Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome
- 15 July 2004
- journal article
- Published by American Society of Hematology in Blood
- Vol. 104 (2), 444-452
- https://doi.org/10.1182/blood-2003-10-3532
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. Furthermore, immunophenotypic analysis of circulating T and B lymphocytes reveals a decreased number of memory B cells and of naive T cells and an accumulation of effector memory T cells associated with a restricted T-cell repertoire. Based on our results, we suggest that the altered leukocyte response to CXCL12 may account for the pathologic retention of mature polymorphonuclear cells in the bone marrow (myelokathexis) and for an altered lymphocyte trafficking, which may cause the immunophenotyping abnormalities observed in WHIM patients. (Blood. 2004;104:444-452)Keywords
This publication has 51 references indexed in Scilit:
- Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonistBlood, 2003
- Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokinesBlood, 2003
- Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulationThe Journal of Experimental Medicine, 2002
- Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4Published by Elsevier BV ,2002
- Stromal cell–derived factor 1/CXCR4 signaling is critical for early human T-cell developmentBlood, 2002
- Chemokine stromal cell-derived factor-1α modulates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cellsExperimental Hematology, 2001
- Two subsets of memory T lymphocytes with distinct homing potentials and effector functionsNature, 1999
- Flow cytometric analysis of normal B cell differentiation: a frame of reference for the detection of minimal residual disease in precursor-B-ALLLeukemia, 1999
- Clinical Features of Myelokathexis and Treatment with Hematopoietic CytokinesJournal of Pediatric Hematology/Oncology, 1997
- Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1Nature, 1996