Defective B-cell-negative selection and terminal differentiation in the ICF syndrome
| Autor: | Yun Liang Jiang, Bertrand Roquelaure, Claudine Schiff, Isabelle Thuret, Carla Blanco-Betancourt, Anne Moncla, Evani M. Viegas-Péquignot, Michèle Milili |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Adolescent Immunology DNMT3B Naive B cell Immunoglobulin E Biochemistry Negative selection Antigens CD Chromosomal Instability medicine Humans DNA (Cytosine-5-)-Methyltransferases Lymphocyte Count Child B cell negative selection Immunodeficiency DNA Primers CD86 B-Lymphocytes Base Sequence biology Reverse Transcriptase Polymerase Chain Reaction Immunologic Deficiency Syndromes Cell Differentiation Syndrome Cell Biology Hematology Flow Cytometry medicine.disease Immunoglobulin A Immunoglobulin M Child Preschool Face Immunoglobulin G Mutation biology.protein Female Antibody |
| Zdroj: | Blood. 103:2683-2690 |
| ISSN: | 1528-0020 0006-4971 2683-2690 |
| Popis: | Immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Mutations in the DNA methyltransferase 3B (DNMT3B) gene are responsible for most ICF cases reported. We investigated the B-cell defects associated with agammaglobulinemia in this syndrome by analyzing primary B cells from 4 ICF patients. ICF peripheral blood (PB) contains only naive B cells; memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long heavy chain variable regions complementarity determining region 3's (VHCDR3's) enriched with positively charged residues, in contrast to normal PB transitional and mature B cells, indicating that negative selection is impaired in patients. Like anergic B cells in transgenic models, newly generated and immature B cells accumulate in PB. Moreover, these cells secrete immunoglobulins and exhibit increased apoptosis following in vitro activation. However, they are able to up-regulate CD86, indicating that mechanisms other than anergy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in immunoglobulin E (IgE) switch induction, suggesting that immunodeficiency could vary with the genetic origin of the syndrome. In this study, we determined that negative selection breakdown and peripheral B-cell maturation blockage contribute to agammaglobulinemia in the ICF syndrome. (Blood. 2004;103:2683-2690) |
| Databáze: | OpenAIRE |
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