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  • The American Association of Immunologists  (5)
  • 1
    Online Resource
    Online Resource
    Cell lineage analysis of KIT D816V and NRAS G12D activating mutations in aggressive systemic mastocytosis (36.25)
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 1_Supplement ( 2010-04-01), p. 36.25-36.25
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 1_Supplement ( 2010-04-01), p. 36.25-36.25
    Abstract: Systemic mastocytosis is a clonal disorder characterized by the abnormal proliferation and accumulation of mast cells within tissues. Over 90% of patients with mastocytosis possess a somatic gain of function mutation involving the tyrosine kinase domain of c-kit (KIT D816V). Recently we identified a patient with aggressive systemic mastocytosis who also harbors a somatic NRAS G12D activating mutation. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by these two mutations. Bone marrow and peripheral blood cells were collected from the patient. CD34+ progenitors, mast cells, neutrophils, monocytes, eosinophils, basophils, T-lymphocytes and B-lymphocytes were separated by fluorescence-activated cell-sorting. cDNA was prepared and the KIT D816V mutation was tested by nested RT-PCR/RFLP. The NRAS G12D mutation was detected by nested RT-PCR followed by sequencing. The KIT D816V and NRAS G12D mutations were detected in both myeloid and lymphoid lineages. Mast cells harbored both mutations. The KIT D816V mutation was not detected in CD34+ progenitors, whereas presence of the NRAS G12D was observed. These findings suggest that the NRAS G12D mutation occurred prior to the KIT D816V mutation in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.184.Supp.36.25
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Meningeal inflammation drives long-term engraftment by monocytes that impair CNS immunity
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 168.4-168.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 168.4-168.4
    Abstract: Tissue-resident macrophages have an embryonic origin and can be replenished by blood monocytes in some tissues during adulthood. Under steady-state conditions, infiltrating monocytes can share phenotypic and genotypic features with their embryonically-derived counterparts. However, little is known about the properties of monocytes/macrophages that establish tissue residency after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of specialized macrophages that serve as immune sentinels. Following infection by lymphocytic choriomeningitis virus (LCMV), these resident macrophages become activated by innate inflammatory cytokines, acquire viral antigens, and are targeted by infiltrating cytotoxic T lymphocytes (CTL), which leads to their depletion. Innate cytokines and chemokines released by CTL also promote a massive recruitment of inflammatory monocytes from the periphery. Surprisingly, these infiltrating monocytes engraft the meningeal niche and remain in situ several months after viral clearance. This leads to significant phenotypic and functional changes in meningeal immunity – a defect that can be partially restored by blocking IFNγ signaling. Importantly, macrophages that establish residency in the meninges after an inflammatory event are deficient in bacterial and immunoregulatory sensors, which impedes their ability to detect pathogens and dampen subsequent meningeal immune responses. Collectively, these data indicate that monocytes can engraft the meninges after an inflammatory challenge and contribute to long-term alterations in CNS immunity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.168.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Unexpected Role for Granzyme K in CD56bright NK Cell-Mediated Immunoregulation of Multiple Sclerosis
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 187, No. 2 ( 2011-07-15), p. 781-790
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 2 ( 2011-07-15), p. 781-790
    Abstract: Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis. NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity toward immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56bright NK cell subset, which is selectively expanded by daclizumab, a CD25-blocking Ab that suppresses multiple sclerosis-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. Although both granzyme A and granzyme K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56bright NK cells, profoundly inhibited the ability of NK-92 cells to kill activated syngeneic T cells. Finally, we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56bright NK cells. Our study describes the important physiological role that GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1100789
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    Helper B Cells Promote Cytotoxic T Cell Survival and Proliferation Independently of Antigen Presentation through CD27/CD70 Interactions
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 180, No. 3 ( 2008-02-01), p. 1362-1372
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 180, No. 3 ( 2008-02-01), p. 1362-1372
    Abstract: CD8-expressing cytotoxic T cell (CTL) interactions with APCs and helper T cells determine their function and ability to survive. In this study, we describe a novel interaction independent of Ag presentation between activated CTLs and bystander CD19-expressing B lymphocytes. Ag-stimulated CTLs serially engage autologous B lymphocytes through CD27/CD70 contact that promotes their survival and proliferation. Moreover, these interactions induce the release of proinflammatory cytokines that follows two general patterns: 1) an epitope-dependent enhancement of cytokine release, and 2) a previously undiscovered coordinate release of cytokines independent of epitope exposure. The latter includes chemoattractants targeting activated T cells. As a result, activated T cells are attracted to B cells, which exert a “helper” role in lymphatic organs or in areas of inflammation. This observation provides a mechanistic explanation to previously reported experimental observations suggesting that B cells are required for T cell priming in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.180.3.1362
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Venous plexus-associated lymphoid hubs support meningeal humoral immunity
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 76.23-76.23
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 76.23-76.23
    Abstract: There is increasing interest in how immune cells in the meninges, the membranes that surround the brain and spinal cord, contribute to homeostasis and disease in the central nervous system. The outer layer of meninges, the dura mater, contains both innate and adaptive immune cells and functions as a site for B cell development. In this study, we identified previously undescribed lymphoid structures surrounding fenestrated venous plexi in the dura mater. We found the most elaborate immune organization, including lymphatic vessels, surrounding the rostral-rhinal confluence of sinuses. We termed this structure that interfaced with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. This hub emerged during development in mice at P8/9 before formation of the superior sagittal sinus. Single cell RNA sequencing demonstrated that rostral rhinal hub hosts a diverse array of resident innate and adaptive immune cells during steady state. Immune aggregates were also present in this structure during homeostasis and expanded with age or following challenge with systemic or nasal antigens. Following intranasal VSV infection, the rostral-rhinal hub supported local germinal center (GC) reactions consisting of T follicular helper cells as well as GC B cells that underwent proliferation, somatic hypermutation, class switch, and conversion into plasma cells locally. These data demonstrate lymphoid architecture around vascular plexi in the dura mater that can sample antigens and rapidly elaborate local humoral immune responses to protect the meninges and underlying brain parenchyma from pathogens. This research was supported by the intramural program of the National Institute of Neurological Disorders and Stroke, NIH
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.76.23
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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