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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2449-2457. Prepublished online as a Blood First Edition Paper on November 9, 2004; DOI 10.1182/blood-2004-06-2289. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-06-2289v1 105/6/2449    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Balabanian, K. Articles by Bachelerie, F. Search for Related Content PubMed PubMed Citation Articles by Balabanian, K. Articles by Bachelerie, F. Related Collections Immunobiology Chemokines, Cytokines, and Interleukins Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12 Karl Balabanian, Bernard Lagane, José Luis Pablos, Lysiane Laurent, Thierry Planchenault, Olivier Verola, Celeste Lebbe, Delphine Kerob, Alain Dupuy, Olivier Hermine, Jean-François Nicolas, Véronique Latger-Cannard, Danièle Bensoussan, Pierre Bordigoni, Françoise Baleux, Françoise Le Deist, Jean-Louis Virelizier, Fernando Arenzana-Seisdedos, and Françoise Bachelerie From the Unité d'Immunologie Virale, Institut Pasteur, Paris, France; the Unité de Chimie Organique, Institut Pasteur, Paris, France; the Servicio de Reumatología, Unidad de Investigación, Hospital 12 de Octubre, Madrid, Spain; the Service d'Anatomie Pathologique, Hôpital Saint-Louis, Paris, France; the Service de Dermatologie, Hôpital Saint-Louis, Paris, France; the Centre National de la Recherche Scientifique Unite Mixte de Recherche 8147, Hôpital Necker, Paris, France; the Institut National de la Santé et de la Recherche Médicale (INSERM) U503, Universite Claude Bernard et Hospices Civils de Lyon, Lyon, France; the Service d'Hématologie Biologique, Centre Hospitalo-Universitaire de Nancy, Vandoeuvre-Les-Nancy, France; the Service de Thérapie Cellulaire et Tissulaire, Centre Hospitalo-Universitaire de Nancy, Vandoeuvre-Les-Nancy, France; the Unité de Transplantation Médullaire, Centre Hospitalo-Universitaire de Nancy, Vandoeuvre-Les-Nancy, France; and the Laboratoire d'Immunologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France. The WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G-protein–coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to 3 different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein–dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biologic trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5, and CCL21, were preserved, suggesting that, in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/CXCR4 axis. We propose that the sustained CXCR4 activity in patient cells accounts for the immune-hematologic clinical manifestations and the profusion of warts characteristic of the WHIM syndrome. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Lagane, K. Y. C. Chow, K. Balabanian, A. Levoye, J. Harriague, T. Planchenault, F. Baleux, N. Gunera-Saad, F. Arenzana-Seisdedos, and F. Bachelerie CXCR4 dimerization and {beta}-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome Blood, July 1, 2008; 112(1): 34 - 44. [Abstract] [Full Text] [PDF] C. Couturier, C. Sarkis, K. Seron, S. Belouzard, P. Chen, A. Lenain, L. Corset, J. Dam, V. Vauthier, A. Dubart, et al. Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity PNAS, December 4, 2007; 104(49): 19476 - 19481. [Abstract] [Full Text] [PDF] H. K. Kim, M. De La Luz Sierra, C. K. Williams, A. V. Gulino, and G. Tosato G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells Blood, August 1, 2006; 108(3): 812 - 820. [Abstract] [Full Text] [PDF] Y. Ueda, N. F. Neel, E. Schutyser, D. Raman, and A. Richmond Deletion of the COOH-Terminal Domain of CXC Chemokine Receptor 4 Leads to the Down-regulation of Cell-to-Cell Contact, Enhanced Motility and Proliferation in Breast Carcinoma Cells Cancer Res., June 1, 2006; 66(11): 5665 - 5675. [Abstract] [Full Text] [PDF]

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