Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular interactions promoting the in vivo expansion of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells for maintenance of immune tolerance remain poorly defined. Here we report that mobilized Lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic progenitor cells (HPCs), unlike medullary hematopoietic stem cells (HSCs), selectively drove the direct, immediate expansion of functional host-derived Treg cells, thereby preventing the progression to overt spontaneous autoimmune diabetes in nonobese diabetic mice. Treg cell expansion required cell-to-cell contact and Notch3 signaling, which was mediated selectively through the Notch ligand Jagged2 expressed by the multipotent HPC subset, as assessed by small interfering RNA (siRNA) silencing. Conversely, notwithstanding their similar multilineage microchimerism, neither sorted Jagged2(-) HPCs nor Jagged2(lo) medullary HSCs were able to expand Treg cells. These data provide evidence for a productive Notch-mediated interaction between a unique subset of mobilized hematopoietic progenitors and Treg cells. They open therapeutic perspectives for autologous transplantation of Jagged2(+) LSK progenitors to promote Treg cell expansion in T cell-mediated diseases.
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PMID:Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. 1708 81

A physiologic role for Notch signaling in hematopoiesis has been clearly defined in lymphoid differentiation, with evidence suggesting a critical role in T-cell versus B-cell fate decisions. Previously, we demonstrated that activation of endogenous Notch receptors by culture of murine lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic progenitors with exogenously presented Notch ligand, Delta1(ext-IgG), consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG(1), promoted early T-cell differentiation and increased the number of progenitors capable of short-term lymphoid and myeloid reconstitution. Here we show that culture of LSK precursors with Delta1(ext-IgG) increases the number of progenitors that are able to rapidly repopulate the thymus and accelerate early T-cell reconstitution with a diversified T-cell receptor repertoire. Most of the early T-cell reconstitution originated from cells that expressed lymphoid-associated antigens: B220, Thy1, CD25, and/or IL7Ralpha, whereas the most efficient thymic repopulation on a per cell basis originated from the smaller number of cultured cells that did not express lymphoid-associated antigens. These findings demonstrate the potential of Delta1(ext-IgG)-cultured cells for accelerating early immune reconstitution after hematopoietic cell transplantation.
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PMID:Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. 1721 87

Mastocytosis is a neoplastic disease involving mast cells (MC) and their CD34+ progenitors. Symptoms in mastocytosis are caused by biological mediators released from MC and/or the infiltration of neoplastic MC in various organs, the skin and the bone marrow being predominantly involved. A WHO consensus classification for mastocytosis exists, which is widely accepted and includes three major categories: (1) Cutaneous mastocytosis (CM), a benign disease in which MC infiltration is confined to the skin, is preferentially seen in young children and exhibits a marked tendency to regress spontaneously. (2) Systemic mastocytosis (SM) which is commonly diagnosed in adults and includes four major subtypes: (i) indolent SM (ISM, the most common form involving mainly skin and bone marrow); (ii) a unique subcategory termed SM with an associated non-mast cell clonal hematological disease (SM-AHNMD); (iii) aggressive SM usually presenting without skin lesions, and (iv) MC leukemia, probably representing the rarest variant of human leukemias. (3) The extremely rare localized extracutaneous MC neoplasms, either presenting as malignancy (MC sarcoma) or as benign tumor termed extracutaneous mastocytoma. Diagnostic criteria for mastocytosis are available and are widely accepted. SM criteria include one major criterion (multifocal compact tissue infiltration by MC) and four minor criteria: (1) prominent spindling of MC; (2) atypical immunophenotype of MC with coexpression of CD2 and/or CD25 (antigens which have not been found to be expressed on normal/reactive MC); (3) activating (somatic) point mutations of the c-kit proto-oncogene usually involving exon 17, with the imatinib-resistant type D816V being most frequent, and (4) persistently elevated serum tryptase level (>20 ng/ml). To establish the diagnosis of SM, at least one major and one minor criterion, or at least three minor criteria, have to be fulfilled. The natural clinical course of mastocytosis is variable. Most patients, in particular those with CM and ISM, remain in an indolent stage over many years or even decades, while others, in particular those with aggressive SM, SM-AHNMD, or mast cell leukemia, show a progressive course, usually with a fatal outcome.
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PMID:Mastocytosis: state of the art. 1758 83

The beta-selection checkpoint in alphabetaT lymphocyte development occurs at the double negative (DN) 3 (CD4(-)CD8(-)CD25(+)c-kit(-)) stage, when further differentiation requires a signal from the newly rearranged TCR beta chain. Thymocytes with mutations in key signaling molecules in the phosphatidylinositol 3-kinase-Akt pathway manifest defects in survival, proliferation, and differentiation past the beta-selection checkpoint. However, little information is available regarding the role of Akt itself in thymocyte development. In this study, we explore the role of the two Akt isoforms most highly expressed in the thymus, Akt1 and Akt2, in early T cell development. Using several complementary approaches, we find that deletion of Akt1 results in only minor defects in thymocyte development. The Akt1(-/-)Akt2(-/-) thymocytes manifest a severe developmental block at the DN3 stage and ultimately fail to repopulate the T cell compartment of an irradiated host. Further, we show that Akt1(-/-)Akt2(-/-) DN3 cells have decreased glucose uptake and die in response to TCR stimulation in vitro. Study of thymocytes from the genetically altered mice suggests that the cause of the developmental defect is due to apoptosis, partially caused by decreased cellular growth and metabolism at the DN3 stage. Our results show that Akt protects thymocytes from cell death during the beta-selection checkpoint.
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PMID:Akt1 and Akt2 are required for alphabeta thymocyte survival and differentiation. 1760 65

