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  1. Article ; Online: High-throughput compound screen reveals mTOR inhibitors as potential therapeutics to reduce (auto)antibody production by human plasma cells.

    Tuijnenburg, Paul / Aan de Kerk, Daan J / Jansen, Machiel H / Morris, Ben / Lieftink, Cor / Beijersbergen, Roderick L / van Leeuwen, Ester M M / Kuijpers, Taco W

    European journal of immunology

    2019  Volume 50, Issue 1, Page(s) 73–85

    Abstract: Antibody production by the B cell compartment is a crucial part of the adaptive immune response. Dysregulated antibody production in the form of autoantibodies can cause autoimmune disease. To date, B-cell depletion with anti-CD20 antibodies is commonly ... ...

    Abstract Antibody production by the B cell compartment is a crucial part of the adaptive immune response. Dysregulated antibody production in the form of autoantibodies can cause autoimmune disease. To date, B-cell depletion with anti-CD20 antibodies is commonly applied in autoimmunity, but pre-existing plasma cells are not eliminated in this way. Alternative ways of more selective inhibition of antibody production would add to the treatment of these autoimmune diseases. To explore novel therapeutic targets in signaling pathways essential for plasmablast formation and/or immunoglobulin production, we performed a compound screen of almost 200 protein kinase inhibitors in a robust B-cell differentiation culture system. This study yielded 35 small cell-permeable compounds with a reproducible inhibitory effect on B-cell activation and plasmablast formation, among which was the clinically applied mammalian target of rapamycin (mTOR) inhibitor rapamycin. Two additional compounds targeting the phosphoinositide 3-kinase-AKT-mTOR pathway (BKM120 and WYE-354) did not affect proliferation and plasmablast formation, but specifically reduced the immunoglobulin production. With this compound screen we successfully applied a method to investigate therapeutic targets for B-cell differentiation and identified compounds in the phosphoinositide 3-kinase-AKT-mTOR pathway that could specifically inhibit immunoglobulin production only. These drugs may well be explored to be of value in current B-cell-depleting treatment regimens in autoimmune disorders.
    MeSH term(s) Aminopyridines/pharmacology ; Antibody Formation/drug effects ; Autoantibodies/biosynthesis ; Autoantibodies/drug effects ; Autoimmune Diseases/immunology ; B-Lymphocytes/drug effects ; B-Lymphocytes/immunology ; Cell Differentiation/drug effects ; Drug Discovery ; High-Throughput Screening Assays ; Humans ; Lymphocyte Activation/drug effects ; Morpholines/pharmacology ; Plasma Cells/drug effects ; Plasma Cells/immunology ; Protein Kinase Inhibitors/pharmacology ; Purines/pharmacology ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors
    Chemical Substances Aminopyridines ; Autoantibodies ; Morpholines ; NVP-BKM120 ; Protein Kinase Inhibitors ; Purines ; WYE-354 ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2019-11-14
    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.201948241
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 489: Show issues Location:
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    Zs.MG 85: Show issues

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  2. Article ; Online: Phenotypic and Functional Comparison of Class Switch Recombination Deficiencies with a Subgroup of Common Variable Immunodeficiencies.

    Aan de Kerk, Daan J / Jansen, Machiel H / Jolles, Stephen / Warnatz, Klaus / Seneviratne, Suranjith L / Ten Berge, Ineke J M / van Leeuwen, Ester M M / Kuijpers, Taco W

    Journal of clinical immunology

    2016  Volume 36, Issue 7, Page(s) 656–666

    Abstract: Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with ... ...

