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Fabien G Lafaille,
Itai M Pessach,
Shen-Ying Zhang,
Michael J Ciancanelli,
Melina Herman,
Avinash Abhyankar,
Shui-Wang Ying,
Sotirios Keros,
Peter A Goldstein,
Gustavo Mostoslavsky, [......],
Edmund Tu,
Yechiel Elkabetz,
Saleh Al-Muhsen,
Marc Tardieu,
Thorsten M Schlaeger,
George Q Daley,
Laurent Abel,
Jean-Laurent Casanova,
Lorenz Studer,
Luigi D Notarangelo
[show abstract]
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ABSTRACT: In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-β (IFN-β) and/or IFN-λ1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-α or IFN-β ( IFN-α/β) but not IFN-λ1. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.
Nature 10/2012; · 36.28 Impact Factor
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Amandine Crequer,
Capucine Picard,
Vincent Pedergnana,
Annick Lim,
Shen-Ying Zhang,
Laurent Abel,
Slawomir Majewski,
Jean-Laurent Casanova,
Stefania Jablonska,
Gerard Orth, Emmanuelle Jouanguy
[show abstract]
[hide abstract]
ABSTRACT: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4(+) and CD8(+) T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4(+) and effector memory CD8(+) T cells, a bias of the TCR Vαβ and Vγδ repertoires and an increase of skin-homing CD4(+) T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both.
Journal of Clinical Immunology 08/2012; · 3.08 Impact Factor
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Amandine Crequer,
Anja Troeger,
Etienne Patin,
Cindy S Ma,
Capucine Picard,
Vincent Pedergnana,
Claire Fieschi,
Annick Lim,
Avinash Abhyankar,
Laure Gineau,
Ingrid Mueller-Fleckenstein,
Monika Schmidt,
Alain Taieb,
James Krueger,
Laurent Abel,
Stuart G Tangye,
Gérard Orth,
David A Williams,
Jean-Laurent Casanova, Emmanuelle Jouanguy
[show abstract]
[hide abstract]
ABSTRACT: Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh-/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.
The Journal of clinical investigation 08/2012; 122(9):3239-47. · 15.39 Impact Factor
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Etienne Patin,
Zoltán Kutalik,
Julien Guergnon,
Stéphanie Bibert,
Bertrand Nalpas, Emmanuelle Jouanguy,
Mona Munteanu,
Laurence Bousquet,
Laurent Argiro,
Philippe Halfon, [......],
Charles M Rice,
Andrew H Talal,
Ira M Jacobson,
Marc Bourlière,
Ioannis Theodorou,
Thierry Poynard,
Francesco Negro,
Stanislas Pol,
Pierre-Yves Bochud,
Laurent Abel
[show abstract]
[hide abstract]
ABSTRACT: Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection.
We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance.
In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 × 10(-9) and 1.1 × 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 × 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages.
Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.
Gastroenterology 07/2012; 143(5):1244-1252.e12. · 11.68 Impact Factor
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Laure Gineau,
Céline Cognet,
Nihan Kara,
Francis Peter Lach,
Jean Dunne,
Uma Veturi,
Capucine Picard,
Céline Trouillet,
Céline Eidenschenk,
Said Aoufouchi,
Alexandre Alcaïs,
Owen Smith,
Frédéric Geissmann,
Conleth Feighery,
Laurent Abel,
Agata Smogorzewska,
Bruce Stillman,
Eric Vivier,
Jean-Laurent Casanova, Emmanuelle Jouanguy
[show abstract]
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ABSTRACT: Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56(dim) NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients' fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients' growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56(dim) subset in patients was associated with a lower rate of NK CD56(bright) cell proliferation, and the maturation of NK CD56(bright) cells toward an NK CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.
The Journal of clinical investigation 03/2012; 122(3):821-32. · 15.39 Impact Factor
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Amandine Crequer,
Capucine Picard,
Etienne Patin,
Aurelia D'Amico,
Avinash Abhyankar,
Martine Munzer,
Marianne Debré,
Shen-Ying Zhang,
Geneviève de Saint-Basile,
Alain Fischer,
Laurent Abel,
Gérard Orth,
Jean-Laurent Casanova, Emmanuelle Jouanguy
[show abstract]
[hide abstract]
ABSTRACT: Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.
