WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
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.
Balabanian
Karl
K
Unité d'Immunologie Virale, Institut Pasteur, 75724 Paris, France.
Lagane
Bernard
B
Pablos
José Luis
JL
Laurent
Lysiane
L
Planchenault
Thierry
T
Verola
Olivier
O
Lebbe
Celeste
C
Kerob
Delphine
D
Dupuy
Alain
A
Hermine
Olivier
O
Nicolas
Jean-François
JF
Latger-Cannard
Véronique
V
Bensoussan
Danièle
D
Bordigoni
Pierre
P
Baleux
Françoise
F
Le Deist
Françoise
F
Virelizier
Jean-Louis
JL
Arenzana-Seisdedos
Fernando
F
Bachelerie
Françoise
F
D000293:Adolescent; D000328:Adult; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000276:immunology; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology*; D018389:Codon, Nonsense; D005260:Female; D019204:GTP-Binding Proteins / Q000276:immunology; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D019655:Quantitative Trait, Heritable; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014860:Warts / Q000235:genetics / Q000276:immunology / Q000473:pathology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D018389:Codon, Nonsense; D019718:Receptors, CXCR4; D019204:GTP-Binding Proteins