Several extrathymic T cell progenitors have been described but their various contributions to the T cell lineage puzzle are unclear. In this study, we provide evidence for a splenic Lin(-)Thy1.2(+) T cell-committed population, rare in B6 mice, abundant in TCRalpha(-/-), CD3epsilon(-/-), and nude mice, and absent in IL-7- and Rag-2-deficient mice. Neither B nor myeloid cells are generated in vivo and in vitro. The incidence of these pre-T cells is under the control of thymus and/or mature T cells, as revealed by graft experiments. Indeed, IL-7 consumption by mature T cells inhibits the growth of these pre-T cells. Moreover, the nude spleen contains an additional Lin(-)Thy1.2(+)CD25(+) subset which is detected in B6 mice only after thymectomy. We establish that the full pre-T cell potential and proliferation capacity are only present in the c-kit(low) fraction of progenitors. We also show that most CCR9(+) progenitors are retained in the spleen of nude mice, but present in the blood of B6 mice. Thus, our data describe a new T cell lineage restricted subset that accumulates in the spleen before migration to the thymus.
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PMID:Identification of an IL-7-dependent pre-T committed population in the spleen. 1770 7

The WHO has published an updated classification of mastocytosis and the criteria for the diagnosis of systemic mastocytosis (SM). These include one major criterion, compact mast cell (MC) infiltrates in extracutaneous tissues, and four minor criteria, i.e. cytomorphologic atypia with spindling of MC (>25 %), detection of the activating somatic c-kit mutation D816 V in MC, aberrant expression of CD2 and/or CD25 on MC, and an elevated serum tryptase level (>20 ng/ml). Systemic mastocytosis is diagnosed when the major plus one minor, or three minor criteria are fulfilled. In the present study, we have established methods for the detection of CD25 and the c-kit mutation D816V in paraffin-embedded bone marrow trephine biopsy specimen of 57 patients with various subtypes of mastocytoses and 239 controls. While MCs in almost all patients with SM (55/57) expressed CD25, only 2/239 of the control samples contained CD25-positive MCs. With newly designed molecular pathological methods, c-kit codon 816 mutations were detected by "peptide nucleic acid" (PNA)-mediated PCR-clamping and/or analysis of microdissected MC in 52/57 cases with SM. All cases with detectable c-kit mutations also contained CD25-positive MC. The c-kit mutation D816 V was also detected in microdissected cells of associated hematologic neoplasias in 6/15 cases. With the methods established for the investigation of paraffine-embedded tissues, the pathologist plays a central role in the diagnosis of SM.
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PMID:[Immunohistochemical and molecular characterization of systemic mastocytoses]. 1803 98

Systemic mastocytosis (SM) is characterized by the accumulation of neoplastic mast cells in bone marrow and other organs. Gastrointestinal (GI) symptoms are common in both SM and cutaneous mastocytosis [urticaria pigmentosa (UP)], and are usually caused by the release of histamine and other inflammatory mediators. Occasionally, neoplastic mast cells may also directly infiltrate the GI tract. Previous studies have suggested that enumeration of the mast cells in GI biopsies may help establish the diagnosis of SM. However, mast cells have been reported to be increased in various inflammatory diseases, and mast cell density has not been systematically evaluated in other GI disorders. Recently, expression of CD25 by mast cells in bone marrow has been shown to be specific for SM. The purpose of this study was (1) to quantitate and compare mast cells in mucosal biopsies from patients with SM involving the GI tract, UP with GI symptoms, and a control group of diverse inflammatory disorders, and (2) to determine whether immunostaining for CD25 can be used to distinguish neoplastic from reactive mast cells in GI biopsies. Seventeen GI biopsies from 6 patients with SM; 17 GI biopsies from 5 patients with UP; and 157 control cases including 10 each normal stomach, duodenum, terminal ileum, and colon, Helicobacter pylori gastritis, bile reflux gastropathy, peptic duodenitis, celiac disease, Crohn disease, ulcerative colitis, lymphocytic colitis, and collagenous colitis, 20 biopsies from 16 patients with irritable bowel syndrome, 8 biopsies from 5 patients with parasitic infections, and 9 biopsies from 7 patients with eosinophilic gastroenteritis were immunostained for mast cell tryptase, c-kit (CD117), and CD25. Mucosal mast cells were quantitated, and the presence or absence of CD25 expression on mast cells was determined. In SM patients, mast cells in the small intestine and colon numbered >100/high-power field (HPF) in nearly all cases (mean 196/HPF; range 74 to 339). This was significantly higher than in GI biopsies from UP patients (mean 17/HPF; range 8 to 32, P<0.0001) and all inflammatory diseases (P<0.01). Mast cell density in other disorders ranged from a mean of 12/HPF in H. pylori gastritis to 47/HPF in parasitic infections. Interestingly, all SM biopsies (and none of the other cases) contained aggregates or confluent sheets of mast cells. In addition, mast cells in all SM cases were positive for CD25, whereas GI mucosal mast cells in UP and all other control cases were negative. In conclusion, quantitation of mast cells can be helpful to diagnose SM in GI mucosal biopsies, although mast cells are also markedly increased in parasitic infections. Aggregates or sheets of mast cells are only seen in SM. Immunoreactivity for CD25 in GI mucosal mast cells is specific for SM and can be used to confirm the diagnosis.
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PMID:Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. 1805 23

