- 作者：Simon T. Cliffe ; Donald B. Bloch ; Santi Suryani ; Erik-Jan Kamsteeg ; Danielle T. Avery ; Umaimainthan Palendira ; Joseph A. Church ; Brynn K. Wainstein ; Antonino Trizzino ; G¨¦rard Lefranc ; Carlo Akatcherian ; Andr¨¦ Megarban¨¦ ; Christian Gilissen ; Despina Moshous ; Janine Reichenbach ; Siraj Misbah ; Uli Salzer ; Mario Abinun ; Peck Y. Ong ; Polina Stepensky ; et al.
- 关键词：Veno-occlusive disease with immunodeficiency ; hypogammaglobulinemia ; SP110 ; B-cell development
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2012
- 出版时间：September, 2012
- 年：2012
- 卷：130
- 期：3
- 页码：735-742.e6
- 全文大小：502 K
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.