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...

No abstract