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Nufar Marcus,
Hidetoshi Takada,
Jason Law,
Morton J Cowan,
Juana Gil,
Jose R Regueiro,
Diego Plaza Lopez de Sabando, Eduardo Lopez-Granados,
Jignesh Dalal,
Wilhelm Friedrich,
Hoenig Manfred,
Imelda Celine Hanson,
Eyal Grunebaum,
William T Shearer,
Chaim M Roifman
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ABSTRACT: CD3δ deficiency is a fatal form of severe combined immunodeficiency that can be cured by hematopoietic stem cell transplantation (HSCT). The presence of a thymus loaded with T-cell progenitors in patients with CD3δ deficiency may require special considerations in choosing the regimen of conditioning and the type of HSCT.
To study the outcome of CD3δ deficiency by using various modalities of stem cell transplantation.
We analyzed data on 13 patients with CD3δ deficiency who underwent HSCT in 7 centers. HSCT was performed by using different sources of donor stem cells as well as various conditioning regimens.
One patient received stem cells from a matched related donor and survived after a second transplant, needing substantial conditioning in order to engraft. Only 2 of 7 other patients who received a mismatched related donor transplant survived; 2 of them had no conditioning, whereas the others received various combinations of conditioning regimens. Engraftment of T cells in the survivors appears incomplete. Three other patients who received stem cells from a matched unrelated donor survived and enjoyed full immune reconstitution. Two patients received unrelated cord blood without conditioning. One of them has had a partial but stable engraftment, whereas the other engrafted well but is only 12 months after HSCT. We also report here for the first time that patients with CD3δ deficiency can present with typical features of Omenn syndrome.
HSCT is a successful treatment for patients with CD3δ deficiency. The small number of patients in this report prevents definitive statements on the importance of survival factors, but several are suggested: (1) HLA-matched donor transplants are associated with superior reconstitution and survival than are mismatched donor transplants; (2) substantial conditioning appears necessary; and (3) early diagnosis and absence of opportunistic infections may affect outcome.
The Journal of allergy and clinical immunology 07/2011; 128(5):1050-7. · 9.17 Impact Factor
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Stéphanie Rigaud, Eduardo Lopez-Granados,
Sophie Sibéril,
Geoffrey Gloire,
Nathalie Lambert,
Christelle Lenoir,
Cindy Synaeve,
Maria Stacey,
Lars Fugger,
Jean-Louis Stephan,
Alain Fischer,
Capucine Picard,
Anne Durandy,
Helen Chapel,
Sylvain Latour
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ABSTRACT: 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.
Blood 05/2011; 118(2):252-61. · 9.90 Impact Factor
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Jana Pachlopnik Schmid,
Danielle Canioni,
Despina Moshous,
Fabien Touzot,
Nizar Mahlaoui,
Fabian Hauck,
Hirokazu Kanegane, Eduardo Lopez-Granados,
Ester Mejstrikova,
Isabelle Pellier, [......],
Stéphanie Rigaud,
Nathalie Lambert,
Michèle Milili,
Claudin Schiff,
Helen Chapel,
Capucine Picard,
Geneviève de Saint Basile,
Stéphane Blanche,
Alain Fischer,
Sylvain Latour
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ABSTRACT: 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.
Blood 02/2011; 117(5):1522-9. · 9.90 Impact Factor
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Eduardo Lopez-Granados
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ABSTRACT: Lymphocyte differentiation from haematopoietic stem cells (HSCs) is a multi-step process in which lineage fate choices are made at crucial branch points. Plasticity of common precursors is evidenced by presence of transcriptionally favourable chromatin structures at several lineage-specific loci, making them poised for further priming and regulation. Down the differentiation tree, the interplay between lineage-specific networks of transcription factors and epigenetic modifications gradually decreases the multipotency ability of precursors and increases the compromise of cells within a particular lineage. The maintenance of a cell-specific phenotype is the result of sustained gene expression programs resulting from activation of lineage-specific and repression of lineage-discrepant loci. Theperipheral functional specialisation oflymphocytes requires furtherplasticity, to allow differentiation onto short term effectors cells, orlong term memory circulating and resident cells. Impaired differentiation of lymphocytes or deregulated or unbalanced production of certain lymphocytes subsets underlies thepathogenesis of lymphoproliferation, autoimmunity and possibly immunodeficiency. Understanding epigenetic mechanisms governing lymphocyte differentiation would allow future therapeutic interventions to prevent aberrant deviations or promote beneficial cell populations.
Advances in experimental medicine and biology 01/2011; 711:26-35. · 1.09 Impact Factor
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ABSTRACT: Common variable immunodeficiency disorders (CVIDs) are the most common forms of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment, although there are few consistent data on optimal dosages and target trough IgG levels required for infection prevention.
