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SPM - Serviço de Pediatria Médica

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Browsing SPM - Serviço de Pediatria Médica by Author "Abel, L."

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  • Inherited p40phox deficiency differs from classic chronic granulomatous disease
    Publication . van de Geer, A.; Nieto-Patlán, A.; Kuhns, D.; Tool, A.; Arias, A.; Bouaziz, M.; de Boer, M.; Franco, J.; Gazendam, R.; van Hamme, J.; van Houdt, M.; van Leeuwen, K.; Verkuijlen, P.; van den Berg, T.; Alzate, J.; Arango-Franco, C.; Batura, V.; Bernasconi, A.; Boardman, B.; Booth, C.; Burns, S.; Cabarcas, .; Bensussan, N.; Charbit-Henrion, F.; Corveleyn, A.; Deswarte, C.; Azcoiti, M.; Foell, D.; Gallin, J.; Garcés, C.; Guedes, M.; Hinze, C.; Holland, S.; Hughes, S.; Ibañez, P.; Malech, H.; Meyts, I.; Moncada-Velez, M.; Moriya, K.; Neves, E.; Oleastro, M.; Perez, L.; Rattina, V.; Oleaga-Quintas, C.; Warner, N.; Muise, A.; López, J.; Trindade, E.; Vasconcelos, J.; Vermeire, S.; Wittkowski, H.; Worth, A.; Abel, L.; Dinauer, M.; Arkwright, P.; Roos, D.; Casanova, J.t; Kuijpers, T.; Bustamante, J.
    Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.
    2018-08-31Journal article Open access Show more
  • Mutations in STAT3 and IL12RB1 impair the development of human IL-17 – producing T cells
    Publication . Beaucoudrey, L.; Puel, A.; Filipe-Santos, O.; Cobat, A.; Ghandil, P.; Chrabieh, M.; Feinberg, J.; Bernuth, H.; Samarina, A.; Jannière, L.; Fieschi, C.; Stéphan, J.; Boileau, C.; Lyonnet, S.; Jondeau, G.; Cormier-Daire, V.; Merrer, M.; Hoarau, C.; Lebranchu, Y.; Lortholary, O.; Chandesris, M.; Tron, F.; Gambineri, E.; Bianchi, L.; Rodriguez-Gallego, C.; Zitnik, S.; Vasconcelos, J.; Guedes, M.; Vitor, A.; Marodi, L.; Chapel, H.; Reid, B.; Roifman, C.; Nadal, D.; Reichenbach, J.; Caragol, I.; Garty, B.; Dogu, F.; Camcioglu, Y.; Gülle, S.; Sanal, O.; Fischer, A.; Abel, L.; Stockinger, B.; Picard, C.; Casanova, J.
    Abstract The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.
    2008-07Journal article Open access Show more