    Abstract Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications. Using a functional read-out, we previously identified a functional subgroup of CVID patients with plasmablasts (PBs) producing IgM only. We have now further characterized such CVID patients by a direct functional comparison with patients having genetically well-characterized CSR defects in CD40L, activation-induced cytidine deaminase (AID) and uracil N-glycosylase activity (UNG). The CSR-like CVID patients showed a failure in B cell activation patterns similar to the classical AID/UNG defects in three out of five CVID patients and distinct more individual defects in the two other CVID cases when tested for cellular activation and PB differentiation. Thus, functional categorization of B cell activation and differentiation pathways extends the expected variation in CVID to CSR-like defects of as yet unknown genetic etiology.
    MeSH term(s) Adolescent ; Adult ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Biomarkers ; Common Variable Immunodeficiency/diagnosis ; Common Variable Immunodeficiency/genetics ; Common Variable Immunodeficiency/immunology ; Female ; Genetic Predisposition to Disease ; Humans ; Immunoglobulin Class Switching/genetics ; Immunoglobulin Class Switching/immunology ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Immunoglobulin M/blood ; Immunoglobulin M/immunology ; Immunophenotyping ; Lymphocyte Activation/immunology ; Male ; Middle Aged ; Phenotype ; Plasma Cells/immunology ; Plasma Cells/metabolism ; Plasma Cells/pathology ; Young Adult
    Chemical Substances Biomarkers ; Immunoglobulin G ; Immunoglobulin M
    Language English
    Publishing date 2016-08-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 779361-3
    ISSN 1573-2592 ; 0271-9142
    ISSN (online) 1573-2592
    ISSN 0271-9142
    DOI 10.1007/s10875-016-0321-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1640: Show issues Location:
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  3. Article ; Online: Identification of B cell defects using age-defined reference ranges for in vivo and in vitro B cell differentiation.

    aan de Kerk, Daan J / Jansen, Machiel H / ten Berge, Ineke J M / van Leeuwen, Ester M M / Kuijpers, Taco W

    Journal of immunology (Baltimore, Md. : 1950)

    2013  Volume 190, Issue 10, Page(s) 5012–5019

    Abstract: Primary immunodeficiencies consist to a large extent of B cell defects, as indicated by inadequate Ab levels or response upon immunization. Many B cell defects have not yet been well characterized. Our objective was to create reliable in vivo and in ... ...

    Abstract Primary immunodeficiencies consist to a large extent of B cell defects, as indicated by inadequate Ab levels or response upon immunization. Many B cell defects have not yet been well characterized. Our objective was to create reliable in vivo and in vitro assays to routinely analyze human B cell differentiation, proliferation, and Ig production and to define reference ranges for different age categories. The in vitro assays were applied to classify the developmental and/or functional B cell defects in patients previously diagnosed with common variable immunodeficiency. Apart from standard immunophenotyping of circulating human B cell subsets, an in vitro CFSE dilution assay was used for the assessment of proliferative capacity comparing T cell-dependent and T cell-independent B cell activation. Plasmablast/plasma cell differentiation was assessed by staining for CD20, CD38, and CD138, and measurement of in vitro Ig secretion. At young age, B cells proliferate upon in vitro activation, but neither differentiate nor produce IgG. These latter functions reached adult levels at 5 and 10 y of age for T cell-dependent versus T cell-independent stimulations, respectively. The capacity of B cells to differentiate into plasmablasts and to produce IgG appeared to be contained within the switched memory B cell pool. Using these assays, we could categorize common variable immunodeficiency patients into subgroups and identified a class-switch recombination defect caused by an UNG mutation in one of the patients. We defined age-related reference ranges for human B cell differentiation. Our findings indicate that in vivo B cell functionality can be tested in vitro and helps to diagnose suspected B cell defects.
    MeSH term(s) ADP-ribosyl Cyclase 1/analysis ; Adult ; Antibodies/blood ; Antigens, CD20/analysis ; B-Lymphocyte Subsets/classification ; B-Lymphocyte Subsets/cytology ; B-Lymphocyte Subsets/immunology ; B-Lymphocytes/classification ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Cell Differentiation/immunology ; Cell Proliferation ; Cells, Cultured ; Common Variable Immunodeficiency/classification ; Common Variable Immunodeficiency/immunology ; Female ; Humans ; Immunoglobulins/biosynthesis ; Immunophenotyping ; Lymphocyte Activation/immunology ; Male ; Reference Values ; Syndecan-1/analysis ; T-Lymphocytes/immunology
    Chemical Substances Antibodies ; Antigens, CD20 ; Immunoglobulins ; Syndecan-1 ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
    Language English
    Publishing date 2013-05-15
    Publishing country United States
    Document type Journal Article
    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.1201807
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ud II Zs.37: Show issues Location:
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  4. Article ; Online: A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells.

