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Blood, 15 July 2004, Vol. 104, No. 2, pp. 444-452. Prepublished online as a Blood First Edition Paper on March 16, 2004; DOI 10.1182/blood-2003-10-3532. This Article Full Text (PDF) All Versions of this Article: 2003-10-3532v1 104/2/444    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gulino, V. Articles by Badolato, R. Search for Related Content PubMed PubMed Citation Articles by Gulino, V. Articles by Badolato, R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 16, 2003 Accepted March 2, 2004 Altered leukocyte response to CXCL12 in patients with Warts Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome Virginia Gulino, Daniele Moratto, Silvano Sozzani, Patrizia Cavadini, Karel Otero, Laura Tassone, Luisa Imberti, Silvia Pirovano, Lucia D Notarangelo, Roberta Soresina, Evelina Mazzolari, David L Nelson, Luigi D Notarangelo, and Raffaele Badolato* Istituto di Medicina Molecolare, Universita' di Brescia, Brescia, Italy; Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Istituto di Medicina Molecolare, Universita' di Brescia, Brescia, Italy Section of General Pathology and Immunology, Universita' di Brescia, Brescia, Italy; Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy Terzo Servizio Analisi, Spedali Civili, Brescia, Italy Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA * Corresponding author; email: badolato{at}med.unibs.it. 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 three 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 pathological 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The WHIMs of leukocytes Steven M. Holland Blood 2004 104: 301-302. [Full Text] [PDF] This article has been cited by other articles: B. Lagane, K. Y. C. Chow, K. Balabanian, A. Levoye, J. Harriague, T. Planchenault, F. Baleux, N. Gunera-Saad, F. Arenzana-Seisdedos, and F. Bachelerie CXCR4 dimerization and {beta}-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome Blood, July 1, 2008; 112(1): 34 - 44. [Abstract] [Full Text] [PDF] M. Carneiro-Sampaio and A. Coutinho Immunity to Microbes: Lessons from Primary Immunodeficiencies Infect. Immun., April 1, 2007; 75(4): 1545 - 1555. [Full Text] [PDF] T. Kawai, U. Choi, L. Cardwell, S. S. DeRavin, N. Naumann, N. L. Whiting-Theobald, G. F. Linton, J. Moon, P. M. Murphy, and H. L. Malech WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4 Blood, January 1, 2007; 109(1): 78 - 84. [Abstract] [Full Text] [PDF] H. K. Kim, M. De La Luz Sierra, C. K. Williams, A. V. Gulino, and G. Tosato G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells Blood, August 1, 2006; 108(3): 812 - 820. [Abstract] [Full Text] [PDF] S. Fontana, S. Parolini, W. Vermi, S. Booth, F. Gallo, M. Donini, M. Benassi, F. Gentili, D. Ferrari, L. D. Notarangelo, et al. Innate immunity defects in Hermansky-Pudlak type 2 syndrome Blood, June 15, 2006; 107(12): 4857 - 4864. [Abstract] [Full Text] [PDF] K. Balabanian, B. Lagane, J. L. Pablos, L. Laurent, T. Planchenault, O. Verola, C. Lebbe, D. Kerob, A. Dupuy, O. Hermine, et al. WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12 Blood, March 15, 2005; 105(6): 2449 - 2457. [Abstract] [Full Text] [PDF]

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