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Article ; Online: What Makes a pDC: Recent Advances in Understanding Plasmacytoid DC Development and Heterogeneity.

Musumeci, Andrea / Lutz, Konstantin / Winheim, Elena / Krug, Anne Barbara

2019 Volume 10, Page(s) 1222

Abstract: Dendritic cells (DCs) are professional antigen presenting cells (APCs) that originate in the bone marrow and are continuously replenished from hematopoietic progenitor cells. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) are distinguished by ... ...

Abstract	Dendritic cells (DCs) are professional antigen presenting cells (APCs) that originate in the bone marrow and are continuously replenished from hematopoietic progenitor cells. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) are distinguished by morphology and function, and can be easily discriminated by surface marker expression, both in mouse and man. Classification of DCs based on their ontology takes into account their origin as well as their requirements for transcription factor (TF) expression. cDCs and pDCs of myeloid origin differentiate from a common DC progenitor (CDP) through committed pre-DC stages. pDCs have also been shown to originate from a lymphoid progenitor derived IL-7R
MeSH term(s)	Animals ; Cell Differentiation/immunology ; Cell Plasticity/immunology ; Computational Biology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Humans ; Lymphoid Progenitor Cells/cytology ; Lymphoid Progenitor Cells/metabolism ; Lymphoid Tissue/cytology ; Lymphoid Tissue/immunology ; Lymphoid Tissue/metabolism ; Myeloid Progenitor Cells/cytology ; Myeloid Progenitor Cells/metabolism ; Signal Transduction
Language	English
Publishing date	2019-05-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01222
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Article ; Online: Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection.

Nature communications

2024 Volume 15, Issue 1, Page(s) 1696

Abstract: The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus ... ...

Abstract	The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus (TBEV) vaccine on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv) and 22 individuals sampled one-year pv. Our findings indicate that previous TBEV vaccination does not affect the early IgM-driven neutralizing response to YF17D. However, pre-vaccination sera enhance YF17D virus infection in vitro via antibody-dependent enhancement (ADE). Following YF17D vaccination, TBEV-pre-vaccinated individuals develop high amounts of cross-reactive IgG antibodies with poor neutralizing capacity. In contrast, TBEV-unvaccinated individuals elicit a non-cross-reacting neutralizing response. Using YF17D envelope protein mutants displaying different epitopes, we identify quaternary dimeric epitopes as the primary target of neutralizing antibodies. Additionally, TBEV-pre-vaccination skews the IgG response towards the pan-flavivirus fusion loop epitope (FLE), capable of mediating ADE of dengue and Zika virus infections in vitro. Together, we propose that YF17D vaccination conceals the FLE in individuals without prior flavivirus exposure but favors a cross-reactive IgG response in TBEV-pre-vaccinated recipients directed to the FLE with potential to enhance dengue virus infection.
MeSH term(s)	Humans ; Yellow Fever Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing ; Encephalitis Viruses, Tick-Borne ; Zika Virus ; Zika Virus Infection/prevention & control ; Epitopes ; Immunoglobulin G ; Dengue/prevention & control
Chemical Substances	Yellow Fever Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing ; Epitopes ; Immunoglobulin G
Language	English
Publishing date	2024-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45806-x
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Article ; Online: Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages.

Andersen, Line Lykke / Huang, Yiqi / Urban, Christian / Oubraham, Lila / Winheim, Elena / Stafford, Che / Nagl, Dennis / O'Duill, Fionan / Ebert, Thomas / Engleitner, Thomas / Paludan, Søren Riis / Krug, Anne / Rad, Roland / Hornung, Veit / Pichlmair, Andreas

The EMBO journal

2023 Volume 42, Issue 23, Page(s) e113279

Abstract: The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune ... ...

