is essential for the normal expression of these proteins and the regulation of immune responses.