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Find video protocols related to scientific articles indexed in Pubmed.
A modified ?-retrovirus vector for X-linked severe combined immunodeficiency.
N. Engl. J. Med.
PUBLISHED: 10-09-2014
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In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based ?-retrovirus vector expressing interleukin-2 receptor ?-chain (?c) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.
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Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations.
J. Clin. Invest.
PUBLISHED: 09-18-2014
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Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in TMEM173, which encodes stimulator of type I IFN gene (STING), in the affected individuals. STING is a key signaling molecule in cytosolic DNA-sensing pathways, and STING activation normally requires dimerization, which is induced by 2'3' cyclic GMP-AMP (cGAMP) produced by the cGAMP synthase in response to cytosolic DNA. Structural modeling supported constitutive activation of the mutant STING protein based on stabilized dimerization. In agreement with the model predictions, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts and is constitutively active in the absence of exogenous 2'3'-cGAMP in vitro. Accordingly, we observed elevated serum IFN activity and a type I IFN signature in peripheral blood from affected family members. These findings highlight the key role of STING in activating both the innate and adaptive immune responses and implicate aberrant STING activation in features of human lupus.
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Contribution of high-throughput DNA sequencing to the study of primary immunodeficiencies.
Eur. J. Immunol.
PUBLISHED: 09-12-2014
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Primary immunodeficiencies (PIDs) are inborn errors of the immune system. PIDs have been characterized immunologically for the last 60 years and genetically, principally by Sanger DNA sequencing, over the last 30 years. The advent of next-generation sequencing (NGS) in 2011, with the development of whole-exome sequencing in particular, has facilitated the identification of previously unknown genetic lesions. NGS is rapidly generating a stream of candidate variants for an increasing number of genetically undefined PIDs. The use of NGS technology is ushering in a new era, by facilitating the discovery and characterization of new PIDs in patients with infections and other phenotypes, thereby helping to improve diagnostic accuracy. This review provides a historical overview of the identification of PIDs before NGS, and the advances and limitations of the use of NGS for the diagnosis and characterization of PIDs.
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott-Aldrich syndrome-like platelet defect.
Nat Commun
PUBLISHED: 09-04-2014
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Wiskott-Aldrich syndrome (WAS) is caused by mutations in the WAS gene and is characterized by immunodeficiency, eczema and microthrombocytopenia. The molecular link between WAS mutations and microthrombocytopenia is unknown. Profilin1 (Pfn1) is a key actin-regulating protein that, besides actin, interacts with phosphoinositides and multiple proline-rich proteins, including the WAS protein (WASp)/WASp-interacting protein (WIP) complex. Here we report that mice with a megakaryocyte/platelet-specific Pfn1 deficiency display microthrombocytopenia due to accelerated turnover of platelets and premature platelet release into the bone marrow. Both Pfn1-null mouse platelets and platelets isolated from WAS patients contained abnormally organized and hyperstable microtubules. These results reveal an unexpected function of Pfn1 as a regulator of microtubule organization and point to a previously unrecognized mechanism underlying the platelet formation defect in WAS patients.
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Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.
J. Allergy Clin. Immunol.
PUBLISHED: 08-27-2014
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Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases can provide insight into the pathogenesis of IBD.
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A human immunodeficiency caused by mutations in the PIK3R1 gene.
J. Clin. Invest.
PUBLISHED: 08-18-2014
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Recently, patient mutations that activate PI3K signaling have been linked to a primary antibody deficiency. Here, we used whole-exome sequencing and characterized the molecular defects in 4 patients from 3 unrelated families diagnosed with hypogammaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85? subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85? protein that lacks part of the PI3K p110-binding domain. The hypothetical loss of p85?-mediated inhibition of p110 activity was supported by elevated phosphorylation of the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patient blood revealed that naive T and memory B cell counts were low, and T cell blasts displayed enhanced activation-induced cell death, which was corrected by addition of the PI3K? inhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response to activation via the B cell receptor and TLR9, indicating a B cell defect. The phenotype exhibited by patients carrying the PIK3R1 splice site mutation is similar to that of patients carrying gain-of-function mutations in PIK3CD. Our results suggest that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
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Prevention of infections during primary immunodeficiency.
Clin. Infect. Dis.
