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Centenary Institute - Medical Research
Centenary Institute - Medical Research

Clinical, Molecular and Cellular Immunology Findings in SP110-associated Veno-occlusive Disease with Immunodeficiency Syndrome

BACKGROUND:

Mutations in the SP110 gene result in infantile onset of the autosomal recessive primaryimmunodeficiency disease veno-occlusive disease with immunodeficiency syndrome (VODI), which is characterized by hypogammaglobulinemia, T-cell dysfunction, and a high frequency of hepatic veno-occlusivedisease.

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 thediagnosis 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.

Simon T Cliffe, Donald B Bloch, Santi Suryani, Erik-Jan Kamsteeg, Umaimainthan Palendira, Danielle T Avery, Joseph Church, Brynn Wainstein, Antonino Trizzino, Gérard Lefranc, Carlo Akatchérian, André Mégarbané, Christian Gilissen, Despina Moshous, Janine Reichenbach, Siraj Misbah, Uli Salzer, Mario Abinun, Peck Ong, Polina Stepensky, Ezia Ruga, John B Ziegler, Melanie Wong, Stuart G Tangye, Robert Lindeman, Michael Francis Buckley, Tony Roscioli.

JACI 2012 Sep;130(3):735-742.

Date: 2012