Center detude des deficits immunitaires

Paris, France

Center detude des deficits immunitaires

Paris, France

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Schuetz C.,University of Ulm | Neven B.,Unite dImmuno Hematologie | Neven B.,University of Paris Descartes | Dvorak C.C.,University of California at San Francisco | And 29 more authors.
Blood | Year: 2014

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 nonhomologous end joining 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 might be more prominent compared with patients with T -B-NK+SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease 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. (Blood. 2014;123(2):281-289). © 2014 by The American Society of Hematology.


Al-Herz W.,Kuwait University | Al-Herz W.,Al Sabah Hospital | Bousfiha A.,Hassan II University | Casanova J.-L.,Rockefeller University | And 20 more authors.
Frontiers in Immunology | Year: 2014

We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases. © 2014 Al-Herz, Bousfiha, Casanova, Chatila, Conley, Cunningham-Rundles, Etzioni, Franco, Gaspar, Holland, Klein, Nonoyama, Ochs, Oksenhendler, Picard, Puck, Sullivan and Tang.


Moshous D.,French Institute of Health and Medical Research | Moshous D.,University of Paris Descartes | Martin E.,French Institute of Health and Medical Research | Martin E.,University of Paris Descartes | And 24 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: 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, 7, and 14 months, respectively) and profound naive T-cell lymphopenia. Objective: On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect. Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results: We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers. Conclusions: Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation. © 2013 American Academy of Allergy, Asthma & Immunology.


Hauck F.,French Institute of Health and Medical Research | Hauck F.,University of Paris Descartes | Randriamampita C.,French Institute of Health and Medical Research | Martin E.,French Institute of Health and Medical Research | And 21 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte-specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. Objective: We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. Methods: Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. Results: The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4+ T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca2+ mobilization in response to TCR stimulation. Conclusion: We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity. © 2012 American Academy of Allergy, Asthma & Immunology.


PubMed | Grenoble University Hospital Center and Center detude des deficits immunitaires
Type: Journal Article | Journal: Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | Year: 2016

Postvaccination osteo-articular mycobacterial infectious disease is a rare and potentially serious complication after Bacillus Calmette-Gurin (BCG) vaccine. We report on a case of a former preterm baby born at 30weeks of gestation who was vaccinated with BCG Copenhagen strain at 2months of age. He presented 6months later with a painful limp, which was found to be a mono-articular osteitis of the right ankle. Histology of the biopsy showed signs of mycobacterial infection and molecular analysis confirmed a BCG infection. Blood tests did not reveal any immunodeficiency associated with the disease (IFN-gamma levels were normal). The course of the disease was favorable with 9months of antibiotic therapy against mycobacteria. BCG complications should lead to screening for immunodeficiency. The prognosis of BCG osteitis is excellent if the disease is localized. No link between prematurity and BCG complications has been found to date. BCG vaccination of premature infant should be the same as for the general population.


Fischer A.,French Institute of Health and Medical Research | Fischer A.,University of Paris Descartes | Picard C.,University of Paris Descartes | Picard C.,Center dEtude des Deficits Immunitaires | And 8 more authors.
Seminars in Immunopathology | Year: 2010

The protein tyrosine kinase ZAP70 became the subject of intense scrutiny in the early nineties, when ZAP70 mutations were characterized in several young patients presenting with severe T cell immunodeficiencies. The association of a lack of expression of ZAP70 with an immunodeficiency consisting in a markedly reduced T lymphocyte-mediated immunity highlighted the crucial role of this tyrosine kinase in T cell development and function. This discovery was soon accompanied by the characterization of the substrates of ZAP70 and the signalling cascades that depend on ZAP70 activity. These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. Recently, a revival of interest for this protein came again from studies associating abnormal ZAP70 expression with pathological conditions. Some chronic lymphocytic leukemia B cells were shown to express ZAP70, and this expression was correlated with bad prognosis. Mouse models also revealed that partial defects in ZAP70 activity can be associated with autoimmunity. These last results suggested that ZAP70 is involved in the fine balance between immunity and tolerance. In this review, we will discuss the role of ZAP70 in T cell activation and focus on what we learnt from pathological conditions associated with defective expression or activity of the ZAP70 kinase. © 2010 Springer-Verlag.


De Saint Basile G.,French Institute of Health and Medical Research | De Saint Basile G.,University of Paris Descartes | De Saint Basile G.,Center dEtude des Deficits Immunitaires | Menasche G.,French Institute of Health and Medical Research | And 3 more authors.
Nature Reviews Immunology | Year: 2010

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. © 2010 Macmillan Publishers Limited. All rights reserved.


Schmid J.P.,French Institute of Health and Medical Research | Schmid J.P.,University of Paris Descartes | Cote M.,French Institute of Health and Medical Research | Cote M.,University of Paris Descartes | And 13 more authors.
Immunological Reviews | Year: 2010

Summary: 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 γ-interferon as an attractive therapeutic target to downregulate uncontrolled macrophage activation, which sustains clinical and biological features of HLH. © 2010 John Wiley & Sons A/S.


Gerart S.,French Institute of Health and Medical Research | Gerart S.,University of Paris Descartes | Siberil S.,French Institute of Health and Medical Research | Siberil S.,University of Paris Descartes | And 12 more authors.
Blood | Year: 2013

Invariant natural killer (iNKT) T cells and mucosal-associated invariant T (MAIT) cells represent peculiar T-lymphocyte subpopulations with innate-like properties that differ from conventional T cells. iNKT are reduced in the primary immunodeficiency caused by mutations in the X-linked inhibitor of apoptosis (XIAP). By studying the mechanism of this depletion, we herein report that iNKT cells exhibit a high susceptibility to apoptosis that is not observed with conventional T cells. Elevated expression of caspases 3 and 7 accounts for the proapoptotic phenotype of iNKT cells, which is inhibited by XIAP although it exerts a moderate effect in conventional T cells. Similarly, MAIT cells exhibit a proapoptotic propensity with elevated expression of activated caspases and are decreased in XIAP-deficient individuals. Knockdown of the transcription factor PLZF/ ZBTB-16, which is involved in the effector program of iNKT cells, diminishes their proapoptotic phenotype. Conversely, overexpression of PLZF/ZBTB-16 in conventional T cells leads to a proapoptotic phenotype. Our findings identify a previously unknown pathway of regulation of innate-like T-cell homeostasis depending on XIAP and PLZF. The proapoptotic feature of iNKT cells also gives a reliable explanation of their exhaustion observed in different human conditions including the XIAP immunodeficiency. © 2013 by The American Society of Hematology.

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