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Le Touquet – Paris-Plage, France

Puel A.,French Institute of Health and Medical Research | Puel A.,University of Paris Descartes | Cypowyj S.,Rockefeller University | Marodi L.,Debrecen University | And 6 more authors.
Current Opinion in Allergy and Clinical Immunology

Purpose of reviewChronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent symptomatic infection of the nails, skin and mucosae mostly by Candida albicans. CMC is common in patients with profound primary T-cell immunodeficiency, who often display multiple infectious and autoimmune diseases. Patients with syndromic CMC, including autosomal dominant hyper IgE syndrome (AD-HIES) and autosomal recessive autoimmune polyendocrinopathy syndrome type I (APS-I), display fewer other infections. Patientswith isolated CMC (CMCD) rarely display any other severe disease. We review here recent progress in the genetic dissection of these three types of inherited CMC. Recent findings Low IL-17 T-cell proportions were reported in patients with AD-HIES bearing heterozygous STAT3 mutations,prone to CMC and staphylococcal diseases, and in a kindred with autosomal recessive CARD9 deficiency, prone to CMC and other fungal infections. High levels of neutralizing autoantibodies against IL-17 cytokines were documented in patients with APS-I presenting with CMC as their only infectious disease. The first three genetic causes of CMCD were then reported: autosomal recessive IL-17RA and autosomal dominant IL-17F deficiencies and autosomal dominant STAT1 gain-of-function, impairing IL-17-roducing T-cell development. Summary Inborn errors of human IL-17 immunity underlie CMC. Impaired IL-17 immunity may therefore account for CMC in other settings, including patients with acquired immunodeficiency. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Ouederni M.,Pediatric Hematology Immunology Unit | Vincent Q.B.,University of Paris Descartes | Vincent Q.B.,French Institute of Health and Medical Research | Frange P.,Pediatric Hematology Immunology Unit | And 23 more authors.

Inherited deficiency of major histocompatibility complex (MHC) class II molecules impairs antigen presentation to CD4 +T cells and results in combined immunodeficiency (CID). Autosomal-recessive mutations in the RFXANK gene account for two-thirds of all cases of MHC class II deficiency. We describe here the genetic, clinical, and immunologic features of 35 patients from 30 unrelated kindreds from North Africa sharing the same RFXANK founder mutation, a 26-bp deletion called I5E6-25-I5E6 + 1), and date the founder event responsible for this mutation in this population to approximately 2250 years ago (95% confidence interval [CI]: 1750-3025 years). Ten of the 23 patients who underwent hematopoietic stem cell transplantation (HSCT) were cured, with the recovery of almost normal immune functions. Five of the patients from this cohort who did not undergo HSCT had a poor prognosis and eventually died (at ages of 1-17 years). However, 7 patients who did not undergo HSCT (at ages of 6-32 years) are still alive on Ig treatment and antibiotic prophylaxis. RFXANK deficiency is a severe, often fatal CID for which HSCT is the only curative treatment. However, some patients may survive for relatively long periods if multiple prophylactic measures are implemented. © 2011 by The American Society of Hematology. Source

von Bernuth H.,Humboldt University of Berlin | von Bernuth H.,Labor Berlin Charite Vivantes GmbH | Picard C.,Study Center for Primary Immunodeficiencies | Picard C.,French Institute of Health and Medical Research | And 7 more authors.
European Journal of Immunology

Most Toll-like-receptors (TLRs) and interleukin-1 receptors (IL-1Rs) signal via myeloid differentiation primary response 88 (MyD88) and interleukin-1 receptor-associated kinase 4 (IRAK-4). The combined roles of these two receptor families in the course of experimental infections have been assessed in MyD88- and IRAK-4-deficient mice for almost fifteen years. These animals have been shown to be susceptible to 46 pathogens: 27 bacteria, eight viruses, seven parasites, and four fungi. Humans with inborn MyD88 or IRAK-4 deficiency were first identified in 2003. They suffer from naturally occurring life-threatening infections caused by a small number of bacterial species, although the incidence and severity of these infections decrease with age. Mouse TLR- and IL-1R-dependent immunity mediated by MyD88 and IRAK-4 seems to be vital to combat a wide array of experimentally administered pathogens at most ages. By contrast, human TLR- and IL-1R-dependent immunity mediated by MyD88 and IRAK-4 seems to be effective in the natural setting against only a few bacteria and is most important in infancy and early childhood. The roles of TLRs and IL-1Rs in protective immunity deduced from studies in mutant mice subjected to experimental infections should therefore be reconsidered in the light of findings for natural infections in humans carrying mutations as discussed in this review. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Ciancanelli M.J.,Rockefeller University | Huang S.X.L.,Columbia University | Luthra P.,Mount Sinai School of Medicine | Garner H.,Kings College London | And 45 more authors.

Severe influenza disease strikes otherwise healthy children and remains unexplained.We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication.These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity. © 2015, American Association for the Advancement of Science. All rights reserved. Source

LeGuen T.,French Institute of Health and Medical Research | LeGuen T.,Paris-Sorbonne University | Jullien L.,French Institute of Health and Medical Research | Jullien L.,Paris-Sorbonne University | And 21 more authors.
Human Molecular Genetics

Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrowfailure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomeredysfunctionandthese diseases.Bycombining whole-genomelinkage analysisandexomesequencing,we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans. © The Author 2013. Published by Oxford University Press. All rights reserved. Source

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