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Ouederni M.,Pediatric Hematology Immunology Unit | Ouederni M.,Tunis el Manar University | Sanal O.,Ankara University | Ikinciogullari A.,Hacettepe University | And 51 more authors.
Clinical Infectious Diseases | Year: 2014

Background. Interleukin 12Rβ1 (IL-12Rβ1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency.Results. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin.Conclusions. Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients. © The Author 2013.


Jabot-Hanin F.,French Institute of Health and Medical Research | Jabot-Hanin F.,University of Paris Descartes | Cobat A.,French Institute of Health and Medical Research | Cobat A.,University of Paris Descartes | And 29 more authors.
Journal of Infectious Diseases | Year: 2016

Background. Interferon γ (IFN-γ) release assays (IGRAs) provide an in vitro measurement of antimycobacterial immunity that is widely used as a test for Mycobacterium tuberculosis infection. IGRA outcomes are highly heritable in various populations, but the nature of the involved genetic factors remains unknown. Methods. We conducted a genome-wide linkage analysis of IGRA phenotypes in families from a tuberculosis household contact study in France and a replication study in families from South Africa to confirm the loci identified. Results. We identified a major locus on chromosome 8q controlling IFN-γ production in response to stimulation with live bacillus Calmette-Guerin (BCG; LOD score, 3.81; P = 1.40 × 10-5). We also detected a second locus, on chromosome 3q, that controlled IFN-γ levels in response to stimulation with 6-kDa early secretory antigen target, when accounting for the IFN-γ production shared with that induced by BCG (LOD score, 3.72; P = 1.8 × 10-5). Both loci were replicated in South African families, where tuberculosis is hyperendemic. These loci differ from those previously identified as controlling the response to the tuberculin skin test (TST1 and TST2) and the production of TNF-α (TNF1). Conclusions. The identification of 2 new linkage signals in populations of various ethnic origins living in different M. tuberculosis exposure settings provides new clues about the genetic control of human antimycobacterial immunity. © The Author 2015.


Lanternier F.,French Institute of Health and Medical Research | Lanternier F.,Paris-Sorbonne University | Lanternier F.,Necker Enfants Malades Hospital | Barbati E.,French Institute of Health and Medical Research | And 49 more authors.
Journal of Infectious Diseases | Year: 2015

Background. Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. Methods. We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. Results. We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. Conclusions. These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections. © 2015 The Author. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.


Cushing L.,Pfizer | Stochaj W.,Pfizer | Siegel M.,Pfizer | Czerwinski R.,Pfizer | And 16 more authors.
Journal of Biological Chemistry | Year: 2014

Background: IRAK4 is a central kinase in IL-1R/TLR signaling. Results: IRAK4 is activated by autophosphorylation, and its inhibition reduces cytokine induction in human monocytes but not dermal fibroblasts. Conclusion: IL-1R/TLR-induced autophosphorylation activates IRAK4 and controls cytokine induction in a cell type-specific manner. Significance: Our data provide the mechanism of IRAK4 activation and role in cytokine induction in human cells. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

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