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Capucine Picard

Publications and source records attributed to Capucine Picard.

At least 37 records · Page 2Linked to original sources
PubMed2005

NEMO mutations in 2 unrelated boys with severe infections and conical teeth.

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-kappaB essential modulator (NEMO), which is essential for nuclear factor-kappaB activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our observations indicate that conical incisors should prompt the search for NEMO mutations in boys with unusual infectious diseases.

Anodontia↗
PubMed2005

Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency.

BACKGROUND: Inherited interleukin-1-receptor-associated kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.

Anti-Bacterial Agents↗
PubMed2005

Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses.

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.

Fibroblasts↗
PubMed2005

From idiopathic infectious diseases to novel primary immunodeficiencies.

Primary immunodeficiencies are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional primary immunodeficiencies, we describe nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes. Conventional primary immunodeficiencies are suspected on the basis of a rare, striking, clinical phenotype and are defined on the basis of an overt immunologic phenotype, often leading to identification of the disease-causing gene. Nonconventional primary immunodeficiencies are defined on the basis of a more common and less marked clinical phenotype, which remains isolated until molecular cloning of the causal gene reveals a hitherto undetected immunologic phenotype. Similar concepts can be applied to primary immunodeficiencies presenting other clinical features, such as allergy and autoimmunity. Nonconventional primary immunodeficiencies thus expand the clinical boundaries of this group of inherited disorders considerably, suggesting that Mendelian primary immunodeficiencies are more common in the general population than previously thought and might affect children with a single infectious, allergic, or autoimmune disease.

Agammaglobulinemia↗
PubMed2005

Inherited disorders of human Toll-like receptor signaling: immunological implications.

In vitro nine of 10 known human Toll-like receptors (TLRs) are engaged by well-defined chemical agonists that mimic microbial compounds, raising the possibility that human TLRs play a critical role in protective immunity in vivo. We thus review here the recently described human primary immunodeficiencies caused by germline mutations in genes encoding molecules involved in cell signaling downstream from TLRs. Subjects with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) carry either X-linked recessive hypomorphic mutations in NEMO or autosomal dominant hypermorphic mutations in IKBA. Their cells show a broad defect in nuclear factor-kappaB (NF-kappaB) activation, with an impaired, but not abolished response to a large variety of stimuli including TLR agonists. EDA-ID patients show developmental anomalies of skin appendages and a broad spectrum of infectious diseases. Patients with autosomal recessive amorphic mutations in IRAK4 present a purely immunological syndrome and more restricted defects, with specific impairment of the Toll and interleukin-1 receptor (TIR)-interleukin-1 receptor-associated kinase (IRAK) signaling pathway. In these subjects, the NF-kappaB- and mitogen-activated protein kinase-mediated induction of inflammatory cytokines in response to TIR agonists is impaired. The patients present a narrow range of pyogenic bacterial infections that become increasingly rare with age. Altogether, these data suggest that human TLRs play a critical role in host defense. However, they do not provide compelling evidence, as even the infectious phenotype of patients with mutations in IRAK4 may result from impaired signaling via receptors other than TLRs. Paradoxically, these experiments of nature raise the possibility that the entire set of human TLRs is largely redundant in protective immunity in vivo.

Animals↗
PubMed2005

Heritable defects of the human TLR signalling pathways.

Recently, three human primary immunodeficiencies associated with impaired TLR signalling were described. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), either X-linked recessive or autosomal dominant, is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in nuclear factor-kappaB (NF-kappaB) activation. These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients' cells showed an impaired, but not abolished, NF-kappaB activation in response to a large set of stimuli, including TLR agonists. More recently, patients with autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. In vitro studies carried out with these patients' cells showed a specific impairment of the Toll-interleukin-1 receptor (TIR)-interleukin-1 receptor associated kinase (IRAK) signalling pathway. NF-kappaB- and mitogen activated protein kinase (MAPK) pathways are impaired in response to all TIR agonists tested. These data, therefore, suggest that TLRs play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans.

Ectodermal Dysplasia↗
PubMed2004

Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans.

Patients with inherited deficiency of the interleukin (IL)-12/IL-23-interferon (IFN)- gamma axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23-component deficiency had a history of salmonella disease than did those with IFN- gamma -component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN- gamma -independent pathways. Investigation of the IL-12/IL-23-IFN- gamma axis should be considered in patients with invasive salmonella disease.

Adolescent↗
PubMed2004

Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes.

