Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome

Abstract

The chemokine receptor CXCR4 and its functional ligand, CXCL12, are essential regulators of development and homeostasis of hematopoietic and lymphoid organs. Heterozygous truncating mutations in the CXCR4 intracellular tail cause a rare genetic disease known as WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), whose pathophysiology remains unclear. We report CXCR4 function in 3 patients with WHIM syndrome carrying heterozygous truncating mutations of CXCR4. We show that CXCR4 gene mutations in WHIM patients do not affect cell surface expression of the chemokine receptor and its internalization upon stimulation with CXCL12. Moreover, no significant differences in calcium mobilization in response to CXCL12 are found. However, the chemotactic response of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is increased. IntroductionWHIM syndrome is a rare disease characterized by warts, hypogammaglobulinemia, recurrent respiratory bacterial infections, and myelokathexis, defined as the presence of an increased proportion of mature myeloid cells with degenerative changes in the bone marrow, associated with severe neutropenia in the peripheral blood. [1][2][3] This condition, most often inherited as an autosomal dominant trait, is caused by heterozygous truncating mutations in the C-terminus tail of the chemokine receptor CXCR4. 4 CXCR4 is the only cognate receptor for the CXC-chemokine L12 (CXCL12, or stromal-derived factor-1␣ ). 5 CXCL12 is constitutively produced by stromal and endothelial cells (ECs) ubiquitously; the highest concentrations of CXCL12 are found in bone marrow, spleen red pulp, and lymph node medulla. CXCR4-CXCL12 interaction plays a key role in regulating bone marrow homeostasis [6][7][8][9] and is involved in lymphocyte trafficking. 10,11 Chemotaxis and integrin-mediated adhesion are the main cellular responses to CXCL12 9,12-16 ; in addition, CXCR4 signaling participates in several cellular activation and proliferation processes. 17,18 Both CXCR4-and CXCL12-deficient mice display a lethal phenotype, with severe impairment of myeloid and B-cell generation, reduced proliferation of both triple-negative and doublepositive thymocytes, and developmental defects in cerebellum, heart, and gut vascularization. These abnormalities illustrate that this pair of molecules plays an indispensable role in controlling cell migration and influences (either directly or indirectly) survival/ proliferation of different cell types during embryogenesis. [19][20][21] Mice reconstituted with progenitor cells infected with CXCL12 intrakine (which prevents surface CXCR4 expression) suffer from impaired hematopoiesis that involves both myeloid and lymphoid cell lineages. 22 AMD3100, a pharmacologic CXCR4 antagonist, induces a rapid mobilization of hematopoietic progenitors and mature cells in a dose-dependent manner. 23 In contrast, overexpression of CXCR4 in transgenic T lymphocytes induces their accumulation in the bone marrow and causes a reduction of these cells in peripheral...

WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus–truncated CXCR4

“…Specific mutations identified in some families with myelokathexis include R334X, S339fs342X, E343X, and G335 X. 2,6,7 CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1; also known as CXCL12), play a central role in BM homing and trafficking of hematopoietic progenitor cells, mobilization of lymphocytes, and release of developing neutrophils from bone marrow. 1,[8][9][10] Mice lacking CXCR4 demonstrate defective hematopoiesis and cerebellar and cardiovascular development and die perinatally, highlighting the importance of CXCR4 in these organ systems.…”

Hématopoïèse humaine : des cellules CD34 aux lymphocytes T

“…D'une façon similaire, aucun rôle de la chaîne γ commune (γc) du récepteur des cytokines hématopoïétiques n'est attendu dans la formation du CLP chez l'homme, compte tenu de la présence dans la moelle osseuse des patients porteurs de mutations d'un pourcentage normal de précurseurs lymphoïdes CD10 + (Isabelle André-Schmutz, données non publiées). En revanche, cette chaîne joue un rôle majeur dans le développement lymphocytaire T et NK ; l'arrêt de la maturation lymphocytaire T est en effet dû à l'absence de signalisation via le récepteur spécifique de l'IL-7, formé des deux sousunités α et γc [28].…”

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].…”