Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome - 29/08/12
Abstract |
Background |
Mutations in the SP110 gene result in infantile onset of the autosomal recessive primary immunodeficiency disease veno-occlusive disease with immunodeficiency syndrome (VODI), which is characterized by hypogammaglobulinemia, T-cell dysfunction, and a high frequency of hepatic veno-occlusive disease.
Objectives |
We sought to further characterize the clinical features, B-lineage cellular immunologic findings, and molecular pathogenesis of this disorder in 9 patients with new diagnoses, including 4 novel mutations from families of Italian, Hispanic, and Arabic ethnic origin.
Methods |
Methods used include clinical review; Sanger DNA sequencing of the SP110 gene; determination of transfected mutant protein function by using immunofluorescent studies in Hep-2 cells; quantitation of B-cell subsets by means of flow cytometry; assessments of B-cell function after stimulation with CD40 ligand, IL-21, or both; and differential gene expression array studies of EBV-transformed B cells.
Results |
We confirm the major diagnostic criteria and the clinical utility of SP110 mutation testing for the diagnosis of VODI. Analysis of 4 new alleles confirms that VODI is caused by reduced functional SP110 protein levels. Detailed B-cell immunophenotyping demonstrated that Sp110 deficiency compromises the ability of human B cells to respond to T cell–dependent stimuli and differentiate into immunoglobulin-secreting cells in vitro. Expression microarray studies have identified pathways involved in B-lymphocyte differentiation and macrophage function.
Conclusion |
These studies show that a range of mutations in SP110 that cause decreased SP110 protein levels and impaired late B-cell differentiation cause VODI and that the condition is not restricted to the Lebanese population.
Le texte complet de cet article est disponible en PDF.Key words : Veno-occlusive disease with immunodeficiency, hypogammaglobulinemia, SP110, B-cell development
Abbreviations used : BMT, CD40L, CMV, DAVID, hVOD, IVIG, SAM, VODI
Plan
Infrastructure support was provided by the Department of Haematology and Genetics, South Eastern Area Laboratory Services, Sydney, and the Department of Human Genetics, Radboud University, Nijmegen Medical Centre. D.B.B. is supported by a grant from the Massachusetts General Hospital. C.A. and A.M. were supported in part by the Research Council of the Saint Joseph University, Beirut. D.M. was supported by the Robert A Good/Jeffrey Modell Fellowship in Transplantation and Immunodeficiency. J.R. was supported by the Gebert Rüf Stiftung, Program Rare Diseases–New Approaches, grant no. GRS-046/10. S.G.T. is an NHMRC Senior Research Fellow with research funding provided by NHMRC Program Grant no. 427620. M.F.B. is the recipient of a Marie Curie Fellowship (PIIF-GA-2008-221048) from the EU Science Directorate. T.R. is supported by an Australian NHMRC postdoctoral research fellowship. |
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Disclosure of potential conflict of interest: D. Moshous has received research support from the Jeffrey Modell Foundation. J. Reichenbach has received research support from the Chronic Granulomatous Disorder Research Trust and Gebert Rüf Stiftung. M. F. Buckley has received research support from the European Union Directorate of Science. The rest of the authors declare they have no relevant conflicts of interest. |
Vol 130 - N° 3
P. 735 - septembre 2012 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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