Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression and the functional activities of different chemokine receptors (CC motif: CCR1, CCR2, CCR3, CCR5, CCR6; CXC motif: CXCR1, CXCR2, CXCR3, CXCR4, CXCR5) were investigated in 12 patients with lymphoproliferative disease of granular lymphocytes (LDGL). Six patients were characterized by the proliferation of CD3+ve GL and six patients by the expansion of CD3-ve GL. The interleukin 8 (IL-8/CXCL8) receptor CXCR1 was expressed in 12/12 patients, the CXCR4 in 6/12 patients (four CD3+ve and two CD3-ve) and the CXCR3 in 3/12 patients (one CD3+ve and two CD3-ve). CXCR1 was expressed only by proliferating GL. Other CC and CXC receptors were not expressed on proliferating GL (< 2%). In functional assays, purified GL from the patients displayed significant migration in response to specific chemokines, indicating that CXCR1, CXCR3 and CXCR4 were functionally active in these patients. In addition, a significant reduction of IL-8/CXCL8-mediated cell migration was reported in the presence of anti-CXCR1 monoclonal antibody. Our results indicate that expanding cells from patients with LDGL express specific CXCR. These data may help to define functional properties of proliferating GL in patients with LDGL and contribute toward the understanding of the complex clinical features of this disease. In particular, as CXCR1 was expressed in all of the patients studied, we speculate that abnormal expression of this receptor on proliferating GL might play a role in the pathogenesis of neutropenia, which represents a common feature in LDGL patients.
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PMID:Upregulation of CXCR1 by proliferating cells in patients with lymphoproliferative disease of granular lymphocytes. 1261 7

WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.
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PMID:Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. 1269 54

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.
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PMID:WHIM syndrome: a defect in CXCR4 signaling. 1609 Dec 5

We investigated the role of a mutation of the CXCR4 gene in 11-year-old twin sisters with WHIM syndrome. The mutated gene may result in production of the mutant CXCR4 protein causing abnormal apoptosis and migratory function, which are thought to be related to the cause of chronic neutropenia in WHIM syndrome.
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PMID:The role of a mutation of the CXCR4 gene in WHIM syndrome. 1615 52

Warts, hypogammaglobulinaemia, infections, myelokathexis (WHIM) syndrome is an inherited immune disorder associated with CXCR4 gene mutations. Recent studies suggested that impaired receptor downregulation and enhanced chemotactic responsiveness to stromal-derived factor-1 (SDF-1), the sole cognate ligand for CXCR4, may account for the characteristic features of WHIM patients. This study evaluated whether the interaction of SDF-1 with CXCR4 could block constitutive apoptosis of peripheral blood neutrophils from congenital neutropenia patients and controls. SDF-1 was found to be a potent anti-apoptotic factor for WHIM neutrophils harbouring a truncating CXCR4 mutation, but not for neutrophils from control individuals, thus supporting the notion that such mutations may confer enhanced functional responses.
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PMID:Stromal-derived factor-1 abolishes constitutive apoptosis of WHIM syndrome neutrophils harbouring a truncating CXCR4 mutation. 1689 28

WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34(+) peripheral blood-mobilized stem cells (PBSCs) with retrovirus vector encoding wild-type (wt) CXCR4 or WHIM-type mutated CXCR4 and studied these cells ex vivo in culture and after engraftment in a nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model. Neither wt CXCR4 nor mutated CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by a CXCR4 agonist, stromal cell-derived factor-1 (SDF-1 [CXCL12]). Excess wt CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated CXCR4.
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PMID:WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4. 1694 1

WHIM (warts-hypogammaglobulinemia-infections-myelokathexis) syndrome is a recently described primary immunodeficiency disorder caused by mutation of the CXCR4 chemokine receptor gene. We report here of a 6.5-yr-old girl with bacterial infections, severe chronic neutropenia, and hypogammaglobulinemia. Sequencing the CXCR4 gene revealed a c.1013C > G sequence variant suggesting WHIM syndrome. Recurrent c.1013C > G sequence variant of the CXCR4 gene resulting in p.S338X truncation mutation of this chemokine receptor protein is first reported here.
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PMID:Recurrent CXCR4 sequence variation in a girl with WHIM syndrome. 1708 43