PLoS ONE 01/2012; 7(8):e44010. · 4.09 Impact Factor
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[show abstract]
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ABSTRACT: The three types of interferon (IFNs) are essential for immunity against at least some viruses in the mouse model of experimental infections, type I IFNs displaying the broadest and strongest anti-viral activity. Consistently, human genetic studies have shown that type II IFN is largely redundant for immunity against viruses in the course of natural infections. The precise contributions of human type I and III IFNs remain undefined. However, various inborn errors of anti-viral IFN immunity have been described, which can result in either broad or narrow immunological and viral phenotypes. The broad disorders impair the response to (STAT1, TYK2) or the production of at least type I and type III IFNs following multiple stimuli (NEMO), resulting in multiple viral infections at various sites, including herpes simplex encephalitis (HSE). The narrow disorders impair exclusively (TLR3) or mostly (UNC-93B, TRIF, TRAF3) the TLR3-dependent induction of type I and III IFNs, leading to HSE in apparently otherwise healthy individuals. These recent discoveries highlight the importance of human type I and III IFNs in protective immunity against viruses, including the TLR3-IFN pathway in protection against HSE.
Current opinion in virology. 12/2011; 1(6):487-96.
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Vanessa Sancho-Shimizu,
Rebeca Pérez de Diego,
Lazaro Lorenzo,
Rabih Halwani,
Abdullah Alangari,
Elisabeth Israelsson,
Sylvie Fabrega,
Annabelle Cardon,
Jerome Maluenda,
Megumi Tatematsu, [......], Emmanuelle Jouanguy,
Nima Rezaei,
Tsukasa Seya,
Misako Matsumoto,
Damien Chaussabel,
Anne Puel,
Shen-Ying Zhang,
Laurent Abel,
Saleh Al-Muhsen,
Jean-Laurent Casanova
[show abstract]
[hide abstract]
ABSTRACT: Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1-infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.
The Journal of clinical investigation 11/2011; 121(12):4889-902. · 15.39 Impact Factor
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Katrina L Randall,
Stephanie S-Y Chan,
Cindy S Ma,
Ivan Fung,
Yan Mei,
Mehmet Yabas,
Andy Tan,
Peter D Arkwright,
Wafaa Al Suwairi,
Saul Oswaldo Lugo Reyes, [......],
Satoshi Okada, Emmanuelle Jouanguy,
Jean-Laurent Casanova,
Teresa Lambe,
Richard J Cornall,
Sarah Russell,
Jane Oliaro,
Stuart G Tangye,
Edward M Bertram,
Christopher C Goodnow
[show abstract]
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ABSTRACT: In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA(+)CCR7(-) phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells.
Journal of Experimental Medicine 10/2011; 208(11):2305-20. · 13.85 Impact Factor
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Yiqi Guo,
Magali Audry,
Michael Ciancanelli,
Laia Alsina,
Joana Azevedo,
Melina Herman,
Esperanza Anguiano,
Vanessa Sancho-Shimizu,
Lazaro Lorenzo,
Elodie Pauwels, [......],
Pierre Lebon,
Sabine Plancoulaine,
Marc Tardieu,
Valérie Doireau, Emmanuelle Jouanguy,
Damien Chaussabel,
Frederic Geissmann,
Laurent Abel,
Jean-Laurent Casanova,
Shen-Ying Zhang
[show abstract]
[hide abstract]
ABSTRACT: Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-β and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient's fibroblasts with HSV-1, the impairment of IFN-β and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient's peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14(+) and/or CD16(+) monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.