Abstract	The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y family. Time-resolved transcriptomic analysis showed that adenine- and uridine-based nucleotides induce a specific, immediate, and transient cytokine response through the MAPK signaling pathway that regulates transcriptional activation by AP-1. Using receptor trans-complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities, and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.
MeSH term(s)	Humans ; Cytokines ; Immunity ; Macrophages/metabolism ; Nucleotides/metabolism ; Signal Transduction ; Virus Replication
Chemical Substances	Cytokines ; Nucleotides ; P2RY11 protein, human
Language	English
Publishing date	2023-10-26
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2022113279
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Article ; Online: Ly6D

Lutz, Konstantin / Musumeci, Andrea / Sie, Christopher / Dursun, Ezgi / Winheim, Elena / Bagnoli, Johannes / Ziegenhain, Christoph / Rausch, Lisa / Bergen, Volker / Luecken, Malte D / Oostendorp, Robert A J / Schraml, Barbara U / Theis, Fabian J / Enard, Wolfgang / Korn, Thomas / Krug, Anne B

Nature communications

2022 Volume 13, Issue 1, Page(s) 3456

Abstract: Plasmacytoid and conventional dendritic cells (pDC and cDC) are generated from progenitor cells in the bone marrow and commitment to pDCs or cDC subtypes may occur in earlier and later progenitor stages. Cells within the ... ...

Abstract	Plasmacytoid and conventional dendritic cells (pDC and cDC) are generated from progenitor cells in the bone marrow and commitment to pDCs or cDC subtypes may occur in earlier and later progenitor stages. Cells within the CD11c
MeSH term(s)	Animals ; Antigens, Ly/genetics ; Antigens, Ly/metabolism ; CD11c Antigen/metabolism ; Cell Differentiation/genetics ; Dendritic Cells/metabolism ; GPI-Linked Proteins/metabolism ; Mice ; Sialic Acid Binding Immunoglobulin-like Lectins/genetics ; Sialic Acid Binding Immunoglobulin-like Lectins/metabolism ; Stem Cells/metabolism ; Transcription Factors
Chemical Substances	Antigens, Ly ; CD11c Antigen ; GPI-Linked Proteins ; Ly6d protein, mouse ; Sialic Acid Binding Immunoglobulin-like Lectins ; Transcription Factors ; Zbtb46 protein, mouse
Language	English
Publishing date	2022-06-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-31054-4
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Article ; Online: CCL17 Promotes Colitis-Associated Tumorigenesis Dependent on the Microbiota.

Metzger, Rebecca / Winter, Lis / Bouznad, Nassim / Garzetti, Debora / von Armansperg, Benedikt / Rokavec, Matjaz / Lutz, Konstantin / Schäfer, Yvonne / Krebs, Sabrina / Winheim, Elena / Friedrich, Verena / Matzek, Dana / Öllinger, Rupert / Rad, Roland / Stecher, Bärbel / Hermeking, Heiko / Brocker, Thomas / Krug, Anne B

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 209, Issue 11, Page(s) 2227–2238

Abstract: Colorectal cancer is one of the most common cancers and a major cause of mortality. Proinflammatory and antitumor immune responses play critical roles in colitis-associated colon cancer. CCL17, a chemokine of the C-C family and ligand for CCR4, is ... ...

Abstract	Colorectal cancer is one of the most common cancers and a major cause of mortality. Proinflammatory and antitumor immune responses play critical roles in colitis-associated colon cancer. CCL17, a chemokine of the C-C family and ligand for CCR4, is expressed by intestinal dendritic cells in the steady state and is upregulated during colitis in mouse models and inflammatory bowel disease patients. In this study, we investigated the expression pattern and functional relevance of CCL17 for colitis-associated colon tumor development using CCL17-enhanced GFP-knockin mice. CCL17 was highly expressed by dendritic cells but also upregulated in macrophages and intermediary monocytes in colon tumors induced by exposure to azoxymethane and dextran sodium sulfate. Despite a similar degree of inflammation in the colon, CCL17-deficient mice developed fewer tumors than did CCL17-competent mice. This protective effect was abrogated by cohousing, indicating a dependency on the microbiota. Changes in microbiota diversity and composition were detected in separately housed CCL17-deficient mice, and these mice were more susceptible to azoxymethane-induced early apoptosis in the colon affecting tumor initiation. Immune cell infiltration in colitis-induced colon tumors was not affected by the lack of CCL17. Taken together, our results indicate that CCL17 promotes colitis-associated tumorigenesis by influencing the composition of the intestinal microbiome and reducing apoptosis during tumor initiation.
MeSH term(s)	Mice ; Animals ; Colitis ; Carcinogenesis ; Cell Transformation, Neoplastic ; Azoxymethane/toxicity ; Colonic Neoplasms/pathology ; Gastrointestinal Microbiome ; Chemokine CCL17
Chemical Substances	Azoxymethane (MO0N1J0SEN) ; Ccl17 protein, mouse ; Chemokine CCL17
Language	English
Publishing date	2022-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2100867
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Article ; Online: Convalescent COVID-19 Patients Without Comorbidities Display Similar Immunophenotypes Over Time Despite Divergent Disease Severities.

