Publications by authors named "Virginia Gulino"

8 Publications

  • Page 1 of 1

Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor.

PLoS One 2009 Dec 1;4(12):e8102. Epub 2009 Dec 1.

The Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since beta-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779657PMC
December 2009

Hepatitis B and C in hematopoietic stem cell transplant.

Mediterr J Hematol Infect Dis 2009 Dec 3;1(3):e2009016. Epub 2009 Dec 3.

Pediatric Hematology Hematology Departments, San Camillo Hospital, Circonvallazione Gianicolense 87, 00152 Rome, Italy.

Although the risk of acquisition of hepatitis B or hepatitis C virus through blood products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short and long term liver complications. The evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg-positive before transplant reactivate after transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should be individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT ≥ 10N concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive geno-identical donor, the risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4084/MJHID.2009.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033124PMC
December 2009

G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells.

Blood 2006 Aug 14;108(3):812-20. Epub 2006 Mar 14.

Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

CXCR4 receptor expression is required for the retention of granulocyte precursors and mature neutrophils within the bone marrow, and disruption of the SDF-1/CXCR4 axis in the bone marrow results in the mobilization of myeloid lineage cells to the peripheral circulation. We report that G-CSF down-regulates CXCR4 expression in bone marrow-derived murine and human myeloid lineage cells. When exposed to G-CSF, murine Gr1(+) bone marrow myeloid cells display a time-dependent reduction of cell-surface CXCR4 and respond poorly to SDF-1 in attachment and migration assays. Bone marrow-derived cells of nonmyeloid lineage display no change in surface CXCR4 expression upon exposure to G-CSF. Compared with controls, mice treated with G-CSF for mobilization of hematopoietic progenitor cells display reduced levels of CXCR4 selectively in bone marrow Gr1(+) myeloid cells. Since bone marrow myeloid cells express G-CSF receptors and G-CSF rapidly reduces CXCR4 expression in purified Gr1(+) cells populations, these results provide evidence that G-CSF acts directly on myeloid lineage cells to reduce CXCR4 expression. By down-regulating CXCR4 expression in bone marrow myeloid cells and attenuating their responsiveness to SDF-1, G-CSF promotes their mobilization from the bone marrow to the peripheral blood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2005-10-4162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895847PMC
August 2006

WHIM syndrome: a defect in CXCR4 signaling.

Curr Allergy Asthma Rep 2005 Sep;5(5):350-5

Department of Human Genetics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1498, New York, NY 10029, USA.

The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling cascades underlying the developmental and functional regulation of the human immune system. The first example of a human immunologic disease caused by mutation of a chemokine receptor was provided by WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, a rare, combined immunodeficiency featuring an unusual form of neutropenia. Subsequent studies following the initial description of mutations in the CXCR4 gene have revealed a striking concordance in the types of mutations observed, suggesting that impaired regulation of receptor signaling by truncation of the cytoplasmic tail domain is an essential aspect in disease pathogenesis. Biochemical studies have provided support for the model that impaired receptor downregulation leads to the characteristic immunologic and hematologic disturbances. Interestingly, these genetic studies have also identified phenocopies with the same clinical features but without mutation of CXCR4, suggesting that mutations in as yet uncharacterized downstream regulators of the receptor may be involved in a proportion of cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11882-005-0005-0DOI Listing
September 2005

Primary immune deficiencies unravel the molecular basis of immune response.

Rev Clin Exp Hematol 2003 Mar;7(1):84-111

Department of Pediatrics and Institute of Molecular Medicine Angelo Nocivelli, University of Brescia, Spedali Civili, 25123 Brescia, Italy.

Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed analysis of the clinical and laboratory features associated with these unique and rare disorders have shed light on the complex array of signals and processes that govern development and activation of the immune system. While the first examples of PID pertained to severe defects in lymphoid development, more recently a variety of gene defects have been identified in humans that do not compromize the ability to generate lymphocytes, but rather result in profound immune dysregulation. In many cases, identification of the molecular and cellular bases of PID has preceeded development of animal models by gene targeting. Finally, since the very first cases reported in humans, PID have also represented a unique tool to investigate the efficacy of novel therapeutic approaches (from molecular therapy to hematopoietic stem cell transplantation to somatic cells gene therapy), that have been applied or may apply to a variety of more common human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2003

WHIM syndrome: a genetic disorder of leukocyte trafficking.

Curr Opin Allergy Clin Immunol 2003 Dec;3(6):443-50

Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00130832-200312000-00005DOI Listing
December 2003

Tracking gene expression in primary immunodeficiencies.

Curr Opin Allergy Clin Immunol 2003 Dec;3(6):437-42

National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Purpose Of Review: Extensive research on molecular genetics in recent decades has provided a wealth of information about the mechanisms of primary immunodeficiency diseases. Microarray technology enables the survey of the expression of thousands of genes simultaneously. This review focuses on the commonly used arrays and initial applications in the study of primary immunodeficiency diseases. The application of this technology has been found to accelerate the discovery rate of gene expression disturbances in primary immunodeficiency diseases and provide potential molecular diagnostic tools.

Recent Findings: The important role of microarray technology in functional genomic study has been demonstrated by the exponential growth in the number of scientific publications in the last few years. Microarray analysis has been used to study gene expression in several immunodeficiency diseases with known gene mutations as well as those with unknown causes. It has provided snapshots of gene expression and has presented the molecular phenotypes in the cells at defined times and under certain stimulation conditions. Studies comparing differential gene expression in patients and normal controls have allowed us to better understand the immunodeficiencies at the molecular level.

Summary: Application of microarray technology in immunodeficiency study has facilitated tracking the expression of thousands of genes simultaneously. The molecular phenotypes obtained from microarray results can be used in diagnosis of diseases, supplemental to clinical phenotypes. It is a powerful survey tool that can detect disturbed gene expression in immunodeficiency diseases, which will provide clues for disease gene discovery and potential targets for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00130832-200312000-00004DOI Listing
December 2003

Hyper IgM syndromes.

Curr Opin Rheumatol 2003 Jul;15(4):422-9

Department of Pediatrics, University of Brescia, Italy.

The immune defense against extracellular pathogens is largely dependent on antibody production. Class switch recombination and somatic hypermutation shape the secondary antibody repertoire in peripheral lymphoid tissue. In the past few years, a series of primary immune deficiencies characterized by defects in these processes and collectively referred to as hyper-IgM syndromes, have been described. Careful investigation of these rare "experiments of nature" has enabled to identify novel genes and molecular events that drive terminal B-cell differentiation. Abnormalities in these genes are likely involved also in lymphoid tumorigenesis and autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00002281-200307000-00009DOI Listing
July 2003