Journal of Experimental Medicine 09/2011; 208(10):2083-98. · 13.85 Impact Factor
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Luyan Liu,
Satoshi Okada,
Xiao-Fei Kong,
Alexandra Y Kreins,
Sophie Cypowyj,
Avinash Abhyankar,
Julie Toubiana,
Yuval Itan,
Magali Audry,
Patrick Nitschke, [......],
Matias Oleastro,
Amos Etzioni,
Claudia Traidl-Hoffmann,
Ellen D Renner,
Laurent Abel,
Capucine Picard,
László Maródi,
Stéphanie Boisson-Dupuis,
Anne Puel,
Jean-Laurent Casanova
[show abstract]
[hide abstract]
ABSTRACT: Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
Journal of Experimental Medicine 08/2011; 208(8):1635-48. · 13.85 Impact Factor
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Magali Audry,
Michael Ciancanelli,
Kun Yang,
Aurelie Cobat,
Huey-Hsuan Chang,
Vanessa Sancho-Shimizu,
Lazaro Lorenzo,
Tim Niehues,
Janine Reichenbach,
Xiao-Xia Li,
Alain Israel,
Laurent Abel,
Jean-Laurent Casanova,
Shen-Ying Zhang, Emmanuelle Jouanguy,
Anne Puel
[show abstract]
[hide abstract]
ABSTRACT: Children with germline mutations in Toll-like receptor 3 (TLR3), UNC93B1, TNF receptor-associated factor 3, and signal transducer and activator of transcription 1 are prone to herpes simplex virus-1 encephalitis, owing to impaired TLR3-triggered, UNC-93B-dependent, IFN-α/β, and/or IFN-λ-mediated signal transducer and activator of transcription 1-dependent immunity.
We explore here the molecular basis of the pathogenesis of herpes simplex encephalitis in a child with a hypomorphic mutation in nuclear factor-κB (NF-κB) essential modulator, which encodes the regulatory subunit of the inhibitor of the Iκβ kinase complex.
The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-β, IFN-λ, and IL-6 mRNA and protein levels, by quantitative PCR and ELISA, respectively, upon TLR3 stimulation (TLR3 agonists or TLR3-dependent viruses). NF-κB activation was assessed by electrophoretic mobility shift assay and interferon regulatory factor 3 dimerization on native gels after stimulation with a TLR3 agonist.
The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-β, IFN-λ, and IL-6 production, owing to impaired activation of both NF-κB and IRF-3. Moreover, vesicular stomatitis virus, a potent IFN-inducer in human fibroblasts, and herpes simplex virus-1, induced only low levels of IFN-β and IFN-λ in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts.
Herpes simplex encephalitis may occur in patients carrying NF-κB essential modulator mutations, due to the impairment of NF-κB- and interferon regulatory factor 3-dependent-TLR3-mediated antiviral IFN production.
The Journal of allergy and clinical immunology 06/2011; 128(3):610-7.e1-4. · 9.17 Impact Factor
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Laurent Abel,
Sabine Plancoulaine, Emmanuelle Jouanguy,
Shen-Ying Zhang,
Nora Mahfoufi,
Nathalie Nicolas,
Vanessa Sancho-Shimizu,
Alexandre Alcaïs,
Yiqi Guo,
Annabelle Cardon, [......],
Bénédicte Héron,
Leila Lazaro,
Josette Mancini,
Jean-Michel Pedespan,
François Rivier,
Louis Vallée,
Pierre Lebon,
Flore Rozenberg,
Jean-Laurent Casanova,
Marc Tardieu
[show abstract]
[hide abstract]
ABSTRACT: To test the hypothesis that predisposition to childhood herpes simplex virus (HSV) type 1 encephalitis (HSE) may be determined in part by human genetic factors.
A genetic epidemiologic survey of childhood HSE (onset at age 3 months to 15 years) over a 20-year period (1985-2004) was conducted throughout France (comprising 29 university hospital neuropediatric centers). A total of 85 children fulfilled the diagnostic criteria for inclusion. Family and personal histories were obtained by face-to-face interview for 51 patients.
No familial cases of HSE were identified in our survey; however, a high proportion (20%) of the children interviewed had a relevant family history: parental consanguinity (12% of patients), early-onset herpetic keratitis in a first-degree relative (6%), or both (2%). The narrow window of high susceptibility to HSE before age 3 years (62% of patients) further indicates that predisposition to HSE is tightly age-dependent.
