DEWTON DE MORAES VASCONCELOS
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
5 resultados
Resultados de Busca
Agora exibindo 1 - 5 de 5
- Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency(2018) KONG, Xiao-Fei; MARTINEZ-BARRICARTE, Ruben; KENNEDY, James; MELE, Federico; LAZAROV, Tomi; DEENICK, Elissa K.; MA, Cindy S.; BRETON, Gaelle; LUCERO, Kimberly B.; LANGLAIS, David; BOUSFIHA, Aziz; AYTEKIN, Caner; MARKLE, Janet; TROUILLET, Celine; JABOT-HANIN, Fabienne; ARLEHAMN, Cecilia S. Lindestam; RAO, Geetha; PICARD, Capucine; LASSEAU, Theo; LATORRE, Daniela; HAMBLETON, Sophie; DESWARTE, Caroline; ITAN, Yuval; ABARCA, Katia; MORAES-VASCONCELOS, Dewton; AILAL, Fatima; IKINCIOGULLARI, Aydan; DOGU, Figen; BENHSAIEN, Ibtihal; SETTE, Alessandro; ABEL, Laurent; BOISSON-DUPUIS, Stephanie; SCHROEDER, Bernd; NUSSENZWEIG, Michel C.; LIU, Kang; GEISSMANN, Frederic; TANGYE, Stuart G.; GROS, Philippe; SALLUSTO, Federica; BUSTAMANTE, Jacinta; CASANOVA, Jean-LaurentHuman inborn errors of IFN-gamma immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12-and IL-23-producing CD1c(+) conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory T(H)1(star) cells selectively fail to produce IFN-gamma when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a(-/-) mice lack cDC2s, have CD4(+) T cells that produce small amounts of IFN-gamma after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-gamma production by mycobacterium-specific memory T(H)1(star) cells.
- Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-alpha production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1(2012) PEDROZA, Luis A.; KUMAR, Vipul; SANBORN, Keri B.; MACE, Emily M.; NIINIKOSKI, Harri; NADEAU, Kari; VASCONCELOS, Dewton de Moraes; PEREZ, Elena; JYONOUCHI, Soma; JYONOUCHI, Harumi; BANERJEE, Pinaki P.; RUUSKANEN, Olli; CONDINO-NETO, Antonio; ORANGE, Jordan S.Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity. Objective: To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of beta-glucan through the Dectin-1 pathway, which is required for defense against Candida species. Methods: Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy. Results: PBMCs from patients with APECED syndrome had reduced TNF-alpha responses after Dectin-1 ligation but in part used a Raf-1-mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-a release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain-containing protein 9 after receptor ligation and localized with Dectin-1 at the cell membrane. Conclusion: AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome. (J Allergy Clin Immunol 2012;129:464-72.)
- Hereditary Autoinflammatory Syndromes: A Brazilian Multicenter Study(2012) JESUS, Adriana A.; FUJIHIRA, Erika; WATASE, Mariana; TERRERI, Maria T.; HILARIO, Maria O.; CARNEIRO-SAMPAIO, Magda; LEN, Claudio A.; OLIVEIRA, Sheila K.; RODRIGUES, Marta C.; PEREIRA, Rosa M.; BICA, Blanca; SILVA, Nilzio A.; CAVALCANTI, Andre; MARINI, Roberto; SZTAJNBOK, Flavio; QUINTERO, Maria V.; FERRIANI, Virginia P.; MORAES-VASCONCELOS, Dewton; SILVA, Clovis A.; OLIVEIRA, Joao B.To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. Clinical diagnoses of the 102 patients were: CAPS (n = 28), TRAPS (n = 31), FMF (n = 17), MKD (n = 17) and PGA (n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis.
- IRF8 Mutations and Human Dendritic-Cell Immunodeficiency(2011) HAMBLETON, Sophie; SALEM, Sandra; BUSTAMANTE, Jacinta; BIGLEY, Venetia; BOISSON-DUPUIS, Stephanie; AZEVEDO, Joana; FORTIN, Anny; HANIFFA, Muzlifah; CERON-GUTIERREZ, Lourdes; BACON, Chris M.; MENON, Geetha; TROUILLET, Celine; MCDONALD, David; CAREY, Peter; GINHOUX, Florent; ALSINA, Laia; ZUMWALT, Timothy J.; KONG, Xiao-Fei; KUMARARATNE, Dinakantha; BUTLER, Karina; HUBEAU, Marjorie; FEINBERG, Jacqueline; AL-MUHSEN, Saleh; CANT, Andrew; ABEL, Laurent; CHAUSSABEL, Damien; DOFFINGER, Rainer; TALESNIK, Eduardo; GRUMACH, Anete; DUARTE, Alberto; ABARCA, Katia; MORAES-VASCONCELOS, Dewton; BURK, David; BERGHUIS, Albert; GEISSMANN, Frederic; COLLIN, Matthew; CASANOVA, Jean-Laurent; GROS, PhilippeBACKGROUND The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guerin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.)
- Clearance of Persistent SARS-CoV-2 RNA Detection in a NF kappa B-Deficient Patient in Association with the Ingestion of Human Breast Milk: A Case Report(2022) SABINO, Janine S.; AMORIM, Mariene R.; SOUZA, William M. de; MAREGA, Lia F.; MOFATTO, Luciana S.; TOLEDO-TEIXEIRA, Daniel A.; FORATO, Julia; STABELI, Rodrigo G.; COSTA, Maria Laura; SPILKI, Fernando R.; SABINO, Ester C.; FARIA, Nuno R.; BENITES, Bruno D.; ADDAS-CARVALHO, Marcelo; STUCCHI, Raquel S. B.; VASCONCELOS, Dewton M.; WEAVER, Scott C.; GRANJA, Fabiana; PROENCA-MODENA, Jose Luiz; VILELA, Maria Marluce dos S.Currently, there are no evidence-based treatment options for long COVID-19, and it is known that SARS-CoV-2 can persist in part of the infected patients, especially those with immunosuppression. Since there is a robust secretion of SARS-CoV-2-specific highly-neutralizing IgA antibodies in breast milk, and because this immunoglobulin plays an essential role against respiratory virus infection in mucosa cells, being, in addition, more potent in neutralizing SARS-CoV-2 than IgG, here we report the clinical course of an NF kappa B-deficient patient chronically infected with the SARS-CoV-2 Gamma variant, who, after a non-full effective treatment with plasma infusion, received breast milk from a vaccinated mother by oral route as treatment for COVID-19. After such treatment, the symptoms improved, and the patient was systematically tested negative for SARS-CoV-2. Thus, we hypothesize that IgA and IgG secreted antibodies present in breast milk could be useful to treat persistent SARS-CoV-2 infection in immunodeficient patients.