WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12

Blood. 2005 Mar 15;105(6):2449-57. doi: 10.1182/blood-2004-06-2289. Epub 2004 Nov 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Chemokine CXCL12
  • Chemokines, CC / immunology
  • Chemokines, CXC / genetics
  • Chemokines, CXC / immunology*
  • Codon, Nonsense*
  • Female
  • GTP-Binding Proteins / immunology
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / immunology
  • Genetic Diseases, Inborn / pathology
  • Heterozygote
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / pathology
  • Lymphocytes / immunology
  • Lymphocytes / pathology
  • Male
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Open Reading Frames / genetics
  • Open Reading Frames / immunology
  • Pedigree
  • Quantitative Trait, Heritable*
  • Receptors, CXCR4 / genetics*
  • Receptors, CXCR4 / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Warts / genetics
  • Warts / immunology
  • Warts / pathology

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CC
  • Chemokines, CXC
  • Codon, Nonsense
  • Receptors, CXCR4
  • GTP-Binding Proteins