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

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 sus- IntroductionThe CXC chemokine stromal cell-derived factor 1 (SDF-1/ CXCL12) 1,2 is the sole natural ligand for CXCR4, 3,4 a broadly expressed G-protein-coupled receptor (GPCR). 5 The unique, nonpromiscuous interaction between CXCL12 and CXCR4 is critically involved in the organogenesis of a number of phylogenetically distant animal species. [6][7][8][9][10][11] In addition, B-cell lymphopoiesis and bone marrow (BM) myelopoiesis are regulated by the CXCL12/ CXCR4 axis during embryogenesis. [12][13][14] In postnatal life, the CXCL12/CXCR4 couple controls the BM homing of CD34 ϩ cells and lymphocyte trafficking. [15][16][17][18] Besides the regulation of homeostatic processes, CXCR4 has been implicated in the development of infectious 3,19 and inflammatory diseases as well as tumor metastasis. [20][21][22][23] Recently, inherited heterozygous autosomal dominant mutations of the CXCR4 gene, which result in the truncation of the carboxyl-terminus (C-tail) of the receptor, were found to be associated with the WHIM syndrome. 24 This rare immunodeficiency disease is characterized by disseminated human papillomavirus (HPV)-induced warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis, a form of neutropenia associated with abnormal retention of mature neutrophils in the BM. [25][26][27] Patients with WHIM also exhibit a marked T-cell lymphopenia. The disorder is clinically and genetically heterogeneous, 28 since hypogammaglobulinemia and verrucosis were absent in some cases, 29 and individuals with isolated myelokathexis were found to be wild type for the CXCR4 gene. 24 However, the altered mechanism accounting for the pathogenesis of the WHIM syndrome not associated to CXCR4 mutations remains unknown. Here, we provide original...

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“…7,8 Compelling evidence established that CXCR4 and its unique ligand SDF1/CXCL12 are essential for the retention of granulocytes and other myeloid-lineage cells in the bone marrow, and that disruption of CXCR4 signaling is sufficient for mobilization of neutrophils and other myeloid-lineage cells to the peripheral circulation. [9][10][11][12] Patients with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) are neutropenic because of reduced neutrophil mobilization attributable, in most cases, to "gain-of-function" mutations of CXCR4. 13,14 Selective deletion of CXCR4 in myeloid cells causes a redistribution of neutrophils from the bone marrow to the blood resulting in neutrophilia.…”

CXCR4, une cible thérapeutique dans certains déficits immunitaires rares?

“…Des anomalies ciblant des étapes différentes de la signalisation de CXCR4 ont été identifiées dans deux déficits immunitaires rares chez l'homme : la lymphopé-nie T CD4 + idiopathique (LCI) et le syndrome WHIM (SW, ou warts, hypogammaglobulinemia, infections, and myelokathexis syndrome). La LCI est associée à une altération du recyclage membranaire de CXCR4 qui entraîne une perte de fonction du RCK, alors que le SW est lié à un défaut d'inactivation de CXCR4 qui se traduit par un gain de fonction [5,6] Ce schéma présente les principales voies de signalisation associées à l'activation et à l'inactivation de CXCR4 en réponse à CXCL12. Dans le SW, la désensibilisation de CXCR4 est altérée (cadre rouge), tandis que dans la LCI, il s'agit d'un défaut de recyclage membranaire de CXCR4 (cadre bleu).…”

“…(Figure 3) [3,17]. Des formes familiales sans anomalie de CXCR4 ont également été identifiées, WHIM sauvage(s) , soulignant une hétérogénéité génétique du SW [6,20]. L'intégrité du domaine carboxy-terminal étant requise pour l'inactivation de CXCR4 (Figure 1), il était logique de suspecter que les mutations altèrent ce processus et conduisent à un gain de fonction du RCK.…”

“…Cette anomalie de l'inactivation se traduit par un gain de fonction de CXCR4, comme l'illustre l'hypersensibilité des leucocytes de ces patients à l'action chimiotactique de CXCL12. De plus, les leucocytes de patients WHIM s présentent des dysfonctionnements spécifiques de CXCR4 semblables à ceux qui sont décrits chez les patients WHIM m (Figure 3) [6]. Malgré leurs différences géné-tiques, les deux formes du SW présentent donc comme élément pathogénique commun un gain de fonction de CXCR4.…”

CXCR4, un récepteur de chimiokine aux multiples talents

“…Chez l'homme, des mutations de CXCR4 entraînant une hyper-activation de l'axe SDF-1/CXCR4 sont associées à une neutropénie avec myélokathexis, le syndrome de WHIM (Warts Hypogammaglobulinemia Infections and Myelokathexis) [6,7]. Cette neutropénie est caractérisée par une rétention anormale de neutrophiles matures dans la moelle osseuse [8].…”