The significance of a population in mouse bone marrow of lineage-negative (Lin(-)), Sca1-positive, c-kit-negative (LSK(-)) cells, which is reported to be devoid of long-term repopulation capacity or myeloid potential, is unknown. In this study, we show that the LSK(-) population is composed of several subsets defined by the expression of flt3, CD25, and IL-7Ralpha. The first subset was CD25(-) and more than 90% expressed either flt3, IL-7Ralpha, or both. The CD25(-)LSK(-) population had T cell, B cell, and NK cell potential in vivo, and most of this activity was localized in the flt3(+) subset, irrespective of the expression of IL-7Ralpha. Although lymphoid potential of flt3(+)LSK(-) cells in vivo was 3-fold lower than that of lin(-)Sca1(low)kit(low)IL7Ralpha(+) common lymphoid progenitors (CLPs), their cloning efficiency in vitro was 10-fold lower than that of CLPs. Furthermore, although the myeloid potential of flt3(+)LSK(-) cells was 10-fold lower than that of CLPs in the absence of M-CSF, the relative myeloid potential of both populations was similar in its presence. These observations suggest differential growth factor requirements of both populations. The second subset of LSK(-) cells was homogeneously CD25(+)flt3(-)IL7Ralpha(+) and could be generated from both CD25(-)LSK(-) cells and from CLPs, but did not engraft in immunodeficient Rag1(-/-) or Rag1(-/-)gamma(c)(-/-) hosts. This population, of which the significance is unclear, was increased in Rag1(-/-) mice and in old mice. Thus, the LSK(-) population is phenotypically and functionally heterogeneous and contains early lymphoid-committed precursors. Our findings imply that the early stages of lymphoid commitment are more complex than was thus far assumed.
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PMID:Lin-Sca1+kit- bone marrow cells contain early lymphoid-committed precursors that are distinct from common lymphoid progenitors. 1901 40

An 11-year old Caucasian female with a remote history of urticaria pigmentosa presented with a neck mass. A biopsy demonstrated a large intradermal nodule composed of unusually large epithelioid mast cells, including a prominent subset with bi-lobed and multi-lobed nuclei. By immunohistochemistry, the cells expressed CD117 (C-Kit), mast cell tryptase, CD68, and CD25, and were negative for CD163, CD1a, and S-100, confirming the diagnosis of mastocytoma. Equally prominent was an admixed infiltrate of CD68 and CD163-positive xanthomatous histiocytes that included Touton-type giant cells. Eosinophils were abundant. At 7 months follow-up, there was no recurrence of the lesion following complete excision. However, given the unusual cytologic features, close clinical observation is warranted, as the long-term biologic potential of mastocytoma with this degree of cytologic atypia is uncertain. Awareness of this unusual morphologic variant is also important as the histologic features may mimic such childhood neoplasms as juvenile xanthogranuloma and Langerhans cell histiocytosis.
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PMID:Histiocyte-rich pleomorphic mastocytoma: an uncommon variant mimicking juvenile xanthogranuloma and Langerhans cell histiocytosis. 1960 70

It is known that patients with mastocytosis have an increased risk of anaphylaxis. This also appears to be the case with patients with evidence of a clonal mast cell disorder resulting in the monoclonal mast cell activation syndrome (MMAS) who do not express the full mastocytosis phenotype. Most patients with mastocytosis are recognized by their characteristic skin lesions. An increased level of baseline serum mast cell tryptase is also an indicator for a possible clonal mast cell disorder including mastocytosis. Other markers for mast cell clonality and for mastocytosis include abnormal immunostaining of mast cells with CD25 and CD2, clustering of mast cells in tissues, abnormal mast cell morphology, and the presence of a mutation in the proto-oncogene c-kit encoding for the mast cell growth receptor KIT. As recognition depends on an understanding of mastocytosis, and this disease should be considered in patients with recurrent anaphylaxis, we describe the features of mast cell clonality, MMAS and mastocytosis, and review recent findings.
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PMID:Mastocytosis. 2051 85


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