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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2683-2690. Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-08-2632. This Article Full Text (PDF) All Versions of this Article: 2003-08-2632v1 103/7/2683    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Blanco-Betancourt, C. E Articles by Schiff, C. Search for Related Content PubMed PubMed Citation Articles by Blanco-Betancourt, C. E Articles by Schiff, C. Social Bookmarking                   What's this? Submitted August 1, 2003 Accepted November 20, 2003 B-cell negative selection and terminal differentiation are defective in the ICF syndrome Carla E Blanco-Betancourt, Anne Moncla, Michele Milili, Yun Liang Jiang, Evani M Viegas-Pequignot, Bertrand Roquelaure, Isabelle Thuret, and Claudine Schiff* Centre d'Immunologie de Marseille-Luminy, Marseille, France Departement de Genetique, Service de Gastroenterologie and Service d Hematologie Pediatrique, Hopital d'enfants de la Timone, Marseille, France Institut Jacques Monod, Paris, France * Corresponding author; email: schiff{at}ciml.univ-mrs.fr. ICF syndrome is a rare autosomal recessive disease characterized by variable Immunodeficiency, Centromeric instability and Facial anomalies. 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 and memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long VH CDR3s 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 Igs and exhibit increased apoptosis following in vitro activation. However, they are able to upregulate CD86, indicating that mechanisms other than anergy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. R. Gennery, M. A. Slatter, R. G. Bredius, M. M. Hagleitner, C. Weemaes, A. J. Cant, and A. C. Lankester Hematopoietic Stem Cell Transplantation Corrects the Immunologic Abnormalities Associated With Immunodeficiency Centromeric Instability Facial Dysmorphism Syndrome Pediatrics, November 1, 2007; 120(5): e1341 - e1344. [Abstract] [Full Text] [PDF] G. P. Sims, R. Ettinger, Y. Shirota, C. H. Yarboro, G. G. Illei, and P. E. Lipsky Identification and characterization of circulating human transitional B cells Blood, June 1, 2005; 105(11): 4390 - 4398. [Abstract] [Full Text] [PDF] N. Andre, B. Roquelaure, M. Caillez, M. Chrestian, A. Moncla, C. Blanco-Betancourt, and C. Schiff Macrophage Activation Syndrome Mimicking Life-Threatening Infection in a Patient With Variable Immunodeficiency, Centromeric Instability, and Facial Anomalies Pediatrics, October 1, 2004; 114(4): 1127 - 1127. [Full Text] [PDF]

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