Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5 + CD19 + B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to...
Gespeichert in:
| Veröffentlicht in: | Leukemia 2014-10, Vol.28 (10), p.2005-2015 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2015 |
|---|---|
| container_issue | 10 |
| container_start_page | 2005 |
| container_title | Leukemia |
| container_volume | 28 |
| creator | Saulep-Easton, D Vincent, F B Le Page, M Wei, A Ting, S B Croce, C M Tam, C Mackay, F |
| description | Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5
+
CD19
+
B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL. |
| doi_str_mv | 10.1038/leu.2014.105 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4100939</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A386613412</galeid><sourcerecordid>A386613412</sourcerecordid><originalsourceid>FETCH-LOGICAL-c609t-9caa81a014b1291acc7b3a811915279cfe0afb58fc1a33dd15676f37384a66c83</originalsourceid><addsrcrecordid>eNqNkkuLFDEUhQtRnHZ051oKBHFhtXlUXpuBofEFA250J4R0KunOTCppk6qB_vcm9Dh2yyCSRR7nuye5ubdpXkKwhADz997MSwRgX3bkUbOAPaMdIQQ-bhaAc9ZRgfqz5lnO1wBUkT5tzlDPEGSMLJofq_0Ub1ww3ZDcrQmtjzm30bY7r_KodFHd0A4mFHlyutXG-9bOQU8uhtaFVm9TDEXw-3G3jYWvazPfmNGp580Tq3w2L-7m8-b7xw_fVp-7q6-fvqwurzpNgZg6oZXiUJXXrSESUGnN1ricQAEJYkJbA5RdE241VBgPAySUUYsZ5r2iVHN83lwcfHfzejSDNmFKystdcqNKexmVk6dKcFu5ibeyhwAILIrB2zuDFH_OJk9ydLmmqoKJc5aQIkQBI5j_BwoEAZwwVNDXf6HXcU6h_IREtCespwDyf1HVq74QiT_URnkjXbCxJKLr1fISc0oh7mG9cfkAVcZQyqFjMNaV85OAN0cBW6P8tM3Rz7W6-RR8dwB1Kg2SjL3_XQhk7UNZii5rH5YdKfir44rcw78brwDdAchFChuTjrJ-yPAXd8HlhQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1609100929</pqid></control><display><type>article</type><title>Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia</title><source>MEDLINE</source><source>Nature</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Saulep-Easton, D ; Vincent, F B ; Le Page, M ; Wei, A ; Ting, S B ; Croce, C M ; Tam, C ; Mackay, F</creator><creatorcontrib>Saulep-Easton, D ; Vincent, F B ; Le Page, M ; Wei, A ; Ting, S B ; Croce, C M ; Tam, C ; Mackay, F</creatorcontrib><description>Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5
+
CD19
+
B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2014.105</identifier><identifier>PMID: 24721775</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/21 ; 13/31 ; 631/67/1990/283/1895 ; 64/110 ; Animals ; Antigens ; Antineoplastic Agents - chemistry ; Antiviral agents ; Cancer Research ; CD19 antigen ; CD5 antigen ; Chronic lymphocytic leukemia ; CpG Islands ; Critical Care Medicine ; Cytokines ; Cytokines - metabolism ; Cytomegalovirus ; Defects ; Dendritic cells ; Dendritic Cells - cytology ; Disease ; Disease Progression ; Effector cells ; Flexible manufacturing systems ; Flt3 protein ; fms-Like Tyrosine Kinase 3 - metabolism ; Gene expression ; Gene Expression Regulation, Leukemic ; Genetic aspects ; Hematology ; Hepatitis ; Humans ; Immune system ; Immunity ; Immunodeficiency ; Immunology ; Infections ; Intensive ; Interferon ; Interferon-alpha - metabolism ; Internal Medicine ; Kinases ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - immunology ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Lymphatic leukemia ; Lymphocytes - cytology ; Lymphocytes B ; Lymphocytic leukemia ; Medical prognosis ; Medical research ; Medicine ; Medicine & Public Health ; Mice ; Oncology ; Organs ; original-article ; Patients ; Peripheral blood ; Physiological aspects ; Protein-tyrosine kinase ; Receptors ; Recurrent infection ; TLR9 protein ; Toll-Like Receptor 9 - metabolism ; Toll-like receptors ; Transforming Growth Factor beta - metabolism ; Tumor necrosis factor ; Tumors ; Tyrosine ; Viral infections ; α-Interferon</subject><ispartof>Leukemia, 2014-10, Vol.28 (10), p.2005-2015</ispartof><rights>Macmillan Publishers Limited 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 2014</rights><rights>Macmillan Publishers Limited 2014.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c609t-9caa81a014b1291acc7b3a811915279cfe0afb58fc1a33dd15676f37384a66c83</citedby><cites>FETCH-LOGICAL-c609t-9caa81a014b1291acc7b3a811915279cfe0afb58fc1a33dd15676f37384a66c83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24721775$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saulep-Easton, D</creatorcontrib><creatorcontrib>Vincent, F B</creatorcontrib><creatorcontrib>Le Page, M</creatorcontrib><creatorcontrib>Wei, A</creatorcontrib><creatorcontrib>Ting, S B</creatorcontrib><creatorcontrib>Croce, C M</creatorcontrib><creatorcontrib>Tam, C</creatorcontrib><creatorcontrib>Mackay, F</creatorcontrib><title>Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5