This survey suggests that childhood HSE, although sporadic, may result from Mendelian predisposition (from autosomal recessive susceptibility in particular), at least in some children. There likely is incomplete penetrance, however, which may reflect, at least in part, the impact of age at the time of HSV-1 infection.
The Journal of pediatrics 10/2010; 157(4):623-9, 629.e1. · 4.02 Impact Factor
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Rebeca Pérez de Diego,
Vanessa Sancho-Shimizu,
Lazaro Lorenzo,
Anne Puel,
Sabine Plancoulaine,
Capucine Picard,
Melina Herman,
Annabelle Cardon,
Anne Durandy,
Jacinta Bustamante, [......],
Françoise Cascarrigny,
Pierre Lebon,
Flore Rozenberg,
Michael Karin,
Marc Tardieu,
Saleh Al-Muhsen, Emmanuelle Jouanguy,
Shen-Ying Zhang,
Laurent Abel,
Jean-Laurent Casanova
[show abstract]
[hide abstract]
ABSTRACT: Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple TNF receptors and receptors that induce interferon-α (IFN-α), IFN-β, and IFN-λ production, including Toll-like receptor 3 (TLR3), which is deficient in some patients with herpes simplex virus-1 encephalitis (HSE). Mice lacking TRAF3 die in the neonatal period, preventing direct investigation of the role of TRAF3 in immune responses and host defenses in vivo. Here, we report autosomal dominant, human TRAF3 deficiency in a young adult with a history of HSE in childhood. The TRAF3 mutant allele is loss-of-expression, loss-of-function, dominant-negative and associated with impaired, but not abolished, TRAF3-dependent responses upon stimulation of both TNF receptors and receptors that induce IFN production. TRAF3 deficiency is associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN. Thus, TLR3-mediated immunity against primary infection by HSV-1 in the central nervous system is critically dependent on TRAF3.
Immunity 09/2010; 33(3):400-11. · 21.64 Impact Factor
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Minji Byun,
Avinash Abhyankar,
Virginie Lelarge,
Sabine Plancoulaine,
Ayse Palanduz,
Leyla Telhan,
Bertrand Boisson,
Capucine Picard,
Scott Dewell,
Connie Zhao, Emmanuelle Jouanguy,
Stefan Feske,
Laurent Abel,
Jean-Laurent Casanova
[show abstract]
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ABSTRACT: Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca(2+) entry. STIM1 mRNA splicing, protein production, and Ca(2+) influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.
Journal of Experimental Medicine 09/2010; 207(11):2307-12. · 13.85 Impact Factor
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Bertrand Nalpas,
Roubila Lavialle-Meziani,
Sabine Plancoulaine, Emmanuelle Jouanguy,
Antoine Nalpas,
Mona Munteanu,
Frederic Charlotte,
Brigitte Ranque,
Etienne Patin,
Simon Heath, [......],
Anaïs Vallet-Pichard,
Dominique Pontoire,
Marc Bourlière,
Jean-Laurent Casanova,
Mark Lathrop,
Christian Bréchot,
Thierry Poynard,
Fumihiko Matsuda,
Stanislas Pol,
Laurent Abel
[show abstract]
[hide abstract]
ABSTRACT: Only a minority of patients with chronic hepatitis C virus (HCV) infection develops severe liver fibrosis, a process that may be controlled by human genetic factors.
To investigate the role of 384 single nucleotide polymorphisms (SNPs) located in 36 candidate genes related to the fibrogenesis/fibrolysis process.
Patients with chronic HCV infection were gathered from two French cohorts (prospectively and retrospectively). The overall sample consisted of 393 HCV-infected subjects without known risk factors for fibrosis progression, including 134 patients with severe liver fibrosis and 259 without severe fibrosis.
