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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.
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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.
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