+
CD19
+
B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.</description><subject>13/1</subject><subject>13/106</subject><subject>13/21</subject><subject>13/31</subject><subject>631/67/1990/283/1895</subject><subject>64/110</subject><subject>Animals</subject><subject>Antigens</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antiviral agents</subject><subject>Cancer Research</subject><subject>CD19 antigen</subject><subject>CD5 antigen</subject><subject>Chronic lymphocytic leukemia</subject><subject>CpG Islands</subject><subject>Critical Care Medicine</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Cytomegalovirus</subject><subject>Defects</subject><subject>Dendritic cells</subject><subject>Dendritic Cells - cytology</subject><subject>Disease</subject><subject>Disease Progression</subject><subject>Effector cells</subject><subject>Flexible manufacturing systems</subject><subject>Flt3 protein</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Genetic aspects</subject><subject>Hematology</subject><subject>Hepatitis</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunity</subject><subject>Immunodeficiency</subject><subject>Immunology</subject><subject>Infections</subject><subject>Intensive</subject><subject>Interferon</subject><subject>Interferon-alpha - metabolism</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - immunology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Lymphatic leukemia</subject><subject>Lymphocytes - cytology</subject><subject>Lymphocytes B</subject><subject>Lymphocytic leukemia</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Oncology</subject><subject>Organs</subject><subject>original-article</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Physiological aspects</subject><subject>Protein-tyrosine kinase</subject><subject>Receptors</subject><subject>Recurrent infection</subject><subject>TLR9 protein</subject><subject>Toll-Like Receptor 9 - metabolism</subject><subject>Toll-like receptors</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Tumor necrosis factor</subject><subject>Tumors</subject><subject>Tyrosine</subject><subject>Viral infections</subject><subject>α-Interferon</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkkuLFDEUhQtRnHZ051oKBHFhtXlUXpuBofEFA250J4R0KunOTCppk6qB_vcm9Dh2yyCSRR7nuye5ubdpXkKwhADz997MSwRgX3bkUbOAPaMdIQQ-bhaAc9ZRgfqz5lnO1wBUkT5tzlDPEGSMLJofq_0Ub1ww3ZDcrQmtjzm30bY7r_KodFHd0A4mFHlyutXG-9bOQU8uhtaFVm9TDEXw-3G3jYWvazPfmNGp580Tq3w2L-7m8-b7xw_fVp-7q6-fvqwurzpNgZg6oZXiUJXXrSESUGnN1ricQAEJYkJbA5RdE241VBgPAySUUYsZ5r2iVHN83lwcfHfzejSDNmFKystdcqNKexmVk6dKcFu5ibeyhwAILIrB2zuDFH_OJk9ydLmmqoKJc5aQIkQBI5j_BwoEAZwwVNDXf6HXcU6h_IREtCespwDyf1HVq74QiT_URnkjXbCxJKLr1fISc0oh7mG9cfkAVcZQyqFjMNaV85OAN0cBW6P8tM3Rz7W6-RR8dwB1Kg2SjL3_XQhk7UNZii5rH5YdKfir44rcw78brwDdAchFChuTjrJ-yPAXd8HlhQ</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Saulep-Easton, D</creator><creator>Vincent, F B</creator><creator>Le Page, M</creator><creator>Wei, A</creator><creator>Ting, S B</creator><creator>Croce, C M</creator><creator>Tam, C</creator><creator>Mackay, F</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141001</creationdate><title>Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia</title><author>Saulep-Easton, D ; Vincent, F B ; Le Page, M ; Wei, A ; Ting, S B ; Croce, C M ; Tam, C ; Mackay, F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c609t-9caa81a014b1291acc7b3a811915279cfe0afb58fc1a33dd15676f37384a66c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/21</topic><topic>13/31</topic><topic>631/67/1990/283/1895</topic><topic>64/110</topic><topic>Animals</topic><topic>Antigens</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antiviral agents</topic><topic>Cancer Research</topic><topic>CD19 antigen</topic><topic>CD5 antigen</topic><topic>Chronic lymphocytic leukemia</topic><topic>CpG Islands</topic><topic>Critical Care Medicine</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Cytomegalovirus</topic><topic>Defects</topic><topic>Dendritic cells</topic><topic>Dendritic