To provide data to support the hypothesis that each patient requires an individual dose of therapeutic immunoglobulin to prevent breakthrough infections and that efficacious trough IgG levels vary between patients.
Data, collected prospectively from a cohort of 90 patients with confirmed CVIDs from 1 center over a follow-up period of 22 years, was validated and analyzed. Immunoglobulin doses had been adjusted in accordance with infections rather than to achieve a particular trough IgG level. Doses to achieve infection-free periods were determined and resultant trough levels analyzed. A smaller group of patients with X-linked agammaglobulinemia was analyzed for comparison.
Patients with a CVID had a range of trough IgG levels that prevented breakthrough bacterial infections (5-17 g/L); viral and fungal infections were rare. Doses of replacement immunoglobulin to prevent breakthrough infections ranged from 0.2 to 1.2 g/kg/mo. Those with proven bronchiectasis or particular clinical phenotypes required higher replacement doses. Patients with X-linked agammaglobulinemia showed a similar range of IgG levels to stay infection-free (8-13 g/L).
These data offer guidance regarding optimal doses and target trough IgG levels in individual patients with CVIDs with or without bronchiectasis and for particular clinical phenotypes. The goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level.
The Journal of allergy and clinical immunology 06/2010; 125(6):1354-1360.e4. · 9.17 Impact Factor
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ABSTRACT: Alterations in nuclear factor kappa B (NF-kappaB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-kappaB inhibitor IkappaBalpha, one of two phosphorylation sites that are essential for targeting IkappaBalpha for proteasomal degradation and hence for activation of NF-kappaB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-kappaB signaling by functioning as a dominant negative on NF-kappaB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-kappaB in the human immune response.
Human Mutation 07/2008; 29(6):861-8. · 5.69 Impact Factor
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ABSTRACT: We report that osteopenia is a prominent and previously unappreciated clinical feature of patients with X-linked hyper-IgM syndrome, an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L). We therefore conducted studies to determine the relationship between CD40L and osteoclastogenesis. Recognizing that activated T cells express surface receptor activator of NF-kappaB ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, we assessed the capacity of wild-type T cells and CD40L(-/-) T cells to induce osteoclastogenesis in vitro. Relative to wild-type T cells, activated CD40L(-/-) T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L(-/-) T cells had normal expression of RANKL, they were deficient in IFN-gamma production. In subsequent studies, we cultured activated CD40L(-/-) T cells in the presence of IFN-gamma, and we found that the osteoclastic capacity of CD40L(-/-) T cells could be greatly diminished. These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome.
Proceedings of the National Academy of Sciences 04/2007; 104(12):5056-61. · 9.68 Impact Factor
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ABSTRACT: Hypomorphic mutations in the zinc finger domain of NF-kappaB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-kappaB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-kappaB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-kappaB activation and candidate factors that may be necessary for CSR and SHM in B cells.
Journal of Clinical Investigation 01/2005; 114(11):1593-602. · 15.39 Impact Factor
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Eduardo Lopez Granados,
Andrea S Porpiglia,
Mary Beth Hogan,
Nuria Matamoros,
Silvia Krasovec,
Claudio Pignata,
C I E Smith,
Lennart Hammarstrom,
Janne Bjorkander,
Bernd H Belohradsky,
G Fontan Casariego,
M C Garcia Rodriguez,
Mary Ellen Conley
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ABSTRACT: Autosomal recessive disorders of B cell development are rare and heterogeneous. To determine the proportion of affected patients who have defects in the micro heavy chain (IGHM) gene, we used single-stranded conformational polymorphism analysis to screen genomic DNA from 40 unrelated patients with early onset infections, profound hypogammaglobulinemia, and absent B cells. All of the patients were genotypically normal in BTK, the gene that underlies X-linked agammaglobulinemia. Eight different mutations in the micro heavy chain were identified in 19 members of 12 unrelated families. Four of the mutations were large deletions that removed more than 40 kb of DNA in the IGHM locus. In six of the 12 families, the affected patients had an identical single base pair substitution, a G-->A, at the -1 position of the alternative splice site. Immunoglobulin haplotype analysis showed that this mutation occurred on at least three different haplotypes, indicating that this is a hot spot for mutations. Compared with patients with mutations in Btk, patients with defects in the micro heavy chain had an earlier onset of disease and more complications. Our study indicates that at least 20-30% of patients with autosomal recessive defects in B cell development have mutations in the micro heavy chain.
Journal of Clinical Investigation 10/2002; 110(7):1029-35. · 15.39 Impact Factor