PUBLISHED: 08-14-2014
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Because infectious diseases are a major source of morbidity and mortality in the majority of patients with primary immunodeficiencies (PIDs), the application of a prophylactic regimen is often necessary. However, because of the variety of PIDs and pathogens involved, and because evidence is scarce, practices are heterogeneous. To homogenize practices among centers, the French National Reference Center for PIDs aimed at elaborating recommendations for anti-infectious prophylaxis for the most common PIDs. We performed a literature review of infectious complications and prophylactic regimens associated with the most frequent PIDs. Then, a working group including different specialists systematically debated about chemoprophylaxis, immunotherapy, immunization, and recommendations for patients. Grading of prophylaxis was done using strength of recommendations (decreasing from A to D) and evidence level (decreasing from I to III). These might help infectious diseases specialists in the management of PIDs and improving the outcome of patients with PIDs.
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Defective anti-polysaccharide response and splenic marginal zone disorganization in ALPS patients.
Blood
PUBLISHED: 06-26-2014
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Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymphocytes is characterized by lymphoproliferation, autoimmunity, but also an increased risk of invasive bacterial infection, notably following splenectomy. We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found that 12 (10 splenectomized) had experienced 23 invasive bacterial infections mainly caused by Streptococcus pneumoniae. This vulnerability was associated with evidence of defective B-cell function characterized by low serum immunoglobulin (Ig) M, low IgM antibody production in response to S pneumoniae following nonconjugated immunization, and low blood memory B-cells counts (including marginal zone [MZ] B-cell counts). This immunodeficiency strongly correlated with intensity of lymphoproliferation. Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) infiltration of the MZ, which was depleted of B cells. MZ in ALPS patients contained an abnormally thick layer of MAdCAM-1((+)) stromal cells and an excess of DN-Ts. DN-Ts were shown to express MAdCAM-1 ligand, the ?4?7 integrin. These observations suggest that accumulating DN-Ts are trapped within stromal cell meshwork and interfere with correct localization of MZ B cells. Similar observations were made in spleens of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody production-specific defect. Splenectomy should be avoided.
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An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex.
J. Allergy Clin. Immunol.
PUBLISHED: 06-24-2014
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Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level.
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CD45RA depletion in HLA-mismatched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study.
J. Allergy Clin. Immunol.
PUBLISHED: 05-22-2014
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Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD).
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The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.
J. Allergy Clin. Immunol.
PUBLISHED: 04-23-2014
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Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor ?B activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor ?B activation and dysregulated B-cell development as defining features. For this "Current perspectives" article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.
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CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation.
Nature
PUBLISHED: 04-22-2014
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Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation. The nucleotide cytidine 5' triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.
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Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease.
J. Allergy Clin. Immunol.
PUBLISHED: 04-04-2014
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Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to diagnose and treat.
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Gene therapy for inherited immunodeficiency.
Expert Opin Biol Ther
PUBLISHED: 03-08-2014
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During the last decade, gene therapy has emerged as a convincing therapy for primary immunodeficiencies (PIDs). Ex vivo gene transfer into autologous hematopoietic stem cells (HSCs) via viral vectors permits sustained correction of T cell immunodeficiency in two forms of severe combined immunodeficiency: X-linked SCID (SCID-X1) (? chain [?c] deficiency) and adenosine deaminase deficiency. However, this success has been balanced by the occurrence of genotoxicity generated by the integration of first-generation retroviral vectors. Recently, the development of safer self-inactivating vectors has led to the initiation of new studies with the hope of equivalent efficacy and a better safety profile.
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Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.
J. Allergy Clin. Immunol.
PUBLISHED: 03-06-2014
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Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients.
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Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.
Lancet
PUBLISHED: 10-23-2013
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In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients.
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SCID patients with ARTEMIS versus RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS deficient SCID.
Blood
PUBLISHED: 10-21-2013
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A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in non-homologous end-joining (NHEJ) of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency early and late complications following hematopoietic cell transplantation (HCT) might be more prominent compared to patients with T(-)B(-)NK(+)SCID caused by RAG1/2 deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG 1/2 deficiencies transplanted either from HLA identical donors without conditioning or from HLA non-identical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host-disease (GvHD) regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however ARTEMIS deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore abnormalities in dental development and endocrine late-effects were associated with alkylation therapy in ARTEMIS deficiency.
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Phosphoinositide 3-kinase ? gene mutation predisposes to respiratory infection and airway damage.
Science
PUBLISHED: 10-17-2013
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Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-? syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110? protein, the catalytic subunit of phosphoinositide 3-kinase ? (PI3K?), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110?. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110? inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.
