Clinical, molecular, and cellular immunologic findings in patients with SP110 -associated veno-occlusive disease with immunodeficiency syndrome

• Published in: Journal of allergy and clinical immunology Vol. 130; no. 3; pp. 735 - 742.e6
• Main Authors: Cliffe, Simon T., BSc(Hons), Bloch, Donald B., MD, PhD, Suryani, Santi, BSc(Hons), PhD, Kamsteeg, Erik-Jan, PhD, Avery, Danielle T., BAppSci, Palendira, Umaimainthan, BSc(Hons), PhD, Church, Joseph A., MD, Wainstein, Brynn K., MBBS, FRACP, Trizzino, Antonino, MD, Lefranc, Gérard, PhD, Akatcherian, Carlo, MD, Megarbané, André, MD, PhD, Gilissen, Christian, PhD, Moshous, Despina, MD, Reichenbach, Janine, MD, Misbah, Siraj, MD, Salzer, Uli, PhD, Abinun, Mario, FRCP, Ong, Peck Y., MD, Stepensky, Polina, MD, Ruga, Ezia, MD, Ziegler, John B., MD, FRACP, Wong, Melanie, MBBS, PhD, FRACP, Tangye, Stuart G., BSc(Hons), PhD, Lindeman, Robert, MBBS, PhD, FRACP, Buckley, Michael F., MBChB, PhD, FRCPA, FRCPath, Roscioli, Tony, MBBS, PhD, FRACP
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.09.2012; Elsevier
• Subjects: Adult; Allergy and Immunology; B-cell development; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Biological and medical sciences; CD40 antigen; Child; Child, Preschool; Differentiation; DNA sequencing; Flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Hepatic Veno-Occlusive Disease - drug therapy; Hepatic Veno-Occlusive Disease - genetics; Hepatic Veno-Occlusive Disease - immunology; Humans; Hypogammaglobulinemia; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunodeficiency; Immunoglobulins, Intravenous - therapeutic use; Immunologic Deficiency Syndromes - drug therapy; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunopathology; Immunophenotyping; Infant; Interleukin 21; Liver diseases; Lymphocytes B; Lymphocytes T; Macrophages; Medical sciences; Minor Histocompatibility Antigens; Mutation; Nuclear Proteins - analysis; Nuclear Proteins - genetics; Quantitation; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; SP110; veno-occlusive disease; Veno-occlusive disease with immunodeficiency; CD40L; Cytomegalovirus; SP110; Hepatic veno-occlusive disease; BMT; Bone marrow transplantation; Intravenous immunoglobulin; DAVID; IVIG; Veno-occlusive disease with immunodeficiency syndrome; hypogammaglobulinemia; Database for Annotation, Visualization and Integrated Discovery; CMV; B-cell development; hVOD; Veno-occlusive disease with immunodeficiency; CD40 ligand; VODI; Statistical Analysis of Microarrays; SAM; Human; Cell proliferation; Immunopathology; Venoocclusive disease; Agammaglobulinemia; B-Lymphocyte; Immune deficiency; Symptomatology; Association; Immunology; Cell
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.02.054

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.