title: Defective B-cell-negative selection and terminal differentiation in the ICF syndrome.
abstract: 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 (V(H)CDR3'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.
authors.affiliation: Centre d'Immunologie de Marseilles-Luminy, Marseilles, France.
authors.forename: Carla E
authors.initials: CE
authors.lastname: Blanco-Betancourt
authors.forename: Anne
authors.initials: A
authors.lastname: Moncla
authors.forename: Michèle
authors.initials: M
authors.lastname: Milili
authors.forename: Yun Liang
authors.initials: YL
authors.lastname: Jiang
authors.forename: Evani M
authors.initials: EM
authors.lastname: Viegas-Péquignot
authors.forename: Bertrand
authors.initials: B
authors.lastname: Roquelaure
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thuret
authors.forename: Claudine
authors.initials: C
authors.lastname: Schiff
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000097:blood; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability / Q000235:genetics / Q000276:immunology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D017931:DNA Primers; D005145:Face / Q000002:abnormalities*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D000097584:DNA Methyltransferase 3B
chemical_list: D015703:Antigens, CD; D004248:DNA (Cytosine-5-)-Methyltransferases; D017931:DNA Primers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000097584:DNA Methyltransferase 3B