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Temporal and spatial compartmentalization of drug-resistant cytomegalovirus (CMV) in a child with CMV meningoencephalitis: implications for sampling in molecular diagnosis.
J. Clin. Microbiol.
PUBLISHED: 10-09-2013
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We describe a case of antiviral-resistant cytomegalovirus meningoencephalitis occurring after hematopoietic stem cell transplantation. Antiviral-resistant cytomegalovirus was identified in blood 16 months earlier. However, wild-type cytomegalovirus was evidenced in blood when the meningoencephalitis was diagnosed. Treatment of meningoencephalitis should be adapted to all previously identified resistance mutations in any compartment.
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A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency.
Blood
PUBLISHED: 10-02-2013
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Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 (n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus-negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor ?B pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.
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Primary antibody deficiencies.
Nat. Rev. Immunol.
PUBLISHED: 06-14-2013
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Primary antibody deficiencies (PADs) are the most common inherited immunodeficiencies in humans. The use of novel approaches, such as whole-exome sequencing and mouse genetic engineering, has helped to identify new genes that are involved in the pathogenesis of PADs and has enabled the characterization of the molecular pathways that are involved in B cell development and function. Here, we review the different PADs in terms of their known or putative mechanisms, which can be B cell intrinsic, B cell extrinsic or not defined so far. We also describe the clinical manifestations (including susceptibility to infections, autoimmunity and cancer) that have been associated with the various PADs.
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Outcome of patients activating an unrelated donor search for severe acquired aplastic anemia.
Am. J. Hematol.
PUBLISHED: 05-15-2013
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Patients with severe aplastic anemia (SAA) without a sibling donor receive immunosuppressive treatment (IST) with anti-thymocyte globulin (ATG). In the case of no response to IST, a voluntary unrelated donor (VUD) search is usually started. This study analyzes the outcome of ATG-refractory SAA patients activating a VUD search. Of 179 patients, 68 had at least one HLA-A, -B, and -DR matched donor identified and underwent HSCT while 50 also with a donor were not transplanted because of early death (8), late response to IST (34), transplant refusal (1), or other (7). Conversely, 61 had no matched donor, 13 of those ultimately received a mismatched HSCT. All but one received marrow stem cells. Among patients aged <17 years, those with at least one matched donor had a significant higher 4-year survival as compared to others (79% ± 6% versus 53% ± 10%, P = 0.01). There was also a survival advantage independent of recipient age when the donor search was initiated in the recent 2000-2005 study-period (74% ± 6% versus 47% ± 10%, P < 0.05). In multivariate analysis, the identification of a matched VUD tended to impact favourably on survival in patients with a recent donor search (P = 0.07). This study provides evidence for the use of unrelated donor HSCT in children and adults with IST-refractory SAA.
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Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.
Hum. Mol. Genet.
PUBLISHED: 04-15-2013
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Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, 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.
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A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside.
J. Clin. Immunol.
PUBLISHED: 04-09-2013
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The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinicians observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.
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Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.
Blood
PUBLISHED: 03-14-2013
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We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.
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Blood CD4+CD45RO+CXCR5+ T cells are decreased but partially functional in signal transducer and activator of transcription 3 deficiency.
J. Allergy Clin. Immunol.
PUBLISHED: 02-10-2013
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The generation of high-affinity antibodies requires the presence of a population of CD4+ T cells (follicular TH [TFH] cells) in the lymph node follicles. These cells differ from TH1, TH2, and TH17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13. Small numbers of nonactivated CD4+CD45RO+CXCR5+ T cells are also found in the blood.
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Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation.
J. Allergy Clin. Immunol.
PUBLISHED: 01-22-2013
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Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia.
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Gene therapy of primary T cell immunodeficiencies.
Gene
PUBLISHED: 01-11-2013
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Gene therapy of severe combined immunodeficiencies has been proven to be effective to provide sustained correction of the T cell immunodeficiencies. This has been achieved for 2 forms of SCID, i.e SCID-X1 (?c deficiency) and adenosine deaminase deficiency. Occurrence of gene toxicity generated by integration of first generation retroviral vectors, as observed in the SCID-X1 trials has led to replace these vectors by self inactivated (SIN) retro(or lenti) viruses that may provide equivalent efficacy with a better safety profile. Results of ongoing clinical studies in SCID as well as in other primary immunodeficiencies, such as the Wiskott Aldrich syndrome, will be thus very informative.