Chu, Chang-Feng / Sabath, Florian / Fibi-Smetana, Silvia / Sun, Shan / Öllinger, Rupert / Noeßner, Elfriede / Chao, Ying-Yin / Rinke, Linus / Winheim, Elena / Rad, Roland / Krug, Anne B / Taher, Leila / Zielinski, Christina E

Frontiers in immunology

2021 Volume 12, Page(s) 601080

Abstract: COVID-19, the disease caused by SARS-CoV-2 infection, can assume a highly variable disease course, ranging from asymptomatic infection, which constitutes the majority of cases, to severe respiratory failure. This implies a diverse host immune response to ...

Abstract	COVID-19, the disease caused by SARS-CoV-2 infection, can assume a highly variable disease course, ranging from asymptomatic infection, which constitutes the majority of cases, to severe respiratory failure. This implies a diverse host immune response to SARS-CoV-2. However, the immunological underpinnings underlying these divergent disease courses remain elusive. We therefore set out to longitudinally characterize immune signatures of convalescent COVID-19 patients stratified according to their disease severity. Our unique convalescent COVID-19 cohort consists of 74 patients not confounded by comorbidities. This is the first study of which we are aware that excludes immune abrogations associated with non-SARS-CoV-2 related risk factors of disease severity. Patients were followed up and analyzed longitudinally (2, 4 and 6 weeks after infection) by high-dimensional flow cytometric profiling of peripheral blood mononuclear cells (PBMCs), in-depth serum analytics, and transcriptomics. Immune phenotypes were correlated to disease severity. Convalescence was overall associated with uniform immune signatures, but distinct immune signatures for mildly
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; COVID-19/immunology ; Convalescence ; Female ; Humans ; Immunophenotyping ; Male ; Middle Aged ; SARS-CoV-2/immunology ; Severity of Illness Index ; Young Adult
Language	English
Publishing date	2021-08-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.601080
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Article ; Online: Binding of phosphatidylserine-positive microparticles by PBMCs classifies disease severity in COVID-19 patients.

Rausch, Lisa / Lutz, Konstantin / Schifferer, Martina / Winheim, Elena / Gruber, Rudi / Oesterhaus, Elina F / Rinke, Linus / Hellmuth, Johannes C / Scherer, Clemens / Muenchhoff, Maximilian / Mandel, Christopher / Bergwelt-Baildon, Michael / Simons, Mikael / Straub, Tobias / Krug, Anne B / Kranich, Jan / Brocker, Thomas

Journal of extracellular vesicles

2021 Volume 10, Issue 14, Page(s) e12173

Abstract: Infection with SARS-CoV-2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID-19 patients. In addition, immune dysfunction occurs in patients characterised by T cell exhaustion and severe lymphopenia. We ...

Abstract	Infection with SARS-CoV-2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID-19 patients. In addition, immune dysfunction occurs in patients characterised by T cell exhaustion and severe lymphopenia. We investigated the distribution of phosphatidylserine (PS), a marker of dying cells, activated platelets and platelet-derived microparticles (PMP), during the clinical course of COVID-19. We found an unexpectedly high amount of blood cells loaded with PS
MeSH term(s)	Adult ; Blood Platelets/immunology ; CD8-Positive T-Lymphocytes/immunology ; COVID-19/blood ; COVID-19/immunology ; COVID-19/physiopathology ; Cell-Derived Microparticles/metabolism ; Flow Cytometry ; Humans ; Leukocytes, Mononuclear/metabolism ; Phosphatidylserines/blood ; Platelet Membrane Glycoprotein IIb ; Severity of Illness Index ; Transcriptome
Chemical Substances	Phosphatidylserines ; Platelet Membrane Glycoprotein IIb
Language	English
Publishing date	2021-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12173
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Article ; Online: Ly6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage

