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  • 1
    Electronic Resource
    Electronic Resource
    Disappearance of factor VIII autoantibodies preceding autoimmune haemolytic anaemia (2000)
    Oxford UK : Blackwell Science Ltd
    Haemophilia 6 (2000), S. 0 
    Details
    ISSN: 1365-2516
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We describe a previously healthy woman who at the age of 44 years developed a factor VIII inhibitor, that over the years increased to a maximum level of 3600 Bethesda units (BU) mL–1 in 1978. The epitope specificity of the factor VIII inhibitor was investigated and antibodies directed against the A2 and C2 domains of factor VIII were detected. The majority of these antibodies were of subclass IgG4. Over the years, the inhibitor titre gradually decreased and in 1989, the inhibitor could no longer be detected. Shortly after, the patient developed autoimmune haemolytic anaemia. A possible link between the disappearance of factor VIII inhibitors and the development of other autoantibodies may be explained by concomitant development of anti-idiotypic antibodies that neutralize the activity of factor VIII inhibitors. We were unable to detect anti-idiotypic antibodies, which could explain the decline in factor VIII inhibitor titre in this patient.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-2516.2000.00430.x
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg593 to Cys mutation (2004)
    Oxford, UK : Blackwell Science Ltd
    Haemophilia 10 (2004), S. 0 
    Details
    ISSN: 1365-2516
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary.  We evaluated inhibitor formation in a group of patients with mild haemophilia A caused by an Arg593 to Cys mutation. A remarkably high cumulative inhibitor incidence of 14% over 22 years was observed. Three of 49 patients developed transient, low-titre inhibitors, which remained below 2.0 BU mL−1. Four patients with an Arg593 to Cys mutation developed high-titre inhibitors (〉5.0 BU mL−1). Three of these patients have been described previously. In this study, we characterized inhibitory antibodies in a fourth patient with high-titre inhibitors. Epitope mapping studies revealed that antibodies were predominantly directed to the A2 domain of factor VIII. We addressed the role of human leucocyte antigen (HLA) class II alleles in inhibitor development in patients with an Arg593 to Cys mutation by HLA genotyping. In the group of inhibitor patients raised frequencies of HLA-DRB1*01 and HLA-DQB1*05 were observed that did not reached statistical significance. Our data suggest that inhibitor development in mild haemophilia A patients with an Arg593 to Cys mutation is not linked to HLA class II profile.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2516.2004.01011.x
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  • 3
    Electronic Resource
    Electronic Resource
    Impact of inhibitor epitope profile on the neutralizing effect against plasma-derived and recombinant factor VIII concentrates in vitro (2003)
    Oxford, UK : Blackwell Science Ltd
    Haemophilia 9 (2003), S. 0 
    Details
    ISSN: 1365-2516
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary.  The inhibitory capacity of plasma samples from 24 patients with severe haemophilia A and high-responding inhibitors were evaluated in a concentrate-based assay using two plasma-derived (Haemate and Monoclate-P) and three recombinant (Helixate, Recombinate and ReFacto) factor VIII concentrates and correlated with the corresponding epitope profile. In most, but not all, inhibitor plasmas with a relatively low reactivity against the von Willebrand-containing product Haemate, the main epitopes were located in the FVIII light chain. The reactivities within the group of recombinant products varied in that the reactivity against the B-domain deleted ReFacto was in general higher than that against Recombinate and Helixate. This difference did not correlate with any particular epitope profile and indicates that the B-domain, type of formulation and/or purification procedures may have an impact on the inhibitor reactivity in vitro. The ratio between the inhibitor titres in the concentrate-based assay and the Bethesda assay was dependent on the inhibitor plasma and concentrate used. Taken together, our results show that the reactivity of inhibitor plasmas varies considerably between different FVIII concentrates and that it does not fully correlate with the epitope profile. Potential clinical implications of the observed differences in inhibitor reactivity are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-2516.2003.00802.x
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  • 4
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    Epac Controls WPB Exocytosis [Signal Transduction] (2012)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2012-07-14
    Description: Endothelial cells contain specialized storage organelles called Weibel-Palade bodies (WPBs) that release their content into the vascular lumen in response to specific agonists that raise intracellular Ca2+ or cAMP. We have previously shown that cAMP-mediated WPB release is dependent on protein kinase A (PKA) and involves activation of the small GTPase RalA. Here, we have investigated a possible role for another PKA-independent cAMP-mediated signaling pathway in the regulation of WPB exocytosis, namely the guanine nucleotide exchange factor Epac1 and its substrate, the small GTPase Rap1. Epinephrine stimulation of endothelial cells leads to Rap1 activation in a PKA-independent fashion. siRNA-mediated knockdown of Epac1 abolished epinephrine-induced activation of Rap1 and resulted in decreased epinephrine-induced WPB exocytosis. Down-regulation of Rap1 expression and prevention of Rap1 activation through overexpression of Rap1GAP effectively reduced epinephrine- but not thrombin-induced WPB exocytosis. Taken together, these data uncover a new Epac-Rap1-dependent pathway by which endothelial cells can regulate WPB exocytosis in response to agonists that signal through cAMP.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 5
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    The macrophage mannose receptor promotes uptake of ADAMTS13 by dendritic cells (2012)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2012-04-20
    Description: ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by cleaving ultra-large VWF multimers on the surfaces of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura. The formation of autoantibodies depends on the activation of CD4 + T cells. This process requires immune recognition, endocytosis, and subsequent processing of ADAMTS13 into peptides that are presented on MHC class II molecules to CD4 + T cells by dendritic cells (DCs). In the present study, we investigated endocytosis of recombinant ADAMTS13 by immature monocyte-derived DCs using flow cytometry and confocal microscopy. After incubation of fluorescently labeled ADAMTS13 with DCs, significant uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked by the addition of EGTA and mannan. ADAMTS13 endocytosis was decreased in the presence of a blocking mAb directed toward the macrophage mannose receptor (MR). Furthermore, siRNA silencing of MR reduced the uptake of ADAMTS13 by DCs. In addition, in vitro binding studies confirmed the interaction of ADAMTS13 with the carbohydrate recognition domains of MR. The results of the present study indicate that sugar moieties on ADAMTS13 interact with MR, thereby promoting its endocytosis by APCs.