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MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival.
Blood
PUBLISHED: 12-14-2011
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The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacterial and viral infections and autoimmune manifestations. MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated. These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency. Our results characterize a new mechanism in primary T-cell immunodeficiencies and highlight a role of the MST1/FOXO1 pathway in controlling the death of human naive T cells.
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Multicentric Castleman disease in an HHV8-infected child born to consanguineous parents with systematic review.
Pediatrics
PUBLISHED: 12-12-2011
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Childhood multicentric Castleman disease (MCD) is a rare and unexplained lymphoproliferative disorder. We report a human herpesvirus-8 (HHV-8)-infected child, born to consanguineous Comorian parents, who displayed isolated MCD in the absence of any known immunodeficiency. We also systematically review the clinical features of the 32 children previously reported with isolated and unexplained MCD. The characteristics of this patient and the geographic areas of origin of most previous cases suggest that pediatric MCD is associated with HHV-8 infection. Moreover, as previously suggested for Kaposi sarcoma, MCD in childhood may result from inborn errors of immunity to HHV-8 infection.
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Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey.
Clin. Infect. Dis.
PUBLISHED: 11-15-2011
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Invasive fungal infection (IFI) represents a life-threatening condition for patients with chronic granulomatous disease (CGD) and causes one-third of deaths in this population. This study offers a descriptive review of invasive mold infection (mIFI) in children with CGD over an extended period of time.
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Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.
Circ Cardiovasc Genet
PUBLISHED: 11-14-2011
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Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described.
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Hematologically important mutations: leukocyte adhesion deficiency (first update).
Blood Cells Mol. Dis.
PUBLISHED: 10-18-2011
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Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, mutations are found in ITGB2, the gene that encodes the ? subunit of the ?(2) integrins. This syndrome is characterized directly after birth by delayed separation of the umbilical cord. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Le(a) and Le(b) blood group antigens. Finally, in LAD-III (also called LAD-I/variant) the conformational activation of the hematopoietically expressed ? integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of ? integrin conformation.
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Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients.
Blood
PUBLISHED: 09-08-2011
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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.
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A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation.
Blood
PUBLISHED: 09-01-2011
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Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients.
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Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency.
Front Immunol
PUBLISHED: 08-25-2011
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We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases.
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Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy.
Mol. Ther.
PUBLISHED: 08-23-2011
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Vector-associated side effects in clinical gene therapy have provided insights into the molecular mechanisms of hematopoietic regulation in vivo. Surprisingly, many retrovirus insertion sites (RIS) present in engrafted cells have been found to cluster nonrandomly in close association with specific genes. Our data demonstrate that these genes directly influence the in vivo fate of hematopoietic cell clones. Analysis of insertions thus far has been limited to individual clinical studies. Here, we studied >7,000 insertions retrieved from various studies. More than 40% of all insertions found in engrafted gene-modified cells were clustered in the same genomic areas covering only 0.36% of the genome. Gene classification analyses displayed significant overrepresentation of genes associated with hematopoietic functions and relevance for cell growth and survival in vivo. The similarity of insertion distributions indicates that vector insertions in repopulating cells cluster in predictable patterns. Thus, insertion analyses of preclinical in vitro and murine in vivo studies as well as vector insertion repertoires in clinical trials yielded concerted results and mark a small number of interesting genomic loci and genes that warrants further investigation of the biological consequences of vector insertions.
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Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita.
J. Allergy Clin. Immunol.
PUBLISHED: 07-07-2011
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Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation.
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Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.
J. Exp. Med.
PUBLISHED: 07-04-2011
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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-?. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-?/?, IFN-?, IFN-?, 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-?/?, IFN-?, 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.
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Cutaneous findings in sporadic and familial autosomal dominant hyper-IgE syndrome: a retrospective, single-center study of 21 patients diagnosed using molecular analysis.
J. Am. Acad. Dermatol.
PUBLISHED: 06-24-2011
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Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES.
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Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study.
Blood
PUBLISHED: 06-09-2011
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In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.
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New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein.