    Kuijpers, Taco W / van Leeuwen, Ester M M / Barendregt, Barbara H / Klarenbeek, Paul / aan de Kerk, Daan J / Baars, Paul A / Jansen, Machiel H / de Vries, Niek / van Lier, René A W / van der Burg, Mirjam

    Haematologica

    2013  Volume 98, Issue 7, Page(s) 1030–1038

    Abstract: Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations ...

    Abstract Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8(+) T cells and increased over time. Only the revertant CD8(+) T cells showed normal expression of CD132 and the various CD8(+) T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ(+) T cells and differentiated CD4(+)CD27(-) effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8(+) T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells.
    MeSH term(s) CD8-Positive T-Lymphocytes/pathology ; CD8-Positive T-Lymphocytes/physiology ; Cell Proliferation ; Child ; Humans ; Interleukin Receptor Common gamma Subunit/genetics ; Interleukin Receptor Common gamma Subunit/physiology ; Lymphocyte Count ; Male ; Mutation/genetics ; Pedigree ; Severe Combined Immunodeficiency/diagnosis ; Severe Combined Immunodeficiency/genetics ; Severe Combined Immunodeficiency/pathology
    Chemical Substances IL2RG protein, human ; Interleukin Receptor Common gamma Subunit
    Language English
    Publishing date 2013-02-12
    Publishing country Italy
    Document type Case Reports ; Journal Article
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2012.077511
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.76: Show issues Location:
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  5. Article ; Online: Aberrant humoral immune reactivity in DOCK8 deficiency with follicular hyperplasia and nodal plasmacytosis.

    aan de Kerk, Daan J / van Leeuwen, Ester M M / Jansen, Machiel H / van den Berg, J Merlijn / Alders, Marielle / Vermont, Clementine L / van Lier, René A W / Pals, Steven T / Kuijpers, Taco W

    Clinical immunology (Orlando, Fla.)

    2013  Volume 149, Issue 1, Page(s) 25–31

    Abstract: Mutations in the DOCK8 gene define the most common form of autosomal-recessive Hyper-IgE-syndrome (AR-HIES/OMIM#243700). In a patient with extensive molluscum contagiosum lesions, a homozygous DOCK8 gene deletion was demonstrated. In-vivo 18-FDG uptake ... ...

