WHIM syndrome: a genetic disorder of leukocyte trafficking A. Virginia Gulino Purpose of review WHIM syndrome (the association of warts, hypogammaglobulinemia, recurrent bacterial infections, and ‘myelokathexis’) is a rare congenital form of neutropenia associated with an unusual immune disorder involving hypogammaglonulinemia and abnormal susceptibility to warts. In this review, we describe the clinical, laboratory and genetic features of WHIM syndrome. Recent findings The identification of chemokine receptor CXCR4 as the causative gene of WHIM syndrome yields new interest in the study of this disease as a model for the comprehension of CXCR4 biology in humans and highlights the importance of the chemokine network for inducing effective immune responses and governing leukocyte trafficking. Summary CXCR4 participates in several biological processes (bone marrow hematopoiesis, cardiogenesis, angiogenesis, neurogenesis) and is implicated in different clinical pathologic conditions (WHIM, HIV infection, tumor metastatization, autoimmunity). Pharmacologic agents that modulate CXCR4 expression/function are already available and promise a wide range of future clinical applications. Keywords WHIM, CXCR4, leukocyte trafficking, hematopoiesis Curr Opin Allergy Clin Immunol 3:443–450. # 2003 Lippincott Williams & Wilkins. Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA and Institute of Molecular Medicine ‘Angelo Nocivelli’, Department of Pediatrics, University of Brescia, Italy Correspondence to A. Virginia Gulino, Building 10, Room 4N112, NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA Tel: +1 301 435 8328; fax: +1 301 402 9641; e-mail: gulinov@mail.nih.gov Current Opinion in Allergy and Clinical Immunology 2003, 3:443–450 Abbreviations EBV Epstein–Barr virus G-CSF granulocyte-colony stimulating factor # 2003 Lippincott Williams & Wilkins 1528-4050 Introduction WHIM syndrome is the association of warts, hypogam- maglobulinemia, recurrent bacterial infections, and ‘myelokathexis’ (severe chronic neutropenia with hyper- plasia of the mature myeloid compartment in the bone marrow; OMIM 193670) [1,2]. Recently, it has been demonstrated that WHIM syndrome is caused by heterozygous mutations in the gene coding for the chemokine receptor CXCR4 [3 .. ]. Chemokines are widely expressed in several tissues and are involved in many biologic processes. Chemokine receptors enable cells to sense gradients of their ligands, thereby promoting cell directional migration. Cell migration is coupled with cytoskeleton reorganization, cell polariza- tion, and integrin activation. The ability of leukocytes to cross endothelial barriers is also controlled by chemo- kine–chemokine receptor interactions [4 . ]. Within the immune system, ‘inducible’ chemokines and their receptors mediate the recruitment of effector cells to sites of inflammation or infection, whereas the ‘homeo- static’ chemokines system, to which CXCL12 and its monogamous receptor CXCR4 belong, organizes both the development and the function of lymphoid organs. Chemokine-mediated migration of leukocytes allows proper time- and space-controlled cell–cell interactions and cell trafficking throughout body tissues, which are essential for induction/maintenance of both adaptive immunity and immunological surveillance [5,6 .. ]. Sev- eral lines of evidence indicate that homing of hemato- poietic cells into the bone marrow is strictly controlled by CXCL12–CXCR4 interaction [7,8 .. ]. B-cell precur- sors and plasma cells rely on CXCR4 to find their supportive niches [9–11]. CXCR4 has been shown to deliver activation/survival signals for certain subsets of cells [12 . ,13,14 .. ,15,16]. CXCR4 knock-out mice die in utero with a failure of myelo and B-lympho-poiesis in the bone marrow and multiple defects in cardiac ventricular sept formation, gut vascularization, and cerebellar neuronal migration [17–20]. Finally, CXCR4 is impli- cated in different clinical pathologic conditions: it acts as co-receptor for T-lymphotropic HIV strains [21], it determines the metastatic localization of a number of cancer types [22,23 . ], and it may promote or sustain autoimmunity [6 .. ,24,25 . ,26 .. ] (Fig. 1). Known for decades as a rare form of congenital chronic neutropenia, WHIM syndrome is a peculiar immune disorder that includes hypogammaglobulinemia and increased morbidity from both human papillomavirus and Epstein–Barr virus (EBV) infections. The discovery of the genetic basis of WHIM syndrome offers new DOI: 10.1097/01.all.0000104449.09202.d8 443