Blood
PUBLISHED: 05-26-2011
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Nuclear factor-?B essential modulator (NEMO), the regulatory subunit of the I?B kinase complex, is a critical component of the NF-?B pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID-causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID-causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients cells showed an impairment of the classic NF-?B signaling pathways after activation of 2 NEMO ubiquitin-binding-dependent receptors, the TNF and IL-1? receptors, and in the CD40-dependent NF-?B pathway. We report the first human NEMO mutations responsible for X-linked EDA-ID found to affect the polyubiquitin binding of NEMO rather than its expression and folding. These experiments demonstrate that the binding of human NEMO to polyubiquitin is essential for NF-?B activation. They also demonstrate that the normal expression and folding of NEMO do not exclude a pathogenic role for NEMO mutations in patients with EDA-ID.
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Loss of p19Arf in a Rag1(-/-) B-cell precursor population initiates acute B-lymphoblastic leukemia.
Blood
PUBLISHED: 05-26-2011
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In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1s role in the development of B-ALL remains unclear. We chose a p19Arf(-/-)Rag1(-/-) mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1(+)CD19(+) precursor cell population and showed that Notch1 expression accelerates the cells self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34(+)CD19(+) population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans.
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Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF-? mAbs.
J. Allergy Clin. Immunol.
PUBLISHED: 05-17-2011
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Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH.
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Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG.
Blood
PUBLISHED: 05-04-2011
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The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.
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Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia.
J. Allergy Clin. Immunol.
PUBLISHED: 04-26-2011
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Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]).
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Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease.
Am. J. Gastroenterol.
PUBLISHED: 04-26-2011
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Early onset inflammatory bowel diseases (EO-IBD) developing during the first year of life are likely to reflect inherited defects in key mechanism(s) controlling intestinal homeostasis, as recently suggested for interleukin 10 (IL10). Thus, we aimed to further elaborate the hypothesis of defective anti-inflammatory responses in patients with IBD.
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Adenoviral infection presenting as an isolated central nervous system disease without detectable viremia in two children after stem cell transplantation.
J. Clin. Microbiol.
PUBLISHED: 04-13-2011
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We report two cases of adenoviral meningoencephalitis in children following allogeneic stem cell transplantation. These cases showed four similarities: isolated neurological involvement, infiltrating hyperintensities next to the third ventricle on the cerebral magnetic resonance image, the absence of concomitant detectable adenoviral viremia, and a severe clinical outcome.
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Gene therapy for primary adaptive immune deficiencies.
J. Allergy Clin. Immunol.
PUBLISHED: 02-28-2011
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Gene therapy has become an option for the treatment of 2 forms of severe combined immunodeficiency (SCID): X-linked SCID and adenosine deaminase deficiency. The results of clinical trials initiated more than 10 years ago testify to sustained and reproducible correction of the underlying T-cell immunodeficiency. Successful treatment is based on the selective advantage conferred on T-cell precursors through their expression of the therapeutic transgene. However, "first-generation" retroviral vectors also caused leukemia in some patients with X-linked SCID because of the constructs tendency to insert into active genes (eg, proto-oncogenes) in progenitor cells and transactivate an oncogene through a viral element in the long terminal repeat. These elements have been deleted from the vectors now in use. Together with the use of lentiviral vectors (which are more potent for transducing stem cells), these advances should provide a basis for the safe and effective extension of gene therapys indications in the field of primary immunodeficiencies. Nevertheless, this extension will have to be proved by examining the results of the ongoing clinical trials.
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Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood.
BMC Pediatr
PUBLISHED: 02-25-2011
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It is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done.
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Is normal hematopoiesis maintained solely by long-term multipotent stem cells?
Blood
PUBLISHED: 02-08-2011
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The understanding of the hierarchical organization of the human hematopoietic system is of major biologic and clinical significance. The validity of the conventional model in which hematopoiesis is solely maintained by a pool of multipotent long-term hematopoietic stem cells (LT-HSCs) has been recently challenged by several mouse studies. These new data point to the existence of a heterogeneous stem cell population that consists of distinct subsets of LT-HSCs, which include stem cells biased toward lineage-specific differentiation programs. This review attempts to discuss the balanced versus biased patterns of lineage output of human LT-HSCs gathered in 3 different gene therapy trials on the basis of vector integration site analysis by deep sequencing. The distribution of integration sites observed tends to support the validity of the revised model.
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Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.
J. Allergy Clin. Immunol.
PUBLISHED: 02-05-2011
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Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers.
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Occurrence of aortic aneurysms in 5 cases of Wiskott-Aldrich syndrome.