    Keywords: Phagocytes, Granulocytes, and Myelopoiesis, Thrombosis and Hemostasis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 6
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    Preferential HLA-DRB1*11-dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells (2013)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2013-04-26
    Description: Autoantibodies directed against ADAMTS13 prohibit the processing of von Willebrand factor multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-derived peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11–positive and -negative donors were pulsed with ADAMTS13, and the HLA-DR–presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations, HLA-DRB1*11- or DRB1*03-positive donors presented a limited number of CUB2-derived peptides. Pulsing of dendritic cells using higher concentrations of ADAMTS13 resulted in the presentation of larger numbers of ADAMTS13-derived peptides by both HLA-DRB1*11–positive and -negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide profiles revealed that CUB2 domain–derived peptides were presented with a higher efficiency when compared with other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13-present derivatives of a single CUB2-derived peptide. We hypothesize that functional presentation of CUB2-derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low-affinity, self-reactive CD4+ T cells.
    Keywords: Thrombocytopenia, Thrombosis and Hemostasis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 7
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    Up or out: polarity of VWF release (2016)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2016-07-15
    Keywords: Free Research Articles
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 8
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    CD4+ T cells from patients with acquired thrombotic thrombocytopenic purpura recognize CUB2 domain-derived peptides (2016)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2016-03-25
    Description: Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder resulting from the development of autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). HLA-DRB1*11 provides a risk factor for developing acquired TTP. Pulsing of antigen-presenting cells from HLA-DRB1*11– and HLA-DRB1*03–positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. Here, we assessed whether FINVAPHAR- or ASYILIRD-reactive CD4 + T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03–positive subjects with acquired TTP. The presence of ADAMTS13-reactive CD4 + T cells was addressed by flow cytometry and the expression of activation marker CD40 ligand by CD4 + T cells. FINVAPHAR-reactive CD4 + T cells were identified in an HLA-DRB1*11–positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4 + T cells were identified in a DRB1*03-positive patient with acquired TTP. Frequencies of CUB2 domain-reactive CD4 + T cells ranged from 3.3% to 4.5%. Control peptides in which the anchor residues were modified did not induce activation of CD4 + T cells. Taken together, our data provide evidence for the involvement of CUB2 domain-reactive CD4 + T cells in the etiology of acquired TTP.
    Keywords: Thrombocytopenia, Platelets and Thrombopoiesis, Thrombosis and Hemostasis, Brief Reports
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 9
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    Altered glycosylation of platelet-derived von Willebrand factor confers resistance to ADAMTS13 proteolysis (2013)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2013-12-13
    Description: Platelet-von Willebrand factor (VWF) is stored within α-granules and accounts for ~20% of total VWF in platelet-rich plasma. This platelet-VWF pool is distinct from plasma-VWF and is enriched in high molecular weight multimers (HMWM). Previous studies have described significant functional discrepancies between platelet-VWF and plasma-VWF; however, the molecular basis of these differences is not well understood. We have characterized terminal glycan expression on platelet-VWF. Our findings demonstrate that platelet-VWF exists as a distinct natural glycoform. In particular, N -linked sialylation is markedly reduced (〉50%) compared with plasma-VWF. Moreover, unlike plasma-VWF, platelet-VWF does not express AB blood group determinants, although precursor H antigen expression is similar to that on plasma-VWF. Because of this differential glycosylation, platelet-VWF exhibits specific resistance to ADAMTS13 proteolysis. Thus platelet activation at sites of vascular injury results in the release of high local concentrations of HMWM platelet-VWF that is more resistant to ADAMTS13, thereby facilitating platelet-plug formation.
    Keywords: Platelets and Thrombopoiesis, Thrombosis and Hemostasis, Brief Reports
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 10
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    STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a (2014)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2014-05-16
    Description: Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormone-evoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. Coimmunoprecipitations showed that STXBP1 interacts with syntaxin-2 and -3, but not with syntaxin-4. Small interfering RNA-mediated silencing of STXBP1 expression impaired histamine- and forskolin-induced VWF secretion. To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1 . STXBP1-haploinsufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A–Slp4-a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature.
    Keywords: Thrombosis and Hemostasis, Vascular Biology
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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