Inhibition of osteoclast (OC) activity has been associated with decreased tumor growth in bone in animal models. Increased recognition of factors that promote osteoclastic bone resorption in cancer patients led us to investigate whether increased OC activation could enhance tumor growth in bone. Granulocyte colony-stimulating factor (G-CSF) is used to treat chemotherapy-induced neutropenia, but is also associated with increased markers of OC activity and decreased bone mineral density (BMD). We used G-CSF as a tool to investigate the impact of increased OC activity on tumor growth in 2 murine osteolytic tumor models. An 8-day course of G-CSF alone (without chemotherapy) significantly decreased BMD and increased OC perimeter along bone in mice. Mice administered G-CSF alone demonstrated significantly increased tumor growth in bone as quantitated by in vivo bioluminescence imaging and histologic bone marrow tumor analysis. Short-term administration of AMD3100, a CXCR4 inhibitor that mobilizes neutrophils with little effect on bone resorption, did not lead to increased tumor burden. However, OC-defective osteoprotegerin transgenic (OPG(Tg)) mice and bisphosphonate-treated mice were resistant to the effects of G-CSF administration upon bone tumor growth. These data demonstrate a G-CSF-induced stimulation of tumor growth in bone that is OC dependent.
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PMID:Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner. 1719 91

Blood neutrophil counts are determined by the differentiation and proliferation of precursor cells, the release of mature neutrophils from the bone marrow, margination, trafficking and transmigration through the endothelial lining, neutrophil apoptosis, and uptake by phagocytes. This brief review summarizes the regulation of blood neutrophil counts, which is in part controlled by G-CSF, IL-17, and IL-23. Neutrophils are retained in the bone marrow through interaction of CXCL12 with its receptor CXCR4. The relevance of this mechanism is illustrated by rare diseases in which disrupting the desensitization of CXCR4 results in failure to release mature neutrophils from bone marrow. Although blood neutrophil numbers in inbred mouse strains and individual human subjects are tightly controlled, their large variation among outbred populations suggests genetic factors. One example is benign ethnic neutropenia, which is found in some African Americans. Reduced and elevated neutrophil counts, even within the normal range, are associated with excess all-cause mortality.
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PMID:Homeostatic regulation of blood neutrophil counts. 1883 68

Neutrophils are a major component of the innate immune response. Their homeostasis is maintained, in part, by the regulated release of neutrophils from the bone marrow. Constitutive expression of the chemokine CXCL12 by bone marrow stromal cells provides a key retention signal for neutrophils in the bone marrow through activation of its receptor, CXCR4. Attenuation of CXCR4 signaling leads to entry of neutrophils into the circulation through unknown mechanisms. We investigated the role of CXCR2-binding ELR+ chemokines in neutrophil trafficking using mouse mixed bone marrow chimeras reconstituted with Cxcr2(-/-) and WT cells. In this context, neutrophils lacking CXCR2 were preferentially retained in the bone marrow, a phenotype resembling the congenital disorder myelokathexis, which is characterized by chronic neutropenia. Additionally, transient disruption of CXCR4 failed to mobilize Cxcr2(-/-) neutrophils. However, neutrophils lacking both CXCR2 and CXCR4 displayed constitutive mobilization, showing that CXCR4 plays a dominant role in neutrophil trafficking. With regard to CXCR2 ligands, bone marrow endothelial cells and osteoblasts constitutively expressed the ELR+ chemokines CXCL1 and CXCL2, and CXCL2 expression was induced in endothelial cells during G-CSF-induced neutrophil mobilization. Collectively, these data suggest that CXCR2 signaling is a second chemokine axis that interacts antagonistically with CXCR4 to regulate neutrophil release from the bone marrow.
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PMID:CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. 2051 41


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