Pediatrics
PUBLISHED: 01-24-2011
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Aortic aneurysms are a rare condition in children. Here we report the occurrence of aortic aneurysms in 5 children with Wiskott-Aldrich syndrome (WAS). Three patients had a WAS score of 4, and 2 patients had a WAS score of 5, but autoimmunity was only present in 1 patient. Discovery was fortuitous in 4 cases after chest radiography or thoracic or abdominal computed tomography, which was performed to investigate unrelated symptoms; in 1 patient, thoracic pain was an alerting sign. Age at diagnosis was 10 to 16 years. Aneurysms were confined to the thoracic aorta in 4 cases and to the abdominal aorta in 1 case and were from 2 to 6 cm in size. Aortic surgery was successfully performed on the single symptomatic patient. Two other patients are alive: there has been a low progression of the aneurysm 15 years after hematopoietic stem cell transplantation in 1 patient and no evidence of progression after 12 years of follow-up without hematopoietic stem cell transplantation in the second patient. Two patients died 2 and 4 years after diagnosis from unrelated complications. A systematic retrospective search of 33 other patients with WAS for whom imaging material was available did not reveal the presence of aortic aneurysms. This unusual frequency of aortic aneurysm found in patients with WAS (5 of 38) indicates that aneurysm can be an underdiagnosed complication of WAS. It is presently unclear whether it is caused by an infectious and/or autoimmune/inflammatory process. Therefore, we suggest that aneurysms of large vessels should be systematically searched for in patients with WAS.
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Gene therapy for primary immunodeficiencies.
Hematol. Oncol. Clin. North Am.
PUBLISHED: 01-18-2011
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The concept of gene therapy emerged as a way of correcting monogenic inherited diseases by introducing a normal copy of the mutated gene into at least some of the patients cells. Although this concept has turned out to be quite complicated to implement, it is in the field of primary immunodeficiencies (PIDs) that proof of feasibility has been undoubtedly achieved. There is now a strong rationale in support of gene therapy for at least some PIDs, as discussed in this article.
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Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 12-06-2010
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Ig class-switch recombination (CSR) is a region-specific process that exchanges the constant Ig heavy-chain region and thus modifies an antibodys effector function. DNA lesions in switch (S) regions are induced by activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2), subsequently processed to DNA breaks, and resolved by either the classical nonhomologous end-joining pathway or the alternative end-joining pathway (XRCC4/DNA ligase 4- and/or Ku70/Ku80-independent and prone to increased microhomology usage). We examined whether the induction of DNA lesions influences DNA end-joining during CSR by analyzing S?-S? recombination junctions in various human Ig CSR defects of DNA lesion induction. We observed a progressive trend toward the usage of microhomology in S?-S? recombination junctions from AID-heterozygous to AID-autosomal dominant to UNG2-deficient B lymphocytes. We thus hypothesize that impaired induction of DNA lesions in S regions during CSR leads to unusual end-processing of the DNA breaks, resulting in microhomology-mediated end-joining, which could be an indication for preferential processing by alternative end-joining rather than by classical nonhomologous end-joining.
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Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
Blood
PUBLISHED: 11-30-2010
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X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.
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Revisiting human IL-12R?1 deficiency: a survey of 141 patients from 30 countries.
Ludovic de Beaucoudrey, Arina Samarina, Jacinta Bustamante, Aurélie Cobat, Stéphanie Boisson-Dupuis, Jacqueline Feinberg, Saleh Al-Muhsen, Lucile Jannière, Yoann Rose, Maylis de Suremain, Xiao-Fei Kong, Orchidée Filipe-Santos, Ariane Chapgier, Capucine Picard, Alain Fischer, Figen Doğu, Aydan Ikinciogullari, Gönül Tanir, Sami Al-Hajjar, Suliman Al-Jumaah, Husn H Frayha, Zobaida AlSum, Sulaiman Al-Ajaji, Abdullah Alangari, Abdulaziz Al-Ghonaium, Parisa Adimi, Davood Mansouri, Imen Ben-Mustapha, Judith Yancoski, Ben-Zion Garty, Carlos Rodríguez-Gallego, Isabel Caragol, Necil Kutukculer, Dinakantha S Kumararatne, Smita Patel, Rainer Doffinger, Andrew Exley, Olle Jeppsson, Janine Reichenbach, David Nadal, Yaryna Boyko, Barbara Pietrucha, Suzanne Anderson, Michael Levin, Liliane Schandené, Kinda Schepers, André Efira, Françoise Mascart, Masao Matsuoka, Tatsunori Sakai, Claire-Anne Siegrist, Klara Frecerova, Renate Blüetters-Sawatzki, Jutta Bernhöft, Joachim