The IL-12/IFN-gamma axis is crucial for protective immunity to Mycobacterium in humans and mice. Our goal was to analyze the relative contribution of various human blood cell subsets and molecules to the production of, or response to IL-12 and IFN-gamma. We designed an assay for the stimulation of whole blood by live M. bovis Bacillus Calmette-Guerin (BCG) alone, or BCG plus IL-12 or IFN-gamma, measuring IFN-gamma and IL-12 levels. We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF-kappaB essential modulator (NEMO), and IL-1 receptor-associated kinase-4 (IRAK-4). Patients with deficiencies in IL-12p40, IL-12 receptor beta1 chain (IL-12Rbeta1), IFN-gammaR1, IFN-gammaR2, and STAT-1 were used as internal controls. We showed that monocytes were probably the main producers of IL-12, and that NK and T cells produced similar amounts of IFN-gamma. NEMO and IRAK-4 were found to be important for IL-12 production and subsequent IFN-gamma production, while a lack of CD40L or HLA class II had no major impact on the IL-12/IFN-gamma axis. The stimulation of whole blood by live BCG thus triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes.

Adult↗
PubMed2004

Inherited disorders of NF-kappaB-mediated immunity in man.

The transcription factors of the NF-kappaB family play an important role in immunity to infection in animal models. Three human primary immunodeficiencies associated with impaired NF-kappaB signaling were recently described. X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB-kinase (IKK) complex. Autosomal dominant EDA-ID (AD-EDA-ID) is caused by a hypermorphic mutation in the gene encoding the inhibitory protein IkappaBalpha. Autosomal recessive immunodeficiency without EDA is caused by mutations in the gene encoding IRAK-4, a kinase acting upstream from the IKK complex in the TIR signaling pathway. The description of the infectious phenotypes associated with these genetic defects has initiated the forward genetic dissection of NF-kappaB-mediated immunity in man.

Animals↗
PubMed2004

HHV-8-associated Kaposi sarcoma in a child with IFNgammaR1 deficiency.

OBJECTIVES: Mediterranean classic Kaposi sarcoma (KS) of childhood is rare and unexplained. Our objective is to describe the case of a child with complete IFNgammaR1 deficiency and severe mycobacterial disease in whom Kaposi sarcoma (KS) developed. RESULTS: Disseminated mycobacterial infection began at the age of 5 months, and at 11 years of age the child had disseminated KS lesions. The histologic appearance of these lesions was typical, with endothelial and spindle cell proliferation. Human herpesvirus-8 (HHV-8)-associated antigens were detected in situ by immunohistochemistry. HHV-8 DNA of K1 molecular subtype A was amplified from tissue lesions, and HHV-8-specific antibodies were detected in the patient's serum. The child died at 12 years of age of disseminated mycobacterial disease and KS. CONCLUSIONS: This is the first identification of a well-defined primary immunodeficiency in a child with KS. Inherited disorders of IFN-gamma-mediated immunity and severe mycobacterial disease may predispose HHV-8-infected children to KS.

Child↗
PubMed2004

Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses.

We previously described a girl with recurrent episodes of pneumococcal pneumonia with septicemia and other infections,(1) found to have interleukin-1 receptor-associated kinase 4 deficiency (IRAK-4) deficiency.(2) In this report, we show that our patient is unable to sustain antibody responses either to polysaccharide or protein antigens or to a neoantigen-bacteriophage.

Antibodies, Bacterial↗
PubMed2004

Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey.

OBJECTIVES: To evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in a series of patients with inherited complete IFN-gamma receptor 1 (IFNgammaR1) deficiency. STUDY DESIGN: We report 8 patients who received altogether 11 HSCT from family donors, including 10 HLA-identical (5 siblings and 5 relatives) and 1 HLA-haplo-identical donors. Five grafts were T-cell depleted, and conditioning regimens varied in intensity. RESULTS: Four patients died within 8 months after HSCT. Two of these deaths were due to specific complications related to mycobacterial infection. There was no or very low (2%) donor cell engraftment in 2 survivors. Only 2 patients are in full remission of mycobacterial disease 5 years after HSCT. These are the only patients who received non-T-cell-depleted grafts from an HLA-identical sibling after a fully myeloablative conditioning regimen. CONCLUSIONS: HSCT can lead to prolonged remission of mycobacterial disease in children with complete IFNgammaR1 deficiency. However, optimal control of mycobacterial infection before HSCT and the use of a non-T-cell-depleted transplant from an HLA-identical sibling after a fully myeloablative conditioning regimen are recommended.

Child↗
PubMed2004

Inherited disorders of cytokines.

PURPOSE OF REVIEW: Cytokines are soluble mediators involved in the development or function of the immune system. This paper reviews the literature on childhood-onset inherited disorders associated with impaired cytokine-mediated immunity. RECENT FINDINGS: Cytokine-mediated immunity defects can be classified into seven different groups: defects in the interleukin (IL)-7 receptor (IL7RA), in the common cytokine receptor gamma chain (gammac) of the IL-2, -4, -7, -15, and -21, and in Jak3 (JAK3) downstream of the gamma chain; mutation in the IL-2 receptor alpha (IL-2RA) and defective expression of the IL-2Rbeta chain; mutations in the gene encoding for a chemokine receptor, CXCR4; mutations in five genes involved in the IL-12/23-interferon-gamma axis (IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1); mutations in three genes involved in the nuclear factor-kappaB signaling pathway (IRAK4, NEMO, IkappaBA); mutations in the tumor necrosis factor receptor signaling pathway (TNFRSF1A); and mutations in the transforming growth factor-1 gene (TGFB1). SUMMARY: Genetic cytokine-mediated immunity defects are associated with a highly heterogeneous group of clinical features, ranging from susceptibility to infections to developmental defects. This heterogeneity highlights the diversity and pleiotropy of cytokines. It is likely that many more cytokine defects and their responsive pathways will be discovered in the coming years, expanding further the heterogeneity associated with this group of childhood-onset illnesses.