    Abstract Mutations in the DOCK8 gene define the most common form of autosomal-recessive Hyper-IgE-syndrome (AR-HIES/OMIM#243700). In a patient with extensive molluscum contagiosum lesions, a homozygous DOCK8 gene deletion was demonstrated. In-vivo 18-FDG uptake showed multiple non-enlarged lymph nodes without uptake in the spleen. Lymph node biopsies for subsequent immunohistochemistry showed clear differences with the mouse model of DOCK8 deficiency in which these mice show no GCs. Unexpectedly, the patient's lymph nodes demonstrated lymphocyte polyclonality, follicular hyperplasia and an unusual IgE(+) plasma cell expansion. In contrast, the proliferative capacity of circulating B-cells was almost absent with little in-vitro Ig production or plasmablast formation. Also the T-cell proliferation indicated a partial defect. Hematopoietic stem cell transplantation (HSCT) was performed resulting in the disappearance of the molluscum contagiosum lesions. In sum, DOCK8 deficiency results in defective antibody responses and undirected plasma cell expansion in the lymph nodes, as part of a combined immunodeficiency cured by HSCT.
    MeSH term(s) Adolescent ; Antibodies/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Cell Proliferation ; Female ; Guanine Nucleotide Exchange Factors/deficiency ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/immunology ; Hematopoietic Stem Cell Transplantation ; Humans ; Hyperplasia/genetics ; Hyperplasia/immunology ; Hyperplasia/pathology ; Hyperplasia/therapy ; Immunity, Humoral ; Immunologic Deficiency Syndromes/genetics ; Immunologic Deficiency Syndromes/immunology ; Immunologic Deficiency Syndromes/pathology ; Immunologic Deficiency Syndromes/therapy ; Lymph Nodes/pathology ; Lymphocyte Count ; Molluscum Contagiosum/genetics ; Molluscum Contagiosum/immunology ; Molluscum Contagiosum/pathology ; Molluscum Contagiosum/therapy ; T-Lymphocytes/immunology ; T-Lymphocytes/pathology
    Chemical Substances Antibodies ; DOCK8 protein, human ; Guanine Nucleotide Exchange Factors
    Language English
    Publishing date 2013-10
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 1459903-x
    ISSN 1521-7035 ; 1521-6616
    ISSN (online) 1521-7035
    ISSN 1521-6616
    DOI 10.1016/j.clim.2013.06.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 880: Show issues Location:
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  6. Article ; Online: Common variable immunodeficiency and hemophagocytic features associated with a FAS gene mutation.

    Kuijpers, Taco W / Baars, Paul A / aan de Kerk, Daan J / Jansen, Machiel H / Dors, Natasja / van Lier, Rene A W / Pals, Steven T

    The Journal of allergy and clinical immunology

    2011  Volume 127, Issue 6, Page(s) 1411–4.e2

    MeSH term(s) Autoimmune Lymphoproliferative Syndrome/complications ; Autoimmune Lymphoproliferative Syndrome/genetics ; Autoimmune Lymphoproliferative Syndrome/immunology ; B-Lymphocytes/immunology ; Child, Preschool ; Common Variable Immunodeficiency/complications ; Common Variable Immunodeficiency/genetics ; Common Variable Immunodeficiency/immunology ; Female ; Humans ; Lymphohistiocytosis, Hemophagocytic/complications ; Lymphohistiocytosis, Hemophagocytic/genetics ; Lymphohistiocytosis, Hemophagocytic/immunology ; Male ; Mutation ; Pedigree ; T-Lymphocytes/immunology ; fas Receptor/genetics
    Chemical Substances FAS protein, human ; fas Receptor
    Language English
    Publishing date 2011-06
    Publishing country United States
    Document type Case Reports ; Letter
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2011.01.046
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.92: Show issues Location:
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  7. Article ; Online: A novel mutation in CD132 causes X-CID with defective T-cell activation and impaired humoral reactivity.

    Kuijpers, Taco W / Baars, Paul A / Aan de Kerk, Daan J / Jansen, Machiel H / Derks, Ingrid A M / Bredius, Robbert G M / Sanders, Elisabeth A M / van der Burg, Mirjam / Alders, Marielle / van Lier, Rene A W

    The Journal of allergy and clinical immunology

    2011  Volume 128, Issue 6, Page(s) 1360–1363.e4

    MeSH term(s) Adolescent ; B-Lymphocytes/immunology ; Child ; Child, Preschool ; DNA Mutational Analysis ; Humans ; Immunity, Humoral/genetics ; Immunity, Humoral/immunology ; Immunologic Memory/genetics ; Immunologic Memory/immunology ; Interleukin Receptor Common gamma Subunit/genetics ; Interleukin Receptor Common gamma Subunit/immunology ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Lymphocyte Count ; Male ; Mutation ; Pedigree ; Severe Combined Immunodeficiency/genetics ; Severe Combined Immunodeficiency/immunology ; T-Lymphocytes/immunology
    Chemical Substances IL2RG protein, human ; Interleukin Receptor Common gamma Subunit
    Language English
    Publishing date 2011-12
    Publishing country United States
    Document type Case Reports ; Letter
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2011.07.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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