title: 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. 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.
authors.affiliation: Clinica Pediatrica, Universita' di Brescia, c/o Spedali Civili, 25 123 Brescia, Italy.
authors.forename: Anna Virginia
authors.initials: AV
authors.lastname: Gulino
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cavadini
authors.forename: Karel
authors.initials: K
authors.lastname: Otero
authors.forename: Laura
authors.initials: L
authors.lastname: Tassone
authors.forename: Luisa
authors.initials: L
authors.lastname: Imberti
authors.forename: Silvia
authors.initials: S
authors.lastname: Pirovano
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Roberta
authors.initials: R
authors.lastname: Soresina
authors.forename: Evelina
authors.initials: E
authors.lastname: Mazzolari
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D009503:Neutropenia / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014860:Warts / Q000235:genetics / Q000276:immunology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002118:Calcium