Adolescent↗
PubMed2004

A novel developmental and immunodeficiency syndrome associated with intrauterine growth retardation and a lack of natural killer cells.

OBJECTIVE: To describe a novel syndrome characterized by severe prenatal and postnatal growth failure, mild skeletal and facial abnormalities, and primary immunodeficiency. DESIGN: The syndrome was observed in 2 sisters. The elder child died of cytomegalovirus infection when she was 18 months old, whereas the younger sister is doing well at 5 years old. We report here clinical, hematologic, and immunologic data for both sisters and compare them with all known inherited disorders with similar clinical or immunologic features. RESULTS: The immune defect consists of a lack of detectable natural killer cells and small numbers of CD8 alphabeta T cells and polymorphonuclear neutrophils. This is the first report of prenatal and postnatal growth failure associated with mild skeletal and facial abnormalities and primary immunodeficiency. CONCLUSION: This novel syndrome probably is caused by an autosomal recessive gene defect impairing both intrauterine growth and natural killer cell development. The identification of other kindreds with this syndrome would facilitate the search for its genetic basis.

Bone Diseases, Metabolic↗
PubMed2003

Pyogenic bacterial infections in humans with IRAK-4 deficiency.

Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.

Alleles↗
PubMed2003

Primary immunodeficiencies associated with pneumococcal disease.

PURPOSE OF REVIEW: Streptococcus pneumoniae may cause disease in patients with a variety of primary immunodeficiencies. However, no previous review has dealt with the issue of which primary immunodeficiencies predispose affected individuals to pneumococcal disease. We thus reviewed the medical literature on cases of S. pneumoniae infection in patients with primary immunodeficiency diseases, with a particular emphasis on invasive pneumococcal disease. RECENT FINDINGS: Primary immunodeficiency diseases comprise over 100 conditions, each associated with a variety of infections. Patients at high risk for pneumococcal disease include most if not all B-cell defects (whether due to an intrinsic B-cell anomaly or an impaired T-cell help), deficiencies of early components of the classical pathway of complement and C3 deficiency, congenital asplenia, anhidrotic ectodermal dysplasia with immunodeficiency (caused by impaired NF-kappaB activation), and interleukin-1 receptor associated kinase-4 deficiency. Patients with other complement deficiencies (alternative and third pathway) and hyperimmunoglobulin E syndrome show a lower risk, whereas patients with other known primary immunodeficiencies, such as phagocytic disorders, do not appear to be particularly vulnerable to S. pneumoniae. SUMMARY: Antibody- and complement-mediated opsonization, splenic macrophages and interleukin-1 receptor associated kinase-4- and nuclear factor kappaB-mediated immune responses are crucial for protective immunity to S. pneumoniae. This information is useful, not only in increasing our understanding of human immunity to S. pneumoniae, but also in the diagnostic investigation of patients with pneumococcal disease.

B-Lymphocytes↗
PubMed2002

Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency.

Four transacting genes, CIITA, RFXANK, RFX5, and RFXAP, control coordinate MHC II expression. In humans, defects in these genes result in the absence of MHC II expression and thus a combined immunodeficiency. CIITA is considered to be a master MHC II regulator and is responsible for the defect in complementation group A. Eight such affected families have been reported. We investigated the molecular basis of the defect in three patients in these families, all presenting a severe immunodeficiency. CIITA transcripts were detected in all three patients but in one at an abnormally low level. Three novel heterozygous mutations of CIITA were found in patients SP and RC. One SP CIITA allele contained a nonsense mutation, G2178A, leading to a premature stop codon and the other allele in SP was found not to be expressed. In patient RC, two in-frame deletions were detected: one of the nucleotides 3003-3084 corresponding to the exon coding from Leu(964)to Asp(991), in the paternal allele, and a CATdel3193-5 of the isoleucine codon at position 1027, in the maternal allele. Transfection of a CIITA-deficient cell line with the recombinant CATdel3193-5-CIITA cDNA revealed a loss of function for this mutant and retention of the protein in the cytoplasm. No mutations were detected in the 4.5-kb cDNA from patient OK but the level of CIITA transcript was found to be profoundly decreased. However, promoters III and IV were not affected. This last case represents the first described CIITA dysfunction due to putative mutation(s) in cis regulatory sequences of CIITA.

Amino Acid Sequence↗