Clinical, molecular, and cellular immunologic findings in patients withSP110-associated veno-occlusive disease with immunodeficiency syndrome

• Published in: Journal of allergy and clinical immunology Vol. 130; no. 3; p. 735
• Main Authors: Cliffe, Simon T, Bloch, Donald B, Suryani, Santi, Kamsteeg, Erik-Jan, Avery, Danielle T, Palendira, Umaimainthan, Church, Joseph A, Wainstein, Brynn K, Trizzino, Antonino, Lefranc, Gérard, Akatcherian, Carlo, Megarbané, André, Gilissen, Christian, Moshous, Despina, Reichenbach, Janine, Misbah, Siraj, Salzer, Uli, Abinun, Mario, Ong, Peck Y, Stepensky, Polina, Ruga, Ezia, Ziegler, John B, Wong, Melanie, Tangye, Stuart G, Lindeman, Robert, Buckley, Michael F, Roscioli, Tony
• Format: Journal Article
• Language: English
• Published: St. Louis Elsevier Limited 01.09.2012
• Subjects: Biopsy; Cytomegalovirus; Gene expression; Immune system; Laboratories; Mortality; Mutation; Rodents
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.02.054

Background Mutations in theSP110gene 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 theSP110gene; 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 ofSP110mutation 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 cellsin vitro. Expression microarray studies have identified pathways involved in B-lymphocyte differentiation and macrophage function. Conclusion These studies show that a range of mutations inSP110that cause decreased SP110 protein levels and impaired late B-cell differentiation cause VODI and that the condition is not restricted to the Lebanese population.