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Find video protocols related to scientific articles indexed in Pubmed.
CD1c+ blood dendritic cells have Langerhans cell potential.
Blood
PUBLISHED: 10-30-2014
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Langerhans cells (LCs) are self-renewing in the steady state but repopulated by myeloid precursors after injury. Human monocytes give rise to langerin positive cells in vitro, suggesting a potential precursor role. However, differentiation experiments with human lineage-negative cells and CD34(+) progenitors suggest that there is an alternative monocyte-independent pathway of LC differentiation. Recent data in mice also show long term repopulation of the LC compartment with alternative myeloid precursors. Here we show that, while monocytes are able to express langerin, when cultured with soluble ligands GM-CSF, TGF? and BMP7, CD1c(+) dendritic cells become much more LC-like with high langerin, Birbeck granules, EpCAM and Ecadherin expression, under the same conditions. These data highlight a new potential precursor function of CD1c(+) DCs and demonstrate an alternative pathway of LC differentiation that may have relevance in vivo.
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Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8K108E mutation.
Blood
PUBLISHED: 08-13-2014
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We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8(K108E)) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD14(+) and CD16(+) monocytes, absence of CD11c(+) conventional dendritic cells (DCs) and of CD11c(+)/CD123(+) plasmacytoid DCs (pDCs), and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8(K108E) patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and -regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD4(+) and CD8(+) T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8(K108E) are anergic. Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased SUMOylation, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8.
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Human dermal CD14? cells are a transient population of monocyte-derived macrophages.
Immunity
PUBLISHED: 05-29-2014
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Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1? CLEC9A? DCs and CD1c? DCs are murine CD103? DCs and CD64? CD11b? DCs. In addition, human tissues also contain CD14? cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14? cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14? monocytes and dermal CD14? cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14? cells are CD11b? CD64? monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.
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BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
J. Exp. Med.
PUBLISHED: 03-17-2014
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Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
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The evolution of cellular deficiency in GATA2 mutation.
Blood
PUBLISHED: 12-17-2013
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Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS) and AML. Here we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of mononuclear cytopenia (DCML deficiency) with elevated Flt3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Embergers syndrome, monoMAC, and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frame-shift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells and naïve T cells and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision making.
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Tumor necrosis factor-costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts.
Arthritis Rheum.
PUBLISHED: 04-12-2013
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The role of tumor necrosis factor (TNF) in systemic sclerosis (SSc) remains controversial. The present study was undertaken to investigate the influence of TNF receptor (TNFR)-costimulated lymphocytes on collagen expression in fibroblasts.
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Human dendritic cell deficiency: the missing ID?
Nat. Rev. Immunol.
PUBLISHED: 08-19-2011
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Animal models and human in vitro systems indicate that dendritic cells (DCs) have a crucial role in priming naive T cells, but just how important are they in the intact human? Recent descriptions of human DC deficiency have begun to shed light on this question and to illuminate other puzzles of human DC biology, including their haematopoietic origin, developmental regulation and homeostatic equilibrium with other leukocytes. In this Review, we explore the recently described DC deficiency syndromes, discussing what these have taught us with regard to DC function in humans and the important issues that remain unsolved.
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Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency.
Blood
PUBLISHED: 07-15-2011
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The human syndrome of dendritic cell, monocyte, B and natural killer lymphoid deficiency presents as a sporadic or autosomal dominant trait causing susceptibility to mycobacterial and other infections, predisposition to myelodysplasia and leukemia, and, in some cases, pulmonary alveolar proteinosis. Seeking a genetic cause, we sequenced the exomes of 4 unrelated persons, 3 with sporadic disease, looking for novel, heterozygous, and probably deleterious variants. A number of genes harbored novel variants in person, but only one gene, GATA2, was mutated in all 4 persons. Each person harbored a different mutation, but all were predicted to be highly deleterious and to cause loss or mutation of the C-terminal zinc finger domain. Because GATA2 is the only common mutated gene in 4 unrelated persons, it is highly probable to be the cause of dendritic cell, monocyte, B, and natural killer lymphoid deficiency. This disorder therefore constitutes a new genetic form of heritable immunodeficiency and leukemic transformation.
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IRF8 mutations and human dendritic-cell immunodeficiency.
N. Engl. J. Med.
PUBLISHED: 04-27-2011
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The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained.
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The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency.
J. Exp. Med.
PUBLISHED: 01-17-2011
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Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR(+) lineage(-) compartment, with virtually no CD123(+) or CD11c(+) dendritic cells (DCs) and very few CD14(+) or CD16(+) monocytes. The only remaining HLA-DR(+) lineage(-) cells were circulating CD34(+) progenitor cells. Dermal CD14(+) and CD1a(+) DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR(+) peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4(+)CD25(hi)FoxP3(+) T cells, supporting a role for DC in T reg cell homeostasis.
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Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation.
J. Exp. Med.
PUBLISHED: 01-26-2009
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Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow-derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45(+)HLA-DR(+) cells: CD1a(+)CD14(-) DC, CD1a(-)CD14(+) DC, and CD1a(-)CD14(+)FXIIIa(+) macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a(+) and CD14(+) DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4(+) T cells, macrophages induce cytokine expression in memory CD4(+) T cells and activation and proliferation of CD8(+) T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells.
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Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells.
Immunity
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Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8(+) T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141(hi) DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c(+) and CD14(+) tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141(hi) DCs were closely related to blood CD141(+) DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.
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Sensitizing primary acute lymphoblastic leukemia to natural killer cell recognition by induction of NKG2D ligands.
Leuk. Lymphoma
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Natural killer (NK) cell immunosurveillance may be impaired by malignant disease, resulting in tumor escape and disease progression. Therapies that enhance NK cytotoxicity may therefore prove valuable in remission-induction and maintenance treatment regimens. Acute lymphoblastic leukemia (ALL) has previously been considered resistant to NK cell lysis and not tractable to this approach. Our study demonstrates that bortezomib, valproate and troglitazone can up-regulate NK activating ligands on a B-ALL cell line and on a proportion but not all adult primary B-ALL samples. Drug-treated ALL cells trigger higher levels of NK degranulation, as measured by CD107a expression, and this effect is dependent on signaling through the NK activating receptor NKG2D. These results suggest that bortezomib, valproate and troglitazone may have clinical utility in sensitizing ALL to NK mediated lysis in vivo.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.