Freihorst, Ulrich Baumann, Darko Richter, Filomeen Haerynck, Frans De Baets, Vas Novelli, David Lammas, Christiane Vermylen, David Tuerlinckx, Chris Nieuwhof, Malgorzata Pac, Walther H Haas, Ingrid Müller-Fleckenstein, Bernhard Fleckenstein, Jacob Levy, Revathi Raj, Aileen Cleary Cohen, David B Lewis, Steven M Holland, Kuender D Yang, Xiaochuan Wang, Xiaohong Wang, Liping Jiang, Xiqiang Yang, Chaomin Zhu, Yuanyuan Xie, Pamela Pui Wah Lee, Koon Wing Chan, Tong-Xin Chen, Gabriela Castro, Ivelisse Natera, Ana Codoceo, Alejandra King, Liliana Bezrodnik, Daniela Di Giovani, María Isabel Gaillard, Dewton de Moraes-Vasconcelos, Anete Sevciovic Grumach, Alberto José da Silva Duarte, Ruth Aldana, Francisco Javier Espinosa-Rosales, Mohammed Bejaoui, Ahmed Aziz Bousfiha, Jamila El Baghdadi, Namik Ozbek, Güzide Aksu, Melike Keser, Ayper Somer, Nevin Hatipoğlu, Cigdem Aydogmus, Suna Asilsoy, Yildiz Camcioğlu, Saniye Gülle, Tuba T Ozgur, Meteran Ozen, Matías Oleastro, Andrea Bernasconi, Setareh Mamishi, Nima Parvaneh, Sergio Rosenzweig, Ridha Barbouche, Sigifredo Pedraza, Yu Lung Lau, Mohammad S Ehlayel, Claire Fieschi, Laurent Abel, Ozden Sanal, Jean-Laurent Casanova.
Medicine (Baltimore)
PUBLISHED: 11-09-2010
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Interleukin-12 receptor ?1 (IL-12R?1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12R?1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
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First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases.
Blood
PUBLISHED: 10-26-2010
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FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm(3) and 1232/mm(3) CD3(+) cells, 647/mm(3) and 868/mm(3) CD4(+) T cells, 213/mm(3) and 425/mm(3) naive CD4(+) T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3(+) cells, respectively. They have normal CD4 T-cell receptor ? variable repertoires. Both subjects developed antigen-specific proliferative responses and have discontinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
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Laronidase for cardiopulmonary disease in Hurler syndrome 12 years after bone marrow transplantation.
Pediatrics
PUBLISHED: 10-25-2010
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A patient with severe mucopolysaccharidosis type I (Hurler syndrome) underwent bone marrow transplantation twice (at the ages of 2 and 2.5 years), both times with his HLA-identical heterozygous brother as the donor. Between the ages of 10 and 14 years, despite 92% donor engraftment and 50% normal ?-L-iduronidase activity, he developed progressive respiratory failure with severe pulmonary arterial hypertension, upper airway obstruction, and interstitial lung disease. Noninvasive ventilation and weekly laronidase therapy were initiated. Within 24 months, his mean pulmonary artery pressure was within the upper limit of normal and interstitial lung disease and airway obstruction improved markedly. He went from using a wheelchair to having full ambulation, he no longer required daytime ventilation, and his quality-of-life scores (Child Health Assessment Questionnaire) significantly improved.
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X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease.
Blood
PUBLISHED: 10-06-2010
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X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.
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Efficacy of gene therapy for X-linked severe combined immunodeficiency.
N. Engl. J. Med.
PUBLISHED: 07-28-2010
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The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain.
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Advances in adoptive immunotherapy to accelerate T-cellular immune reconstitution after HLA-incompatible hematopoietic stem cell transplantation.
Immunotherapy
PUBLISHED: 07-20-2010
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Although partially HLA-mismatched hematopoietic stem cell transplantation (HSCT) has become an important therapeutic option for children with primary immunodeficiencies, delayed reconstitution of the T-cell compartment remains a major clinical concern. Adoptive immunotherapies to provide recipients with a protective and diverse T-cell repertoire in the months following HSCT are warranted. In order to improve T-cell reconstitution after T-cell-depleted HSCT, different strategies are currently being studied. Some are based on administration of modified mature T cells (e.g., allodepleted T cells or pathogen-specific T cells). Others aim at accelerating de novo thymopoiesis from donor-derived hematopoietic stem cells in vivo via the administration of thymopoietic agents or the transfer of large numbers of T-cell precursors generated ex vivo. The present article will provide a brief summary of recent advances in the field of allodepletion and adoptive transfer of pathogen-specific T cells and a detailed discussion of strategies for enhancing thymopoiesis in vivo.