Cells - cytology</topic><topic>Disease</topic><topic>Disease Progression</topic><topic>Effector cells</topic><topic>Flexible manufacturing systems</topic><topic>Flt3 protein</topic><topic>fms-Like Tyrosine Kinase 3 - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Genetic aspects</topic><topic>Hematology</topic><topic>Hepatitis</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunity</topic><topic>Immunodeficiency</topic><topic>Immunology</topic><topic>Infections</topic><topic>Intensive</topic><topic>Interferon</topic><topic>Interferon-alpha - metabolism</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - immunology</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Lymphatic leukemia</topic><topic>Lymphocytes - cytology</topic><topic>Lymphocytes B</topic><topic>Lymphocytic leukemia</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Oncology</topic><topic>Organs</topic><topic>original-article</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Physiological aspects</topic><topic>Protein-tyrosine kinase</topic><topic>Receptors</topic><topic>Recurrent infection</topic><topic>TLR9 protein</topic><topic>Toll-Like Receptor 9 - metabolism</topic><topic>Toll-like receptors</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Tumor necrosis factor</topic><topic>Tumors</topic><topic>Tyrosine</topic><topic>Viral infections</topic><topic>α-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Saulep-Easton, D</creatorcontrib><creatorcontrib>Vincent, F B</creatorcontrib><creatorcontrib>Le Page, M</creatorcontrib><creatorcontrib>Wei, A</creatorcontrib><creatorcontrib>Ting, S B</creatorcontrib><creatorcontrib>Croce, C M</creatorcontrib><creatorcontrib>Tam, C</creatorcontrib><creatorcontrib>Mackay, F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saulep-Easton, D</au><au>Vincent, F B</au><au>Le Page, M</au><au>Wei, A</au><au>Ting, S B</au><au>Croce, C M</au><au>Tam, C</au><au>Mackay, F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>28</volume><issue>10</issue><spage>2005</spage><epage>2015</epage><pages>2005-2015</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5
+
CD19
+
B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24721775</pmid><doi>10.1038/leu.2014.105</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2014-10, Vol.28 (10), p.2005-2015 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4100939 |
| source | MEDLINE; Nature; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | 13/1 13/106 13/21 13/31 631/67/1990/283/1895 64/110 Animals Antigens Antineoplastic Agents - chemistry Antiviral agents Cancer Research CD19 antigen CD5 antigen Chronic lymphocytic leukemia CpG Islands Critical Care Medicine Cytokines Cytokines - metabolism Cytomegalovirus Defects Dendritic cells Dendritic Cells - cytology Disease Disease Progression Effector cells Flexible manufacturing systems Flt3 protein fms-Like Tyrosine Kinase 3 - metabolism Gene expression Gene Expression Regulation, Leukemic Genetic aspects Hematology Hepatitis Humans Immune system Immunity Immunodeficiency Immunology Infections Intensive Interferon Interferon-alpha - metabolism Internal Medicine Kinases Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - immunology Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Lymphatic leukemia Lymphocytes - cytology Lymphocytes B Lymphocytic leukemia Medical prognosis Medical research Medicine Medicine & Public Health Mice Oncology Organs original-article Patients Peripheral blood Physiological aspects Protein-tyrosine kinase Receptors Recurrent infection TLR9 protein Toll-Like Receptor 9 - metabolism Toll-like receptors Transforming Growth Factor beta - metabolism Tumor necrosis factor Tumors Tyrosine Viral infections α-Interferon |
| title | Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T13%3A00%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cytokine-driven%20loss%20of%20plasmacytoid%20dendritic%20cell%20function%20in%20chronic%20lymphocytic%20leukemia&rft.jtitle=Leukemia&rft.au=Saulep-Easton,%20D&rft.date=2014-10-01&rft.volume=28&rft.issue=10&rft.spage=2005&rft.epage=2015&rft.pages=2005-2015&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2014.105&rft_dat=%3Cgale_pubme%3EA386613412%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1609100929&rft_id=info:pmid/24721775&rft_galeid=A386613412&rfr_iscdi=true |