Only two SNPs in strong linkage disequilibrium (LD) in the interferon gamma receptor 2 gene (IFNGR2) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8x10(-5)) was observed with the G/A SNP rs9976971 with an OR of severe fibrosis for AA versus AG or GG subjects at 2.95 (95% CI 1.70 to 5.11). This effect was higher (p=9x10(-7)) when taking into account the time of follow-up, and the hazard ratio of progression towards severe fibrosis for AA patients was 2.62 (1.76 to 3.91). Refined sequencing and analysis of the IFNGR2 region identified two additional variants in strong LD with rs9976971. No haplotypes derived from this cluster of four variants provided stronger evidence for association than rs9976971 alone.
This identification of a cluster of four IFNGR2 variants strongly associated with fibrosis progression in chronic HCV infection underlines the role of IFNgamma in the development of liver fibrosis that may pave the way for new treatments.
Gut 08/2010; 59(8):1120-6. · 10.11 Impact Factor
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Aziz Bousfiha,
Capucine Picard,
Stéphanie Boisson-Dupuis,
Shen-Ying Zhang,
Jacinta Bustamante,
Anne Puel, Emmanuelle Jouanguy,
Fatima Ailal,
Jamila El-Baghdadi,
Laurent Abel,
Jean-Laurent Casanova
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ABSTRACT: The vast majority of primary immunodeficiencies (PIDs) predispose affected individuals to recurrent or chronic infectious diseases, because they affect protective immunity to both primary and secondary or latent infections. We discuss here three recently described groups of PIDs that seem to impair immunity to primary infections without compromising immunity to secondary and latent infections. Patients with mutations in IL12B or IL12RB1 typically present mycobacterial disease in childhood with a favorable progression thereafter. Cross-protection between mycobacterial infections has even been observed. Patients with mutations in IRAK4 or MYD88 suffer from pyogenic bacterial diseases, including invasive pneumococcal diseases in particular. These diseases often recur, although not always with the same serotype, but the frequency of these recurrences tails off, with no further infections observed from adolescence onwards. Finally, mutations in UNC93B1 and TLR3 are associated with childhood herpes simplex encephalitis, which strikes only once in most patients, with almost no recorded cases of more than two bouts of this disease. Unlike infections in patients with other PIDs, the clinical course of which typically deteriorates with age even if appropriate treatment is given, the prognosis of patients with these three newly described PIDs tends to improve spontaneously with age, provided, of course, that the initial infection is properly managed. In other words, although life-threatening in early childhood, these new PIDs are associated with a favorable outcome in adulthood. They provide proof-of-principle that infectious diseases of childhood striking only once may result from single-gene inborn errors of immunity.
Clinical Immunology 03/2010; 135(2):204-9. · 4.05 Impact Factor
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Gürses Sahin,
Ayse Palanduz,
Gonul Aydogan,
Olivier Cassar,
A Ulya Ertem,
Leyla Telhan,
Nur Canpolat, Emmanuelle Jouanguy,
Capucine Picard,
Antoine Gessain,
Laurent Abel,
Jean-Laurent Casanova,
Sabine Plancoulaine
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ABSTRACT: Infection by human herpesvirus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases having been reported since 1960. We recently reported 2 children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this article, we describe 3 unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at 2 years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly, and the patient died within 3 months despite treatment with vincristine. The other 2 children developed a milder form of KS at the age of 9 years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at the age of 14, 2 years after treatment. The second girl is currently stabilized with etoposide, which was begun 4 months ago. None of the 3 children had any relevant familial history or other clinical features. The occurrence of classic KS in 3 unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children.
PEDIATRICS 02/2010; 125(3):e704-8. · 4.47 Impact Factor
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ABSTRACT: This article has been withdrawn at the request of the authors and the Guest Editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
Immunology letters 10/2009; · 2.91 Impact Factor
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Ariane Chapgier,
Xiao-Fei Kong,
Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy,
Diana Averbuch,
Jacqueline Feinberg,
Shen-Ying Zhang,
Jacinta Bustamante,
Guillaume Vogt,
Julien Lejeune,
Eleonore Mayola,
Ludovic de Beaucoudrey,
Laurent Abel,
Dan Engelhard,
Jean-Laurent Casanova
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ABSTRACT: Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
The Journal of clinical investigation 06/2009; 119(6):1502-14. · 15.39 Impact Factor