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Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules.
Nat. Rev. Immunol.
PUBLISHED: 07-16-2010
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Cytotoxic T cells and natural killer cells are crucial for immune surveillance against virus-infected cells and tumour cells. Molecular studies of individuals with inherited defects that impair lymphocyte cytotoxic function have also highlighted the importance of cytotoxicity in the regulation and termination of immune responses. As discussed in this Review, characterization of these defects has contributed to our understanding of the key steps that are required for the maturation of cytotoxic granules and the secretion of their contents at the immunological synapse during target cell killing. This has revealed a marked similarity between cytotoxic granule exocytosis at the immunological synapse and synaptic vesicle exocytosis at the neurological synapse. We explore the possibility that comparison of these two kinetically and spatially regulated secretory pathways will provide clues to uncover additional effectors that regulate the cytotoxic function of lymphocytes.
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Isolated congenital asplenia: a French nationwide retrospective survey of 20 cases.
J. Pediatr.
PUBLISHED: 06-21-2010
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To better describe the natural history, mode of inheritance, and the epidemiological and clinical features of isolated congenital asplenia, a rare and poorly understood primary immunodeficiency.
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Inherited defects in lymphocyte cytotoxic activity.
Immunol. Rev.
PUBLISHED: 06-12-2010
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The granule-dependent cytotoxic activity of lymphocytes plays a critical role in the defense against virally infected cells and tumor cells. The importance of this cytotoxic pathway in immune regulation is evidenced by the severe and often fatal condition, known as hemophagocytic lymphohistiocytic syndrome (HLH) that occurs in mice and humans with genetically determined impaired lymphocyte cytotoxic function. HLH manifests as the occurrence of uncontrolled activation of T lymphocytes and macrophages infiltrating multiple organs. In this review, we focus on recent advances in the characterization of effectors regulating the release of cytotoxic granules, and on the role of this cytotoxic pathway in lymphocyte homeostasis and immune surveillance. Analysis of the mechanisms leading to the occurrence of hemophagocytic syndrome designates gamma-interferon as an attractive therapeutic target to downregulate uncontrolled macrophage activation, which sustains clinical and biological features of HLH.
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Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly.
Blood
PUBLISHED: 06-07-2010
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Seventeen patients transplanted with hematopoietic cells to correct severe T lymphocyte immunodeficiency resulting from complete DiGeorge anomaly were identified worldwide, and retrospective data were obtained using a questionnaire-based survey. Patients were treated at a median age of 5 months (range, 2-53 months) between 1995 and 2006. Bone marrow was used in 11 procedures in 9 cases: 6 from matched unrelated donors, 4 from human leukocyte antigen (HLA)-identical siblings, and one haploidentical parent with T-cell depletion. Unmobilized peripheral blood was used in 8 cases: 5 from HLA-identical siblings, one from a matched unrelated donor, one from an HLA-identical parent, and one unrelated matched cord blood. Conditioning was used in 5 patients and graft-versus-host disease prophylaxis in 11 patients. Significant graft-versus-host disease occurred in 9 patients, becoming chronic in 3. Median length of follow-up was 13 months, with transplantation from HLA-matched sibling showing the best results. Median survival among deceased patients (10 patients) was 7 months after transplantation (range, 2-18 months). The overall survival rate was 41%, with a median follow-up of 5.8 years (range, 4-11.5 years). Among survivors, median CD3 and CD4 counts were 806 (range, 644-1224) and 348 (range, 225-782) cells/mm(3), respectively, CD4(+)/CD45RA(+) cells remained very low, whereas mitogen responses were normalized.
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Indications for hemopoietic stem cell transplantation.
Immunol Allergy Clin North Am
PUBLISHED: 05-25-2010
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A complete list of definite, as well as possible, indications for hemopoietic stem cell transplantation in primary immunodeficiency is provided. Included are: severe combined immunodeficiency, profound T cell defects, autoimmune and autoinflammatory syndromes, innate immune defects, hemophagocytic disorders, and other conditions. Some causes and limitations are included.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.