Konstantin Lutz / Andrea Musumeci / Christopher Sie / Ezgi Dursun / Elena Winheim / Johannes Bagnoli / Christoph Ziegenhain / Lisa Rausch / Volker Bergen / Malte D. Luecken / Robert A. J. Oostendorp / Barbara U. Schraml / Fabian J. Theis / Wolfgang Enard / Thomas Korn / Anne B. Krug

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 15

Abstract: The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate ... ...

Abstract	The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.
Keywords	Science ; Q
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Distinct and dynamic activation profiles of circulating dendritic cells and monocytes in mild COVID-19 and after yellow fever vaccination.

European journal of immunology

2022 Volume 53, Issue 3, Page(s) e2250090

Abstract: Dysregulation of the myeloid cell compartment is a feature of severe disease in hospitalized COVID-19 patients. Here, we investigated the response of circulating dendritic cell (DC) and monocyte subpopulations in SARS-CoV-2 infected outpatients with mild ...

Abstract	Dysregulation of the myeloid cell compartment is a feature of severe disease in hospitalized COVID-19 patients. Here, we investigated the response of circulating dendritic cell (DC) and monocyte subpopulations in SARS-CoV-2 infected outpatients with mild disease and compared it to the response of healthy individuals to yellow fever vaccine virus YF17D as a model of a well-coordinated response to viral infection. In SARS-CoV-2-infected outpatients circulating DCs were persistently reduced for several weeks whereas after YF17D vaccination DC numbers were decreased temporarily and rapidly replenished by increased proliferation until 14 days after vaccination. The majority of COVID-19 outpatients showed high expression of CD86 and PD-L1 in monocytes and DCs early on, resembling the dynamic after YF17D vaccination. In a subgroup of patients, low CD86 and high PD-L1 expression were detected in monocytes and DCs coinciding with symptoms, higher age, and lower lymphocyte counts. This phenotype was similar to that observed in severely ill COVID-19 patients, but less pronounced. Thus, prolonged reduction and dysregulated activation of blood DCs and monocytes were seen in a subgroup of symptomatic non-hospitalized COVID-19 patients while a transient coordinated activation was characteristic for the majority of patients with mild COVID-19 and the response to YF17D vaccination.
MeSH term(s)	Humans ; COVID-19 ; Monocytes ; B7-H1 Antigen/metabolism ; Yellow Fever ; SARS-CoV-2 ; Yellow fever virus ; Vaccination ; Dendritic Cells
Chemical Substances	B7-H1 Antigen
Language	English
Publishing date	2022-12-09
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202250090
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Article ; Online: Impaired function and delayed regeneration of dendritic cells in COVID-19.

Winheim, Elena / Rinke, Linus / Lutz, Konstantin / Reischer, Anna / Leutbecher, Alexandra / Wolfram, Lina / Rausch, Lisa / Kranich, Jan / Wratil, Paul R / Huber, Johanna E / Baumjohann, Dirk / Rothenfusser, Simon / Schubert, Benjamin / Hilgendorff, Anne / Hellmuth, Johannes C / Scherer, Clemens / Muenchhoff, Maximilian / von Bergwelt-Baildon, Michael / Stark, Konstantin /

Straub, Tobias / Brocker, Thomas / Keppler, Oliver T / Subklewe, Marion / Krug, Anne B

PLoS pathogens

2021 Volume 17, Issue 10, Page(s) e1009742

Abstract: Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence ... ...

Abstract	Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.
MeSH term(s)	Adult ; Antigens, CD/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; COVID-19/immunology ; COVID-19/pathology ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Female ; Humans ; Male ; Middle Aged ; Monocytes/immunology ; Monocytes/pathology ; Programmed Cell Death 1 Receptor/immunology ; Regeneration/immunology ; SARS-CoV-2/immunology
Chemical Substances	Antigens, CD ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2021-10-06
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1009742
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